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Lee S, Tak E, Choi J, Kang S, Lee K, Namgoong JM, Kim JK. Evaluation of Hepatic Progenitor and Hepatocyte-Like Cell Differentiation Using Machine Learning Analysis-Assisted Surface-Enhanced Raman Spectroscopy. Biomater Res 2025; 29:0190. [PMID: 40337141 PMCID: PMC12056312 DOI: 10.34133/bmr.0190] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2024] [Revised: 03/06/2025] [Accepted: 03/22/2025] [Indexed: 05/09/2025] Open
Abstract
Technology has been developed to monitor the differentiation process of human mesenchymal stem cells (hMSCs) into hepatocyte-like cells (HLCs) and hepatic progenitor cells (HPCs). These cell lineages, differentiated from MSCs, are ethically unproblematic and are gaining attention as promising cell-based therapies for treating various liver injuries. High-sensitivity, label-free, real-time monitoring technologies integrated with artificial intelligence have been used to evaluate and optimize cell differentiation for enhancing the efficiency of cell therapy delivery. Using an Au-ZnO nanorod array-based surface-enhanced Raman scattering (SERS) sensing chip, cell differentiation from hMSCs to HPCs and HLCs was nondestructively monitored through spectral analysis of cell secretions. Principal component extraction was employed to reduce variables, followed by discriminant analysis (DA). The application of principal component-linear discriminant analysis (PC-LDA), an artificial intelligence algorithm, to spectral data enabled clear grouping of hMSCs, HPCs, and HLCs, with monitoring accuracies of 96.3%, 98.8%, and 98.8%, respectively. Spectral changes observed during the differentiation from hMSCs to HPCs and from HPCs to HLCs over several days demonstrated the effectiveness of SERS combined with machine learning algorithm analysis for differentiation monitoring. This approach enabled real-time, nondestructive observation of cell differentiation with minimal sample labeling and preprocessing, making it useful for sensing differentiation validation and stability. The machine learning- and nanostructure-based SERS evaluation system was applied to the differentiation of ethically sourced MSCs and demonstrated substantial potential for clinical applicability through the use of patient-derived samples.
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Affiliation(s)
- Sanghwa Lee
- Biomedical Engineering Research Center, Asan Medical Center, Seoul 05505, Republic of Korea
| | - Eunyoung Tak
- Department of Convergence Medicine, Brain Korea 21 Project,
University of Ulsan College of Medicine, Seoul 05505, Republic of Korea
| | - Jiwan Choi
- Department of Convergence Medicine, Brain Korea 21 Project,
University of Ulsan College of Medicine, Seoul 05505, Republic of Korea
| | - Seoon Kang
- Department of Convergence Medicine, Brain Korea 21 Project,
University of Ulsan College of Medicine, Seoul 05505, Republic of Korea
| | - Kwanhee Lee
- Department of Convergence Medicine, Brain Korea 21 Project,
University of Ulsan College of Medicine, Seoul 05505, Republic of Korea
| | - Jung-Man Namgoong
- Department of Surgery, Asan Medical Center,
University of Ulsan College of Medicine, Seoul 05505, Republic of Korea
| | - Jun Ki Kim
- Biomedical Engineering Research Center, Asan Medical Center, Seoul 05505, Republic of Korea
- Department of Convergence Medicine, Brain Korea 21 Project,
University of Ulsan College of Medicine, Seoul 05505, Republic of Korea
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Cunanan J, Zhang D, Peired AJ, Barua M. Podocytes in health and glomerular disease. Front Cell Dev Biol 2025; 13:1564847. [PMID: 40342933 PMCID: PMC12058676 DOI: 10.3389/fcell.2025.1564847] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2025] [Accepted: 04/08/2025] [Indexed: 05/11/2025] Open
Abstract
Podocytes are highly specialized, terminally differentiated cells in the glomerulus of the kidney and these cells play a central role in blood filtration. In this review, we comprehensively describe the cell biology of podocytes under healthy conditions and in glomerular disorders wherein podocyte injury is a major pathological mechanism. First, the molecular mechanisms that maintain podocyte actin cytoskeleton structure, permanent cell cycle exit, and metabolism under healthy conditions are described. Secondly, the mechanisms of podocyte injury, including genetic alterations and external insults that ultimately disrupt podocyte actin cytoskeleton dynamics or interrupt podocyte quiescence and mitochondrial metabolism are discussed. This understanding forms the basis of described potential therapeutic agents that act by modulating dysregulated podocyte cytoskeleton organization, prevent or reverse cell cycle re-entry, and re-establish normal mitochondrial energy production. Lastly, the application of modern techniques such as single cell RNA sequencing, super resolution microscopy, atomic force microscopy, and glomerular organoids is improving the resolution of mechanistic podocytopathy knowledge. Taken together, our review provides critical insights into the cellular and molecular mechanisms leading to podocyte loss, necessary for the advancement of therapeutic development in glomerular diseases.
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Affiliation(s)
- Joanna Cunanan
- Division of Nephrology, Toronto General Hospital, University Health Network, Toronto, ON, Canada
- Toronto General Hospital Research Institute, University Health Network, Toronto, ON, Canada
- Institute of Medical Sciences, University of Toronto, Toronto, ON, Canada
| | - Daniel Zhang
- Division of Nephrology, Toronto General Hospital, University Health Network, Toronto, ON, Canada
- Toronto General Hospital Research Institute, University Health Network, Toronto, ON, Canada
- Institute of Medical Sciences, University of Toronto, Toronto, ON, Canada
| | - Anna Julie Peired
- Department of Experimental and Clinical Biomedical Sciences “Mario Serio”, University of Florence (Università degli Studi di Firenze), Florence, Italy
| | - Moumita Barua
- Division of Nephrology, Toronto General Hospital, University Health Network, Toronto, ON, Canada
- Toronto General Hospital Research Institute, University Health Network, Toronto, ON, Canada
- Institute of Medical Sciences, University of Toronto, Toronto, ON, Canada
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3
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Huang P, Qin D, Qin Y, Tao S, Liu G. SIRT3/6/7: promising therapeutic targets for pulmonary fibrosis. Front Cell Dev Biol 2025; 13:1557384. [PMID: 40241794 PMCID: PMC12000143 DOI: 10.3389/fcell.2025.1557384] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2025] [Accepted: 03/24/2025] [Indexed: 04/18/2025] Open
Abstract
Pulmonary fibrosis is a chronic progressive fibrosing interstitial lung disease of unknown cause, characterized by excessive deposition of extracellular matrix, leading to irreversible decline in lung function and ultimately death due to respiratory failure and multiple complications. The Sirtuin family is a group of nicotinamide adenine dinucleotide (NAD+) -dependent histone deacetylases, including SIRT1 to SIRT7. They are involved in various biological processes such as protein synthesis, metabolism, cell stress, inflammation, aging and fibrosis through deacetylation. This article reviews the complex molecular mechanisms of the poorly studied SIRT3, SIRT6, and SIRT7 subtypes in lung fibrosis and the latest research progress in targeting them to treat lung fibrosis.
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Affiliation(s)
- Pingping Huang
- Department of Respiratory and Critical Care Medicine, The Second Affiliated Hospital of Guangxi Medical University, Nanning, China
| | - Dan Qin
- Department of Endocrinology, The Second Affiliated Hospital of Guangxi Medical University, Nanning, China
| | - Yanling Qin
- Department of Respiratory and Critical Care Medicine, The Second Affiliated Hospital of Guangxi Medical University, Nanning, China
| | - Sha Tao
- Department of Respiratory and Critical Care Medicine, The Second Affiliated Hospital of Guangxi Medical University, Nanning, China
| | - Guangnan Liu
- Department of Respiratory and Critical Care Medicine, The Second Affiliated Hospital of Guangxi Medical University, Nanning, China
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Hoseini SM, Montazeri F. Cell origin and microenvironment: The players of differentiation capacity in human mesenchymal stem cells. Tissue Cell 2025; 93:102709. [PMID: 39765135 DOI: 10.1016/j.tice.2024.102709] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2024] [Revised: 12/12/2024] [Accepted: 12/26/2024] [Indexed: 03/05/2025]
Abstract
Mesenchymal stem cells (MSCs) have several important properties that make them desirable for regenerative medicine. These properties include immunomodulatory ability, growth factor production, and differentiation into various cell types. Despite extensive research and promising results in clinical trials, our understanding of MSC biology, their mechanism of action, and their targeted and routine use in clinics is limited. Differentiation of human MSCs (hMSCs) is a complex process influenced by various elements such as growth factors, pharmaceutical compounds, microRNAs, 3D scaffolds, and mechanical and electrical stimulation. Research has shown that different culture conditions can affect the differentiation potential of hMSCs obtained from multiple fetal and adult sources. Additionally, it seems that what affects the differentiation capacities of these cells is their secretory characteristics, which are influenced by the origin of the cells and the local microenvironment where the cells are located. The review can provide insights into the microenvironment-based mechanisms involved in MSC differentiation, which can be valuable for future therapeutic applications.
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Affiliation(s)
- Seyed Mehdi Hoseini
- Biotechnology Research Center, Yazd Reproductive Sciences Institute, Shahid Sadoughi University of Medical Sciences and Health Services, Yazd, Iran; Hematology and Oncology Research Center, Non-communicable Diseases Research Institute, Shahid Sadoughi University of Medical Sciences, Yazd, Iran
| | - Fateme Montazeri
- Abortion Research Center, Yazd Reproductive Sciences Institute, Shahid Sadoughi University of Medical Sciences and Health Services, Yazd, Iran.
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Liang X, Li Y, Wu Y, Wu T, Huang D, Tang Z, Cheng L, Tan C, Liao R, Zhao J, Liao Z, Luo Y, Liu Y. Human umbilical cord mesenchymal stem cell-derived microvesicles alleviate pulmonary fibrosis by inhibiting monocyte‒macrophage migration through ERK1/2 signaling-mediated suppression of CCL2 expression. Stem Cell Res Ther 2025; 16:145. [PMID: 40128840 PMCID: PMC11934500 DOI: 10.1186/s13287-025-04266-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2024] [Accepted: 03/04/2025] [Indexed: 03/26/2025] Open
Abstract
BACKGROUND Pulmonary fibrosis (PF) is a disease with high morbidity and mortality rates, but effective treatment options are extremely limited. Mesenchymal stem cells (MSCs) and their derivatives show promise as potential therapeutics for PF. However, the underlying mechanisms responsible for these beneficial effects remain poorly understood. The objective of this study was to elucidate the specific mechanism through which microvesicles derived from human umbilical cord MSCs (MSC-MVs) alleviate PF. METHODS The effects of MSC-MVs on PF in bleomycin (BLM)-induced mice were assessed via histological staining, flow cytometry, and enzyme-linked immunosorbent assays (ELISAs). The potential therapeutic target was identified via RNA sequencing (RNA-seq) analysis, followed by validation via real-time quantitative polymerase chain reaction (RT‒qPCR), ELISAs, scratch testing, and western blotting (WB). RESULTS MSC-MVs significantly attenuated collagen fiber deposition and downregulated the expression of extracellular matrix components in the lungs of the BLM-induced mice. Moreover, this treatment substantially ameliorated lung inflammation by reducing the monocyte‒macrophage ratio and the TNF-α and IL-6 levels. Further analyses revealed that MSC-MVs inhibited the classic chemotactic CCL2/CCR2 axis of monocyte‒macrophages, leading to reduced recruitment of monocytes‒macrophages to the lungs, which decreased lung inflammation and prevented fibrotic progression. Both in vitro and in vivo findings demonstrated that MSC-MVs suppressed ERK1/2 phosphorylation followed by decreased CCL2 production to modulate monocyte-macrophage migration. CONCLUSIONS Our findings demonstrate that the protective effect of MSC-MVs against BLM-induced lung toxicity was achieved through the inhibition of the ERK1/2 signaling pathway, leading to the suppression of CCL2 expression and subsequent modulation of monocyte-macrophage migration, thereby establishing a theoretical basis for the effect of MSC-MVs in PF.
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Affiliation(s)
- Xiuping Liang
- Department of Rheumatology & Immunology, Laboratory of Rheumatology and Immunology, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Yanhong Li
- Department of Rheumatology & Immunology, Laboratory of Rheumatology and Immunology, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Yinlan Wu
- Department of Rheumatology & Immunology, Laboratory of Rheumatology and Immunology, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Tong Wu
- Department of Rheumatology & Immunology, Laboratory of Rheumatology and Immunology, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Deying Huang
- Department of Rheumatology & Immunology, Laboratory of Rheumatology and Immunology, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Ziyi Tang
- Department of Rheumatology & Immunology, Laboratory of Rheumatology and Immunology, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Lu Cheng
- Department of Pulmonary and Critical Care Medicine, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Chunyu Tan
- Department of Rheumatology & Immunology, Laboratory of Rheumatology and Immunology, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Ronghui Liao
- Department of Rheumatology & Immunology, Laboratory of Rheumatology and Immunology, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Jing Zhao
- Department of Rheumatology & Immunology, Laboratory of Rheumatology and Immunology, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Zehui Liao
- Meishan People's Hospital, Meishan, Sichuan, China
| | - Yubin Luo
- Department of Rheumatology & Immunology, Laboratory of Rheumatology and Immunology, West China Hospital, Sichuan University, Chengdu, Sichuan, China.
| | - Yi Liu
- Department of Rheumatology & Immunology, Laboratory of Rheumatology and Immunology, West China Hospital, Sichuan University, Chengdu, Sichuan, China.
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Campbell TM, Feibel R, Dilworth J, Laneuville O, Trudel G. Capsular stem cell function and tissue composition are associated with symptoms and radiographic severity in people with knee osteoarthritis. Ther Adv Musculoskelet Dis 2025; 17:1759720X251321941. [PMID: 40041009 PMCID: PMC11877474 DOI: 10.1177/1759720x251321941] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2024] [Accepted: 02/04/2025] [Indexed: 03/06/2025] Open
Abstract
Background Osteoarthritis (OA) is associated with lost range of motion in the affected joint(s). Evidence suggests that this may be due to increased activity of posterior capsule fibroblasts, cells in turn derived from mesenchymal stromal cells (MSCs). Objectives To test the hypotheses that (1) MSCs are more numerous in the posterior capsule of patients with knee flexion contracture (FC) and (2) in OA participants with knee FC, the MSC population in the posterior capsule differentiates toward a fibrotic phenotype. In order to complete these objectives, we looked for associations between capsule histologic and MSC outcomes with clinical outcomes. Design Cross-sectional translational research design using data from the Ottawa Knee Osteoarthritis (OKOA) database. Methods A total of 71 OKOA database participants and their relevant clinical and laboratory outcomes were included. Associations were first tested with bivariate correlation, then for p < 0.10, tested using a linear model. Results No lab-based differences between FC and no-FC groups we discovered. In the posterior capsule, there was an association between knee flexion and adipogenic capacity (p = 0.001), osteogenic capacity (p < 0.001), KL grade and percent "other" (mainly neurovascular) tissue (p = 0.039), visual analog scale pain, and percent fibrous tissue (p = 0.014). For the anterior capsule, there was an association between knee flexion (p = 0.002) and extension (p = 0.005) with MSC enumeration, KL grade with MSC fibrogenic capacity (p = 0.002), and Knee Injury and Osteoarthritis Outcome Score quality of life with chondrogenic capacity (p < 0.001). Conclusion Joint capsule composition, MSC enumeration, and function were associated with important clinical OA outcomes. These findings suggest that the entire joint capsule may play an important role in OA-related morbidity and progression and could represent an underappreciated target for OA treatment.
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Affiliation(s)
- T. Mark Campbell
- Department of Physical Medicine and Rehabilitation, Elisabeth Bruyère Hospital, 43 Bruyère Street, Ottawa, Ontario K1N 5C8, Canada
| | - Robert Feibel
- Division of Orthopedic Surgery, Department of Surgery, The Ottawa Hospital, Ottawa, ON, Canada
| | - Jeffrey Dilworth
- Department of Cellular and Molecular Biology, University of Wisconsin–Madison, Madison, WI, USA
| | - Odette Laneuville
- Bone and Joint Research Laboratory, Department of Cellular and Molecular Medicine, Ottawa Hospital Research Institute, Canada
- Department of Biology, University of Ottawa, Ottawa, ON, Canada
| | - Guy Trudel
- Bone and Joint Research Laboratory, Department of Cellular and Molecular Medicine, Ottawa Hospital Research Institute, Canada
- Division of Physical Medicine and Rehabilitation, Faculty of Medicine, Department of Medicine, University of Ottawa, Canada
- Division of Physical Medicine and Rehabilitation, Department of Medicine, The Ottawa Hospital, Ottawa, ON, Canada
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Zhang X, Zhang L, Tian J, Li Y, Wu M, Zhang L, Qin X, Gong L. The application and prospects of drug delivery systems in idiopathic pulmonary fibrosis. BIOMATERIALS ADVANCES 2025; 168:214123. [PMID: 39615374 DOI: 10.1016/j.bioadv.2024.214123] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/11/2024] [Revised: 11/06/2024] [Accepted: 11/25/2024] [Indexed: 12/13/2024]
Abstract
Idiopathic pulmonary fibrosis (IPF) is an interstitial lung disease primarily affecting elderly individuals aged >65 years and has a poor prognosis. No effective treatment is currently available for IPF. The two antipulmonary fibrosis drugs nintedanib and pirfenidone approved by the FDA in the United States have somewhat decelerated IPF progression. However, the side effects of these drugs can lead to poor patient tolerance and compliance with the medications. Researchers have recently developed various methods for IPF treatment, such as gene silencing and pathway inhibitors, which hold great promise in IPF treatment. Nevertheless, the nonselectivity and nonspecificity of drugs often affect their efficacies. Drug delivery systems (DDS) are crucial for delivering drugs to specific target tissues or cells, thereby minimizing potential side effects, enhancing drug bioavailability, and reducing lung deposition. This review comprehensively summarizes the current state of DDS and various delivery strategies for IPF treatment (e.g., nano-delivery, hydrogel delivery, and biological carrier delivery) to completely expound the delivery mechanisms of different drug delivery carriers. Subsequently, the advantages and disadvantages of different DDS are fully discussed. Finally, the challenges and difficulties associated with the use of different DDS are addressed so as to accelerate their rapid clinical translation.
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Affiliation(s)
- Xi Zhang
- School of Biological Engineering, Zunyi Medical University, Guangdong 519000, China; Department of Clinical Medicine, The Fifth Clinical Institution, Zhuhai Campus of Zunyi Medical University, Guangdong 519000, China
| | - Ling Zhang
- Department of Respiratory and Critical Care Medicine, The First People's Hospital of Zunyi (The Third Affiliated Hospital of Zunyi Medical University), GuiZhou 563000, China
| | - Jiahua Tian
- Department of Clinical Medicine, Zunyi Medical University, Zunyi 563000, China
| | - Yunfei Li
- Department of Respiratory and Critical Care Medicine, The First People's Hospital of Zunyi (The Third Affiliated Hospital of Zunyi Medical University), GuiZhou 563000, China
| | - Manli Wu
- Department of Respiratory and Critical Care Medicine, The First People's Hospital of Zunyi (The Third Affiliated Hospital of Zunyi Medical University), GuiZhou 563000, China
| | - Longju Zhang
- Department of Respiratory and Critical Care Medicine, The First People's Hospital of Zunyi (The Third Affiliated Hospital of Zunyi Medical University), GuiZhou 563000, China
| | - Xiaofei Qin
- School of Biological Engineering, Zunyi Medical University, Guangdong 519000, China.
| | - Ling Gong
- Department of Respiratory and Critical Care Medicine, The First People's Hospital of Zunyi (The Third Affiliated Hospital of Zunyi Medical University), GuiZhou 563000, China.
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Chen QH, Zheng JY, Wang DC. Asthma and stem cell therapy. World J Stem Cells 2025; 17:103599. [DOI: 10.4252/wjsc.v17.i2.103599] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/28/2024] [Revised: 12/23/2024] [Accepted: 02/05/2025] [Indexed: 02/24/2025] Open
Abstract
The global incidence of asthma, a leading respiratory disorder affecting more than 235 million people, has dramatically increased in recent years. Characterized by chronic airway inflammation and an imbalanced response to airborne irritants, this chronic condition is associated with elevated levels of inflammatory factors and symptoms such as dyspnea, cough, wheezing, and chest tightness. Conventional asthma therapies, such as corticosteroids, long-acting β-agonists, and anti-inflammatory agents, often evoke diverse adverse reactions and fail to reduce symptoms and hospitalization rates over the long term effectively. These limitations have prompted researchers to explore innovative therapeutic strategies, including stem cell-related interventions, offering hope to those afflicted with this incurable disease. In this review, we describe the characteristics of stem cells and critically assess the potential and challenges of stem cell-based therapies to improve disease management and treatment outcomes for asthma and other diseases.
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Affiliation(s)
- Qiong-Hua Chen
- Department of Respiratory Medicine, Quanzhou Women’s and Children’s Hospital, Clinical Medical College of Fujian Medical University, Quanzhou 362000, Fujian Province, China
| | - Jing-Yang Zheng
- Department of Respiratory Medicine, Quanzhou Women’s and Children’s Hospital, Clinical Medical College of Fujian Medical University, Quanzhou 362000, Fujian Province, China
| | - Da-Chun Wang
- The Brown Foundation Institute of Molecular Medicine for the Prevention of Human Diseases, University of Texas Medical School at Houston, Houston, TX 77030, United States
- Stem Cell Laboratory, Second Affiliated Hospital of Fujian Medical University, Quanzhou 362000, Fujian Province, China
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Zhao S, Xie J, Zhang Q, Ni T, Lin J, Gao W, Zhao L, Yi M, Tu L, Zhang P, Wu D, Tang Q, Ma C, He Y, Li L, Wu G, Yan W. New Anti-Fibrotic Strategies for Keloids: Insights From Single-Cell Multi-Omics. Cell Prolif 2025:e13818. [PMID: 39902627 DOI: 10.1111/cpr.13818] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2024] [Revised: 01/01/2025] [Accepted: 01/15/2025] [Indexed: 02/05/2025] Open
Abstract
Keloids are complex pathological skin scars characterised by excessive growth of fibrous tissue and abnormal accumulation of extracellular matrix (ECM). Despite various treatment options available, the treatment of keloids remains a major clinical challenge due to high recurrence rates and inconsistent therapeutic outcomes. By collecting three keloid tissues and three normal skin samples and utilising single-cell RNA sequencing (scRNA-seq), we delved into the cellular heterogeneity and molecular mechanisms of keloids. Our study identified multiple fibroblast subpopulations within keloid tissue. Enrichment and cell-cell communication analyses revealed that POSTN-positive mesenchymal fibroblasts (POSTN+ mesenchymal fibs) are more prevalent in keloids and exhibit higher transforming growth factor β (TGF-β) signalling activity, potentially playing a central role in excessive fibrosis. In contrast, IGFBP2-positive fibroblasts (IGFBP2+ fibs) are more abundant in normal skin, insensitive to TGF-β and Periostin signalling, and possess anti-fibrotic potential, possibly related to limited tissue repair and regenerative capacity. Trajectory analysis inferred the differentiation states and patterns of different fibroblast subpopulations. Additionally, we explored the heterogeneity of endothelial cells, finding an endothelial cell subpopulation (EC10) exhibiting mesenchymal activation characteristics, which may work with specific fibroblasts to promote abnormal angiogenesis and endothelial-to-mesenchymal transition processes. Spatial transcriptomics analysis has shown that the proportion of IGFBP2+ fibroblasts relatively increases in acne keloidalis after hormonal treatment, further demonstrating their value as potential therapeutic targets. Ultimately, we separated these two subpopulations using flow cytometry, highlighting their opposing roles in the secretion of the ECM. These findings provide new insights into the pathogenesis of keloids and lay the theoretical foundation for the development of innovative anti-fibrotic treatment strategies.
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Affiliation(s)
- Songyun Zhao
- Department of Plastic Surgery, The Affiliated Friendship Plastic Surgery Hospital of Nanjing Medical University, Nanjing, China
- Department of Plastic Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Jiaheng Xie
- Department of Plastic Surgery, The Affiliated Friendship Plastic Surgery Hospital of Nanjing Medical University, Nanjing, China
- Department of Plastic Surgery, Xiangya Hospital, Central South University, Changsha, China
| | - Qian Zhang
- Department of General Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Tianyi Ni
- Department of Burn and Plastic Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Jinde Lin
- Department of Plastic Surgery, The Affiliated Friendship Plastic Surgery Hospital of Nanjing Medical University, Nanjing, China
| | - Weicheng Gao
- Department of Plastic Surgery, The Affiliated Friendship Plastic Surgery Hospital of Nanjing Medical University, Nanjing, China
| | - Liping Zhao
- Department of Plastic Surgery, The Affiliated Friendship Plastic Surgery Hospital of Nanjing Medical University, Nanjing, China
| | - Min Yi
- Department of Plastic Surgery, The Affiliated Friendship Plastic Surgery Hospital of Nanjing Medical University, Nanjing, China
| | - Liying Tu
- Department of Plastic Surgery, The Affiliated Friendship Plastic Surgery Hospital of Nanjing Medical University, Nanjing, China
| | - Pengpeng Zhang
- Department of Lung Cancer Surgery, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China
| | - Dan Wu
- Department of Dermatology, Huashan Hospital of Fudan University, Shanghai, China
| | - Qikai Tang
- Department of Neurosurgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Chenfeng Ma
- Department of Neurosurgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Yucang He
- Department of Plastic Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Liqun Li
- Department of Plastic Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Guoping Wu
- Department of Plastic Surgery, The Affiliated Friendship Plastic Surgery Hospital of Nanjing Medical University, Nanjing, China
| | - Wei Yan
- Department of Burn and Plastic Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
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Gao Y, Wang H, Shi L, Lu P, Dai G, Zhang M, Han B, Cao M, Li Y, Rui Y. Erroneous Differentiation of Tendon Stem/Progenitor Cells in the Pathogenesis of Tendinopathy: Current Evidence and Future Perspectives. Stem Cell Rev Rep 2025; 21:423-453. [PMID: 39579294 DOI: 10.1007/s12015-024-10826-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 11/20/2024] [Indexed: 11/25/2024]
Abstract
Tendinopathy is a condition characterized by persistent tendon pain, structural damage, and compromised functionality. Presently, the treatment for tendinopathy remains a formidable challenge, partly because of its unclear pathogenesis. Tendon stem/progenitor cells (TSPCs) are essential for tendon homeostasis, regeneration, remodeling, and repair. An innovative theory has been previously proposed, with insufficient evidence, that the erroneous differentiation of TSPCs may constitute one of the fundamental mechanisms underpinning tendinopathy. Over the past few years, there has been accumulating evidence for plausibility of this theory. In this review, we delve into alterations in the differentiation potential of TSPCs and the underlying mechanisms in the context of injury-induced tendinopathy, diabetic tendinopathy, and age-related tendinopathy to provide updated evidence on the erroneous differentiation theory. Despite certain limitations inherent in the existing body of evidence, the erroneous differentiation theory emerges as a promising and highly pertinent avenue for understanding tendinopathy. In the future, advanced methodologies will be harnessed to further deepen comprehension of this theory, paving the way for prospective developments in clinical therapies targeting TSPCs for the management of tendinopathy.
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Affiliation(s)
- Yucheng Gao
- Department of Orthopaedics, School of Medicine, Zhongda Hospital, Southeast University, No. 87 Ding Jia Qiao, Nanjing, 210009, Jiangsu, China
- School of Medicine, Southeast University, Nanjing, 210009, Jiangsu, China
| | - Hao Wang
- Department of Orthopaedics, School of Medicine, Zhongda Hospital, Southeast University, No. 87 Ding Jia Qiao, Nanjing, 210009, Jiangsu, China
- School of Medicine, Southeast University, Nanjing, 210009, Jiangsu, China
| | - Liu Shi
- Department of Orthopaedics, School of Medicine, Zhongda Hospital, Southeast University, No. 87 Ding Jia Qiao, Nanjing, 210009, Jiangsu, China
- School of Medicine, Southeast University, Nanjing, 210009, Jiangsu, China
| | - Panpan Lu
- Department of Orthopaedics, School of Medicine, Zhongda Hospital, Southeast University, No. 87 Ding Jia Qiao, Nanjing, 210009, Jiangsu, China
- School of Medicine, Southeast University, Nanjing, 210009, Jiangsu, China
| | - Guangchun Dai
- Department of Orthopaedics, School of Medicine, Zhongda Hospital, Southeast University, No. 87 Ding Jia Qiao, Nanjing, 210009, Jiangsu, China
- School of Medicine, Southeast University, Nanjing, 210009, Jiangsu, China
| | - Ming Zhang
- Department of Orthopaedics, School of Medicine, Zhongda Hospital, Southeast University, No. 87 Ding Jia Qiao, Nanjing, 210009, Jiangsu, China
- School of Medicine, Southeast University, Nanjing, 210009, Jiangsu, China
| | - Bowen Han
- School of Medicine, Southeast University, Nanjing, 210009, Jiangsu, China
| | - Mumin Cao
- Department of Orthopaedics, School of Medicine, Zhongda Hospital, Southeast University, No. 87 Ding Jia Qiao, Nanjing, 210009, Jiangsu, China
- School of Medicine, Southeast University, Nanjing, 210009, Jiangsu, China
| | - Yingjuan Li
- Department of Geriatrics, School of Medicine, Zhongda Hospital, Southeast University, Nanjing, 210009, Jiangsu, China
| | - Yunfeng Rui
- Department of Orthopaedics, School of Medicine, Zhongda Hospital, Southeast University, No. 87 Ding Jia Qiao, Nanjing, 210009, Jiangsu, China.
- School of Medicine, Southeast University, Nanjing, 210009, Jiangsu, China.
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11
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Mailleux AA, Justet A. Tracing the origins of fibrotic fibroblasts: does the name matter? Look at the genes! Eur Respir J 2025; 65:2402170. [PMID: 39915043 DOI: 10.1183/13993003.02170-2024] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2024] [Accepted: 11/17/2024] [Indexed: 04/26/2025]
Affiliation(s)
- Arnaud A Mailleux
- Université Paris Cité, Inserm, Physiopathologie et épidémiologie des maladies respiratoires, Paris, France
| | - Aurélien Justet
- Service de Pneumologie, Centre de Compétence Maladies Pulmonaires Rares - UMR 6030 CNRS-ISTCT, Université de Normandie, Caen, France
- Section of Pulmonary, Critical Care, and Sleep Medicine, Department of Internal Medicine, Yale School of Medicine, New Haven, CT, USA
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12
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Hou J, Ji Q, Tang T, Xue Y, Gao L, Dai L, Xie J. CT-sensitized nanoprobe for effective early diagnosis and treatment of pulmonary fibrosis. J Nanobiotechnology 2025; 23:60. [PMID: 39881299 PMCID: PMC11776250 DOI: 10.1186/s12951-025-03128-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2024] [Accepted: 01/15/2025] [Indexed: 01/31/2025] Open
Abstract
Early diagnosis is critical for providing a timely window for effective therapy in pulmonary fibrosis (PF); however, achieving this remains a significant challenge. The distinct honeycombing patterns observed in computed tomography (CT) for the primary diagnosis of PF are typically only visible in patients with moderate to severe disease, often leading to missed opportunities for early intervention. In this study, we developed a nanoprobe designed to accumulate at fibroblastic foci and loaded with the CT sensitizer iodide to enable effective early diagnosis of PF. An antibody fragment (Fab') targeting the platelet-derived growth factor receptor-α, which specifically binds to (myo)fibroblasts, was conjugated to the nanoprobe surface to enhance targeting of fibroblastic foci. Additionally, collagenase was employed to facilitate nanoprobe penetration by degrading the local collagen fibers within these foci. This approach led to significant accumulation of the CT sensitizer iodide in fibrotic lung tissues, resulting in enhanced CT imaging for the detection of fibroblastic foci and enabling early diagnosis of PF. Moreover, a dual-drug combination of oltipraz and rosiglitazone was co-loaded into the nanoparticles for the treatment of early-diagnosed PF. Remarkable therapeutic efficacy was observed in model mice with early PF using these nanoparticles. Our findings present a promising strategy for the early diagnosis of PF, potentially offering a valuable time window for effective treatment of this life-threatening disease.
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Affiliation(s)
- Jiwei Hou
- School of Medicine, Nanjing University of Chinese Medicine, Nanjing, 210023, China
- Immunology and Reproduction Biology Laboratory & State Key Laboratory of Analytical Chemistry for Life Science, Medical School, Nanjing University, Nanjing, 210093, China
| | - Qijian Ji
- Department of Critical Care Medicine, Xuyi People's Hospital, 28 Hongwu Road, Xuyi, 211700, Jiangsu, China.
- Department of Emergency Medicine, Jinling Hospital, Medical School of Nanjing University, Nanjing, 210002, PR China.
| | - Tianyu Tang
- Nurturing Center of Jiangsu Province for State Laboratory of AI Imaging & Interventional Radiology; Basic Medicine Research and Innovation Center of Ministry of Education, Medical School of Southeast University, 87 Dingjiaqiao, Nanjing, 210009, China
| | - Yonger Xue
- Center for BioDelivery Sciences, School of Pharmacy, Shanghai Jiao Tong University, Shanghai, 200240, China.
| | - Lin Gao
- Nurturing Center of Jiangsu Province for State Laboratory of AI Imaging & Interventional Radiology; Basic Medicine Research and Innovation Center of Ministry of Education, Medical School of Southeast University, 87 Dingjiaqiao, Nanjing, 210009, China
| | - Li Dai
- Department of cariol & endodont, Nanjing Stomatological Hospital, Medical School of Nanjing University, Nanjing, 210008, China
| | - Jinbing Xie
- Nurturing Center of Jiangsu Province for State Laboratory of AI Imaging & Interventional Radiology; Basic Medicine Research and Innovation Center of Ministry of Education, Medical School of Southeast University, 87 Dingjiaqiao, Nanjing, 210009, China.
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13
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Di X, Li Y, Wei J, Li T, Liao B. Targeting Fibrosis: From Molecular Mechanisms to Advanced Therapies. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2025; 12:e2410416. [PMID: 39665319 PMCID: PMC11744640 DOI: 10.1002/advs.202410416] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/28/2024] [Revised: 10/27/2024] [Indexed: 12/13/2024]
Abstract
As the final stage of disease-related tissue injury and repair, fibrosis is characterized by excessive accumulation of the extracellular matrix. Unrestricted accumulation of stromal cells and matrix during fibrosis impairs the structure and function of organs, ultimately leading to organ failure. The major etiology of fibrosis is an injury caused by genetic heterogeneity, trauma, virus infection, alcohol, mechanical stimuli, and drug. Persistent abnormal activation of "quiescent" fibroblasts that interact with or do not interact with the immune system via complicated signaling cascades, in which parenchymal cells are also triggered, is identified as the main mechanism involved in the initiation and progression of fibrosis. Although the mechanisms of fibrosis are still largely unknown, multiple therapeutic strategies targeting identified molecular mechanisms have greatly attenuated fibrotic lesions in clinical trials. In this review, the organ-specific molecular mechanisms of fibrosis is systematically summarized, including cardiac fibrosis, hepatic fibrosis, renal fibrosis, and pulmonary fibrosis. Some important signaling pathways associated with fibrosis are also introduced. Finally, the current antifibrotic strategies based on therapeutic targets and clinical trials are discussed. A comprehensive interpretation of the current mechanisms and therapeutic strategies targeting fibrosis will provide the fundamental theoretical basis not only for fibrosis but also for the development of antifibrotic therapies.
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Affiliation(s)
- Xingpeng Di
- Department of Urology and Institute of UrologyWest China HospitalSichuan UniversityChengduP.R. China
| | - Ya Li
- Department of Urology and Institute of UrologyWest China HospitalSichuan UniversityChengduP.R. China
| | - Jingwen Wei
- Department of Urology and Institute of UrologyWest China HospitalSichuan UniversityChengduP.R. China
| | - Tianyue Li
- Department of Urology and Institute of UrologyWest China HospitalSichuan UniversityChengduP.R. China
| | - Banghua Liao
- Department of Urology and Institute of UrologyWest China HospitalSichuan UniversityChengduP.R. China
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14
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Chen C, Yang J, Shang R, Tang Y, Cai X, Chen Y, Liu Z, Hu W, Zhang W, Zhang X, Huang Y, Hu X, Yin W, Lu Q, Sheng H, Fan D, Ju Z, Luo G, He W. Orchestration of Macrophage Polarization Dynamics by Fibroblast-Secreted Exosomes during Skin Wound Healing. J Invest Dermatol 2025; 145:171-184.e6. [PMID: 38838771 DOI: 10.1016/j.jid.2024.05.007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2024] [Revised: 04/30/2024] [Accepted: 05/04/2024] [Indexed: 06/07/2024]
Abstract
Macrophages undertake pivotal yet dichotomous functions during skin wound healing, mediating both early proinflammatory immune activation and late anti-inflammatory tissue remodeling processes. The timely phenotypic transition of macrophages from inflammatory M1 to proresolving M2 activation states is essential for efficient healing. However, the endogenous mechanisms calibrating macrophage polarization in accordance with the evolving tissue milieu remain undefined. In this study, we reveal an indispensable immunomodulatory role for fibroblast-secreted exosomes in directing macrophage activation dynamics. Fibroblast-derived exosomes permitted spatiotemporal coordination of macrophage phenotypes independent of direct intercellular contact. Exosomes enhanced macrophage sensitivity to both M1 and M2 polarizing stimuli, yet they also accelerated timely switching from M1 to M2 phenotypes. Exosome inhibition dysregulated macrophage responses, resulting in aberrant inflammation and impaired healing, whereas provision of exogenous fibroblast-derived exosomes corrected defects. Topical application of fibroblast-derived exosomes onto chronic diabetic wounds normalized dysregulated macrophage activation to resolve inflammation and restore productive healing. Our findings elucidate fibroblast-secreted exosomes as remote programmers of macrophage polarization that calibrate immunological transitions essential for tissue repair. Harnessing exosomes represents a previously unreported approach to steer productive macrophage activation states with immense therapeutic potential for promoting healing in chronic inflammatory disorders.
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Affiliation(s)
- Cheng Chen
- Institute of Burn Research, State Key Laboratory of Trauma, Burn and Combined Injury, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, China; Chongqing Key Laboratory for Disease Proteomics, Chongqing, China
| | - Jiacai Yang
- Institute of Burn Research, State Key Laboratory of Trauma, Burn and Combined Injury, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, China; Chongqing Key Laboratory for Disease Proteomics, Chongqing, China
| | - Ruoyu Shang
- Institute of Burn Research, State Key Laboratory of Trauma, Burn and Combined Injury, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, China; Chongqing Key Laboratory for Disease Proteomics, Chongqing, China
| | - Yuanyang Tang
- Department of Infectious Diseases, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, China
| | - Xin Cai
- Institute of Burn Research, State Key Laboratory of Trauma, Burn and Combined Injury, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, China; Chongqing Key Laboratory for Disease Proteomics, Chongqing, China
| | - Yunxia Chen
- Institute of Burn Research, State Key Laboratory of Trauma, Burn and Combined Injury, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, China; Chongqing Key Laboratory for Disease Proteomics, Chongqing, China
| | - Zhihui Liu
- Institute of Burn Research, State Key Laboratory of Trauma, Burn and Combined Injury, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, China; Chongqing Key Laboratory for Disease Proteomics, Chongqing, China
| | - Wengang Hu
- Institute of Burn Research, State Key Laboratory of Trauma, Burn and Combined Injury, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, China; Chongqing Key Laboratory for Disease Proteomics, Chongqing, China
| | - Weiguang Zhang
- Department of Intensive Care, Southwest Hospital, Army Medical University, Chongqing, China
| | - Xiaorong Zhang
- Institute of Burn Research, State Key Laboratory of Trauma, Burn and Combined Injury, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, China; Chongqing Key Laboratory for Disease Proteomics, Chongqing, China
| | - Yong Huang
- Institute of Burn Research, State Key Laboratory of Trauma, Burn and Combined Injury, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, China; Chongqing Key Laboratory for Disease Proteomics, Chongqing, China
| | - Xiaohong Hu
- Institute of Burn Research, State Key Laboratory of Trauma, Burn and Combined Injury, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, China; Chongqing Key Laboratory for Disease Proteomics, Chongqing, China
| | - Wenjing Yin
- Institute of Burn Research, State Key Laboratory of Trauma, Burn and Combined Injury, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, China; Chongqing Key Laboratory for Disease Proteomics, Chongqing, China; Academy of Biological Engineering, Chongqing University, Chongqing, China
| | - Qudong Lu
- Department of Urology, Army 73rd Group Military Hospital, Xiamen, China
| | - Hao Sheng
- Department of Urology, The Second Affiliated Hospital, Third Military Medical University (Army Medical University), Chongqing, China
| | - Dejiang Fan
- Institute of Burn Research, State Key Laboratory of Trauma, Burn and Combined Injury, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, China; Chongqing Key Laboratory for Disease Proteomics, Chongqing, China
| | - Zhenyu Ju
- Key Laboratory of Regenerative Medicine of Ministry of Education, Guangzhou Regenerative Medicine and Health Guangdong Laboratory, Institute of Aging and Regenerative Medicine, Jinan University, Guangzhou, China
| | - Gaoxing Luo
- Institute of Burn Research, State Key Laboratory of Trauma, Burn and Combined Injury, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, China; Chongqing Key Laboratory for Disease Proteomics, Chongqing, China.
| | - Weifeng He
- Institute of Burn Research, State Key Laboratory of Trauma, Burn and Combined Injury, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, China; Chongqing Key Laboratory for Disease Proteomics, Chongqing, China.
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15
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Jiang C, Somavarapu S. Design and development of DSPE-PEG2000/DPPC disk-like micelles for targeted delivery of icariin phytochemical in pulmonary fibrosis. Int J Pharm 2024; 667:124837. [PMID: 39414183 DOI: 10.1016/j.ijpharm.2024.124837] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2024] [Revised: 10/09/2024] [Accepted: 10/13/2024] [Indexed: 10/18/2024]
Abstract
Icariin (ICA)-loaded DSPE-PEG2000/DPPC disk-like micelles were synthesized utilizing the thin film hydration method to enhance the solubility and delivery of ICA to the lungs. The micellar formulation significantly improved the water solubility of ICA. This was attributed to the high encapsulation efficiency (95 %) and drug loading capacity (12 %) of the DSPE-PEG2000/DPPC micelles. Comprehensive characterization using Fourier-transform infrared spectroscopy (FT-IR) and X-ray diffraction (XRD). Particle size analysis through dynamic light scattering (DLS) and transmission electron microscopy (TEM) demonstrated the formation of stable micelles with an average particle size around 10 nm. In vitro aerosolization studies using the next-generation impactor (NGI) revealed that the fine particle fraction was 63.5 ± 4 %, which means that over 60 % of the aerosolized ICA/DSPE-PEG2000/DPPC micelles were capable of reaching and targeting the deep lung alveoli, indicating their potential efficacy for pulmonary delivery. Cytotoxicity assessments via the MTT assay showed IC50 values of ICA-loaded DSPE-PEG2000/DPPC micelles were 117 ± 8 μg/mL, 29 ± 3 μg/mL, and 21 ± 1 μg/mL at 24, 48, and 72 h, respectively, highlighting the time-dependent cytotoxic effects of the ICA-loaded micelles on A549 cells. However, the IC50 values of free ICA were > 500 μg/mL, 252 ± 3 μg/mL, and 109 ± 2 μg/mL, respectively at three different time points. That indicated that ICA-loaded nano micelles enhanced the cytotoxicity of ICA. Furthermore, the cellular uptake of the nano micelles by A549 cells was visualized and confirmed using EVOS fluorescence imaging and flow cytometry techniques. In addition, RAW 264.7 M2 polarization studies indicated ICA loaded DSPE-PEG2000/DPPC micelles have potential for treating pulmonary fibrosis. These findings suggest that DSPE-PEG2000/DPPC micelles significantly enhance the solubility and delivery of ICA, presenting a promising nanocarrier system for targeted pulmonary fibrosis therapy.
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Affiliation(s)
- Chengwei Jiang
- Department of Pharmaceutics, School of Pharmacy, University College London, 29-39 Brunswick Square, London WC1N 1AX, UK
| | - Satyanarayana Somavarapu
- Department of Pharmaceutics, School of Pharmacy, University College London, 29-39 Brunswick Square, London WC1N 1AX, UK.
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16
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Sharma Y, Ghatak S, Sen CK, Mohanty S. Emerging technologies in regenerative medicine: The future of wound care and therapy. J Mol Med (Berl) 2024; 102:1425-1450. [PMID: 39358606 DOI: 10.1007/s00109-024-02493-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2024] [Revised: 09/10/2024] [Accepted: 09/23/2024] [Indexed: 10/04/2024]
Abstract
Wound healing, an intricate biological process, comprises orderly phases of simple biological processed including hemostasis, inflammation, angiogenesis, cell proliferation, and ECM remodeling. The regulation of the shift in these phases can be influenced by systemic or environmental conditions. Any untimely transitions between these phases can lead to chronic wounds and scarring, imposing a significant socio-economic burden on patients. Current treatment modalities are largely supportive in nature and primarily involve the prevention of infection and controlling inflammation. This often results in delayed healing and wound complications. Recent strides in regenerative medicine and tissue engineering offer innovative and patient-specific solutions. Mesenchymal stem cells (MSCs) and their secretome have gained specific prominence in this regard. Additionally, technologies like tissue nano-transfection enable in situ gene editing, a need-specific approach without the requirement of complex laboratory procedures. Innovating approaches like 3D bioprinting and ECM bioscaffolds also hold the potential to address wounds at the molecular and cellular levels. These regenerative approaches target common healing obstacles, such as hyper-inflammation thereby promoting self-recovery through crucial signaling pathway stimulation. The rationale of this review is to examine the benefits and limitations of both current and emerging technologies in wound care and to offer insights into potential advancements in the field. The shift towards such patient-centric therapies reflects a paradigmatic change in wound care strategies.
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Affiliation(s)
- Yashvi Sharma
- Stem Cell Facility (DBT-Centre of Excellence for Stem Cell Research), All India Institute of Medical Sciences, New Delhi, Delhi, 110029, India
| | - Subhadip Ghatak
- Indiana Center for Regenerative Medicine and Engineering, Indiana University Health Comprehensive Wound Center, Department of Surgery, Indiana University School of Medicine, Indianapolis, IN, 46202, USA
- McGowan Institute of Regenerative Medicine, Department of Surgery, University of Pittsburgh, 419 Bridgeside Point II, 450 Technology Drive, Pittsburgh, PA, 15219, USA
| | - Chandan K Sen
- Indiana Center for Regenerative Medicine and Engineering, Indiana University Health Comprehensive Wound Center, Department of Surgery, Indiana University School of Medicine, Indianapolis, IN, 46202, USA.
- McGowan Institute of Regenerative Medicine, Department of Surgery, University of Pittsburgh, 419 Bridgeside Point II, 450 Technology Drive, Pittsburgh, PA, 15219, USA.
| | - Sujata Mohanty
- Stem Cell Facility (DBT-Centre of Excellence for Stem Cell Research), All India Institute of Medical Sciences, New Delhi, Delhi, 110029, India.
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17
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Zong R, Zheng Y, Yan Y, Sun W, Kong L, Huang Y, Liu Y, Jiang C, Ping J, Li C. Mesenchymal stem cells-derived exosomes alleviate liver fibrosis by targeting Hedgehog/SMO signaling. Hepatol Int 2024; 18:1781-1791. [PMID: 39138757 DOI: 10.1007/s12072-024-10717-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/30/2024] [Accepted: 07/28/2024] [Indexed: 08/15/2024]
Abstract
BACKGROUND & AIMS Despite increasing knowledge regarding the cellular and molecular mechanisms of liver fibrogenesis, there is currently no approved drug for the treatment of liver fibrosis. Mesenchymal stem cells (MSCs) are multipotent progenitor cells representing an attractive therapeutic tool for tissue damage and inflammation. This study was designed to determine the protective effect and underlying mechanism of human umbilical cord-derived MSCs (UC-MSCs) on thioacetamide-induced liver fibrosis. METHODS Liver fibrosis was induced in mice by intraperitoneal injection of thioacetamide (TAA). Some mice were then given injection of UC-MSCs or UC-MSCs-derived exosomes (UC-MSCs-Exo) via the tail vein. Liver tissues were collected for histologic analysis. RESULTS We found that administration of UC-MSCs significantly reduced serum alanine aminotransferase and aspartate aminotransferase levels, and attenuated hepatic inflammation and fibrosis. Moreover, the therapeutic effect of UC-MSCs-derived exosomes was similar to that of UC-MSCs. Intriguingly, UC-MSCs-Exo treatment downregulated the expression of smoothened (SMO), a fundamental component of Hedgehog signaling which plays a critical role in fibrogenesis, and subsequently inhibited the activation of hepatic stellate cells, a central driver of fibrosis in experimental and human liver injury. Furthermore, the anti-inflammatory and anti-fibrotic effects of UCMSCs- Exo was reversed by the SMO agonist SAG treatment in mice. CONCLUSION Our findings suggest that UC-MSCs-Exo exert therapeutic effects on liver fibrosis, at least in part, through inhibiting the Hedgehog/SMO signaling pathway.
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Affiliation(s)
- Ruobin Zong
- Department of Physiology, School of Basic Medical Sciences, Wuhan University, 115 Donghu Road, Wuhan, 430071, China
| | - Yan Zheng
- Department of Pharmacy, Hubei Aerospace Hospital, Xiaogan, Hubei, China
| | - Yufei Yan
- Department of Physiology, School of Basic Medical Sciences, Wuhan University, 115 Donghu Road, Wuhan, 430071, China
| | - Wenao Sun
- Department of Physiology, School of Basic Medical Sciences, Wuhan University, 115 Donghu Road, Wuhan, 430071, China
| | - Liangyi Kong
- Department of Physiology, School of Basic Medical Sciences, Wuhan University, 115 Donghu Road, Wuhan, 430071, China
| | - Yating Huang
- Department of Physiology, School of Basic Medical Sciences, Wuhan University, 115 Donghu Road, Wuhan, 430071, China
| | - Yujie Liu
- Department of Physiology, School of Basic Medical Sciences, Wuhan University, 115 Donghu Road, Wuhan, 430071, China
| | - Chaochen Jiang
- Department of Pharmacology, School of Basic Medical Sciences, Wuhan University, Wuhan, China
| | - Jie Ping
- Department of Pharmacology, School of Basic Medical Sciences, Wuhan University, Wuhan, China
| | - Changyong Li
- Department of Physiology, School of Basic Medical Sciences, Wuhan University, 115 Donghu Road, Wuhan, 430071, China.
- Xianning Medical College, Hubei University of Science and Technology, Xianning, Hubei, China.
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18
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Chen H, Zheng M, Li M, Zheng Y, Wang X, He Y. Taurine ameliorates radiation-induced oxidative stress in bone marrow mesenchymal stromal cells and promotes osteogenesis. Free Radic Biol Med 2024; 225:805-820. [PMID: 39486749 DOI: 10.1016/j.freeradbiomed.2024.10.308] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/16/2024] [Revised: 10/02/2024] [Accepted: 10/29/2024] [Indexed: 11/04/2024]
Abstract
Osteoradionecrosis of the jaw (ORNJ) is a severe complication following head and neck radiotherapy that significantly impacts the quality of life of patients. Currently, there is a lack of comprehensive understanding of the microenvironmental factors involved in ORNJ. In this study, we reveal the activation of taurine metabolism in irradiated mandibular stromal cells using scRNA-Seq and demonstrate a decrease in taurine levels in irradiated bone marrow mesenchymal stromal cells (BMSCs) through metabolomics. Compared with unirradiated BMSCs, taurine uptake in irradiated BMSCs increases. Taurine concentrations in the peripheral blood and jaws of irradiated mice are significantly lower than those in unirradiated mice (P = 0.0064 and 0.0249 respectively). Supplementation with taurine promotes osteogenic differentiation, reduces oxidative stress, and decreases DNA damage in irradiated BMSCs. Oral administration of taurine significantly improves the survival rate of irradiated mice and enhances osteogenesis in irradiated jaws. Our study highlights the role of taurine in the recovery from radiation-induced jaw injury, and suggests its potential as a non-invasive therapeutic option for combating ORNJ.
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Affiliation(s)
- Heng Chen
- Department of Oral Maxillofacial & Head and Neck Oncology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, College of Stomatology, Shanghai Jiao Tong University, National Center for Stomatology, National Clinical Research Center for Oral Diseases, Shanghai Key Laboratory of Stomatology, Shanghai, 200011, PR China
| | - Mengting Zheng
- Department of Oral Maxillofacial & Head and Neck Oncology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, College of Stomatology, Shanghai Jiao Tong University, National Center for Stomatology, National Clinical Research Center for Oral Diseases, Shanghai Key Laboratory of Stomatology, Shanghai, 200011, PR China
| | - Mengyu Li
- Department of Oral Maxillofacial & Head and Neck Oncology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, College of Stomatology, Shanghai Jiao Tong University, National Center for Stomatology, National Clinical Research Center for Oral Diseases, Shanghai Key Laboratory of Stomatology, Shanghai, 200011, PR China
| | - Yang Zheng
- Department of Oral Maxillofacial & Head and Neck Oncology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, College of Stomatology, Shanghai Jiao Tong University, National Center for Stomatology, National Clinical Research Center for Oral Diseases, Shanghai Key Laboratory of Stomatology, Shanghai, 200011, PR China
| | - Xu Wang
- Department of Oral Maxillofacial & Head and Neck Oncology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, College of Stomatology, Shanghai Jiao Tong University, National Center for Stomatology, National Clinical Research Center for Oral Diseases, Shanghai Key Laboratory of Stomatology, Shanghai, 200011, PR China.
| | - Yue He
- Department of Oral Maxillofacial & Head and Neck Oncology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, College of Stomatology, Shanghai Jiao Tong University, National Center for Stomatology, National Clinical Research Center for Oral Diseases, Shanghai Key Laboratory of Stomatology, Shanghai, 200011, PR China.
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19
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Behnke J, Goetz MJ, Holzfurtner L, Korte P, Weiss A, Shahzad T, Wilhelm J, Schermuly RT, Rivetti S, Bellusci S, Ehrhardt H. Senescence of lung mesenchymal stem cells of preterm infants by cyclic stretch and hyperoxia via p21. Am J Physiol Lung Cell Mol Physiol 2024; 327:L694-L711. [PMID: 39316679 PMCID: PMC11563592 DOI: 10.1152/ajplung.00355.2023] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2023] [Revised: 07/19/2024] [Accepted: 09/02/2024] [Indexed: 09/26/2024] Open
Abstract
Phenotype distortion of lung resident mesenchymal stem cells (MSC) in preterm infants is a hallmark event in the pathogenesis of bronchopulmonary dysplasia (BPD). Here, we evaluated the impact of cyclic mechanical stretch (CMS) and hyperoxia (HOX). The negative action of HOX on proliferation and cell death was more pronounced at 80% than at 40%. Although the impact of CMS alone was modest, CMS plus HOX displayed the strongest effect sizes. Exposure to CMS and/or HOX induced the downregulation of PDGFRα, and cellular senescence preceded by p21 accumulation. p21 interference interfered with cellular senescence and resulted in aggravated cell death, arguing for a prosurvival mechanism. HOX 40% and limited exposure to HOX 80% prevailed in a reversible phenotype with reuptake of proliferation, while prolonged exposure to HOX 80% resulted in definite MSC growth arrest. Our mechanistic data explain how HOX and CMS induce the effects on MSC phenotype disruption. The results are congruent with the clinical observation that preterm infants requiring supplemental oxygen plus mechanical ventilation are at particular risk for BPD. Although inhibiting p21 is not a feasible approach, limiting the duration and magnitude of the exposures is promising.NEW & NOTEWORTHY Rarefication of lung mesenchymal stem cells (MSC) due to exposure to cyclic mechanical stretch (CMS) during mechanical ventilation with oxygen-rich gas is a hallmark of bronchopulmonary dysplasia in preterm infants, but the pathomechanistic understanding is incomplete. Our studies identify a common signaling mechanism mediated by p21 accumulation, leading to cellular senescence and cell death, most pronounced during the combined exposure with in principle reversible phenotype change depending on strength and duration of exposures.
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Affiliation(s)
- Judith Behnke
- Department of General Pediatrics and Neonatology, Justus-Liebig-University Giessen and Universities of Giessen and Marburg Lung Center (UGMLC), Member of the German Center for Lung Research (DZL), Giessen, Germany
| | - Maurizio J Goetz
- Department of General Pediatrics and Neonatology, Justus-Liebig-University Giessen and Universities of Giessen and Marburg Lung Center (UGMLC), Member of the German Center for Lung Research (DZL), Giessen, Germany
| | - Lena Holzfurtner
- Department of General Pediatrics and Neonatology, Justus-Liebig-University Giessen and Universities of Giessen and Marburg Lung Center (UGMLC), Member of the German Center for Lung Research (DZL), Giessen, Germany
| | - Pauline Korte
- Department of General Pediatrics and Neonatology, Justus-Liebig-University Giessen and Universities of Giessen and Marburg Lung Center (UGMLC), Member of the German Center for Lung Research (DZL), Giessen, Germany
| | - Astrid Weiss
- Justus-Liebig-University Giessen and Universities of Giessen and Marburg Lung Center (UGMLC), Excellence Cluster Cardio-Pulmonary Institute (CPI), Member of the German Center for Lung Research (DZL), Giessen, Germany
| | - Tayyab Shahzad
- Department of General Pediatrics and Neonatology, Justus-Liebig-University Giessen and Universities of Giessen and Marburg Lung Center (UGMLC), Member of the German Center for Lung Research (DZL), Giessen, Germany
| | - Jochen Wilhelm
- Justus-Liebig-University Giessen and Universities of Giessen and Marburg Lung Center (UGMLC), Excellence Cluster Cardio-Pulmonary Institute (CPI), Member of the German Center for Lung Research (DZL), Giessen, Germany
- Institute for Lung Health (ILH), Giessen, Germany
| | - Ralph T Schermuly
- Justus-Liebig-University Giessen and Universities of Giessen and Marburg Lung Center (UGMLC), Excellence Cluster Cardio-Pulmonary Institute (CPI), Member of the German Center for Lung Research (DZL), Giessen, Germany
- Institute for Lung Health (ILH), Giessen, Germany
| | - Stefano Rivetti
- Justus-Liebig-University Giessen and Universities of Giessen and Marburg Lung Center (UGMLC), Excellence Cluster Cardio-Pulmonary Institute (CPI), Member of the German Center for Lung Research (DZL), Giessen, Germany
- Institute for Lung Health (ILH), Giessen, Germany
| | - Saverio Bellusci
- Justus-Liebig-University Giessen and Universities of Giessen and Marburg Lung Center (UGMLC), Excellence Cluster Cardio-Pulmonary Institute (CPI), Member of the German Center for Lung Research (DZL), Giessen, Germany
- Institute for Lung Health (ILH), Giessen, Germany
| | - Harald Ehrhardt
- Department of General Pediatrics and Neonatology, Justus-Liebig-University Giessen and Universities of Giessen and Marburg Lung Center (UGMLC), Member of the German Center for Lung Research (DZL), Giessen, Germany
- Division of Neonatology and Pediatric Intensive Care Medicine, Department of Pediatrics and Adolescent Medicine, University Medical Center Ulm, Ulm, Germany
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20
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Zhang D, Gou Z, Qu Y, Su X. Understanding how methyltransferase-like 3 functions in lung diseases: From pathogenesis to clinical application. Biomed Pharmacother 2024; 179:117421. [PMID: 39241568 DOI: 10.1016/j.biopha.2024.117421] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2024] [Revised: 09/02/2024] [Accepted: 09/04/2024] [Indexed: 09/09/2024] Open
Abstract
Lung diseases have complex pathogenesis and treatment challenges, showing an obvious increase in the rate of diagnosis and death every year. Therefore, elucidating the mechanism for their pathogenesis and treatment ineffective from novel views is essential and urgent. Methyltransferase-like 3 (METTL3) is a novel post-transcriptional regulator for gene expression that has been implicated in regulating lung diseases, including that observed in chronic conditions such as pulmonary fibrosis (PF), pulmonary arterial hypertension (PAH), and chronic obstructive pulmonary disease (COPD), as well as acute conditions such as pneumonia, severe acute respiratory syndrome coronavirus 2 infection, and sepsis-induced acute respiratory distress syndrome. Notably, a comprehensive summary and analysis of findings from these studies might help understand lung diseases from the novel view of METTL3-regulated mechanism, however, such a review is still lacking. Therefore, this review aims to bridge such shortage by summarising the roles of METTL3 in lung diseases, establishing their interrelationships, and elucidating the potential applications of METTL3 regarding diagnosis, treatment, and prognosis. The analysis collectively suggests METTL3 is contributable to the onset and progression of these lung diseases, thereby prospecting METTL3 as a valuable biomarker for their diagnosis, treatment, and prognosis. In conclusion, this review offers elucidation into the correlation between METTL3 and lung diseases in both research and clinical settings and highlights potential avenues for exploring the roles of METTL3 in the respiratory system.
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Affiliation(s)
- Deshuang Zhang
- Department of Paediatrics/Key Laboratory of Birth Defects and Related Diseases of Women and Children (Ministry of Education), West China Second University Hospital, Sichuan University, Chengdu 610041, China
| | - Zhixian Gou
- Department of Pediatrics, School of Clinical Medicine & the First Affiliated Hospital of Chengdu Medical College, Chengdu 610500, China
| | - Yi Qu
- Department of Paediatrics/Key Laboratory of Birth Defects and Related Diseases of Women and Children (Ministry of Education), West China Second University Hospital, Sichuan University, Chengdu 610041, China; NHC Key Laboratory of Chronobiology, Sichuan University, Chengdu 610041, China
| | - Xiaojuan Su
- Department of Paediatrics/Key Laboratory of Birth Defects and Related Diseases of Women and Children (Ministry of Education), West China Second University Hospital, Sichuan University, Chengdu 610041, China; NHC Key Laboratory of Chronobiology, Sichuan University, Chengdu 610041, China.
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21
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Suhardi VJ, Oktarina A, Hammad M, Niu Y, Li Q, Thomson A, Lopez J, McCormick J, Ayturk UM, Greenblatt MB, Ivashkiv LB, Bostrom MPG, Yang X. Prevention and treatment of peri-implant fibrosis by functionally inhibiting skeletal cells expressing the leptin receptor. Nat Biomed Eng 2024; 8:1285-1307. [PMID: 39085645 PMCID: PMC12016487 DOI: 10.1038/s41551-024-01238-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2023] [Accepted: 06/25/2024] [Indexed: 08/02/2024]
Abstract
The cellular and molecular mediators of peri-implant fibrosis-a most common reason for implant failure and for surgical revision after the replacement of a prosthetic joint-remain unclear. Here we show that peri-implant fibrotic tissue in mice and humans is largely composed of a specific population of skeletal cells expressing the leptin receptor (LEPR) and that these cells are necessary and sufficient to generate and maintain peri-implant fibrotic tissue. In a mouse model of tibial implantation and osseointegration that mimics partial knee arthroplasty, genetic ablation of LEPR+ cells prevented peri-implant fibrosis and the implantation of LEPR+ cells from peri-implant fibrotic tissue was sufficient to induce fibrosis in secondary hosts. Conditional deletion of the adhesion G-protein-coupled receptor F5 (ADGRF5) in LEPR+ cells attenuated peri-implant fibrosis while augmenting peri-implant bone formation, and ADGRF5 inhibition by the intra-articular or systemic administration of neutralizing anti-ADGRF5 in the mice prevented and reversed peri-implant fibrosis. Pharmaceutical agents that inhibit the ADGRF5 pathway in LEPR+ cells may be used to prevent and treat peri-implant fibrosis.
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Affiliation(s)
- Vincentius Jeremy Suhardi
- Department of Orthopedic Surgery, Hospital for Special Surgery, New York, NY, USA
- Research Institute, Hospital for Special Surgery, New York, NY, USA
| | | | - Mohammed Hammad
- Research Institute, Hospital for Special Surgery, New York, NY, USA
| | - Yingzhen Niu
- Research Institute, Hospital for Special Surgery, New York, NY, USA
- Department of Joint Surgery, The Third Hospital of Hebei Medical University, Shijiazhuang, P. R. China
| | - Qingdian Li
- Research Institute, Hospital for Special Surgery, New York, NY, USA
- Department of Orthopedics, Guangdong Provincial People's Hospital, Southern Medical University, Guangzhou, P. R. China
| | - Andrew Thomson
- Research Institute, Hospital for Special Surgery, New York, NY, USA
| | - Juan Lopez
- Research Institute, Hospital for Special Surgery, New York, NY, USA
| | - Jason McCormick
- Flow Cytometry Core Facility, Weill Cornell Medicine, New York, NY, USA
| | - Ugur M Ayturk
- Research Institute, Hospital for Special Surgery, New York, NY, USA
- Department of Orthopedic Surgery, Weill Cornell Medicine, New York, NY, USA
| | - Matthew B Greenblatt
- Research Institute, Hospital for Special Surgery, New York, NY, USA
- Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, NY, USA
| | | | - Mathias P G Bostrom
- Department of Orthopedic Surgery, Hospital for Special Surgery, New York, NY, USA
- Research Institute, Hospital for Special Surgery, New York, NY, USA
- Department of Orthopedic Surgery, Weill Cornell Medicine, New York, NY, USA
| | - Xu Yang
- Research Institute, Hospital for Special Surgery, New York, NY, USA.
- Department of Orthopedic Surgery, Weill Cornell Medicine, New York, NY, USA.
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22
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Yuce K. The Application of Mesenchymal Stem Cells in Different Cardiovascular Disorders: Ways of Administration, and the Effectors. Stem Cell Rev Rep 2024; 20:1671-1691. [PMID: 39023739 DOI: 10.1007/s12015-024-10765-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 07/11/2024] [Indexed: 07/20/2024]
Abstract
The heart is an organ with a low ability to renew and repair itself. MSCs have cell surface markers such as CD45-, CD34-, CD31-, CD4+, CD11a+, CD11b+, CD15+, CD18+, CD25+, CD49d+, CD50+, CD105+, CD73+, CD90+, CD9+, CD10+, CD106+, CD109+, CD127+, CD120a+, CD120b+, CD124+, CD126+, CD140a+, CD140b+, adherent properties and the ability to differentiate into cells such as adipocytes, osteoblasts and chondrocytes. Autogenic, allogeneic, normal, pretreated and genetically modified MSCs and secretomes are used in preclinical and clinical studies. MSCs and their secretomes (the total released molecules) generally have cardioprotective effects. Studies on cardiovascular diseases using MSCs and their secretomes include myocardial infraction/ischemia, fibrosis, hypertrophy, dilated cardiomyopathy and atherosclerosis. Stem cells or their secretomes used for this purpose are administered to the heart via intracoronary (Antegrade intracoronary and retrograde coronary venous injection), intramyocardial (Transendocardial and epicardial injection) and intravenous routes. The protective effects of MSCs and their secretomes on the heart are generally attributed to their differentiation into cardiomyocytes and endothelial cells, their immunomodulatory properties, paracrine effects, increasing blood vessel density, cardiac remodeling, and ejection fraction and decreasing apoptosis, the size of the wound, end-diastolic volume, end-systolic volume, ventricular myo-mass, fibrosis, matrix metalloproteins, and oxidative stress. The present review aims to assist researchers and physicians in selecting the appropriate cell type, secretomes, and technique to increase the chance of success in designing therapeutic strategies against cardiovascular diseases.
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Affiliation(s)
- Kemal Yuce
- Physiology, Department of Basic Medical Sciences, Medicine Faculty, Selcuk University, Konya, Türkiye.
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23
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Wu M, Liu J, Zhang S, Jian Y, Guo L, Zhang H, Mi J, Qu G, Liu Y, Gao C, Cai Q, Wen D, Liu D, Sun J, Jiang J, Huang H. Shh Signaling from the Injured Lung Microenvironment Drives BMSCs Differentiation into Alveolar Type II Cells for Acute Lung Injury Treatment in Mice. Stem Cells Int 2024; 2024:1823163. [PMID: 39372681 PMCID: PMC11455595 DOI: 10.1155/2024/1823163] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2024] [Revised: 06/22/2024] [Accepted: 08/01/2024] [Indexed: 10/08/2024] Open
Abstract
Alveolar type II (AT2) cells are key effector cells for repairing damaged lungs. Direct differentiation into AT2 cells from bone marrow mesenchymal stem cells (BMSCs) is a promising approach to treating acute lung injury (ALI). The mechanisms of BMSC differentiation into AT2 cells have not been determined. The Sonic Hedgehog (Shh) pathway is involved in regulating multiple differentiation of MSCs. However, the role of the Shh pathway in mediating the differentiation of BMSCs into AT2 cells remains to be explored. The results showed that BMSCs significantly ameliorated lung injury and improved pulmonary function in mice with ALI. These improvements were accompanied by a relatively high proportion of BMSCs differentiate into AT2 cells and an increase in the total number of AT2 cells in the lungs. Lung tissue extracts from mice with ALI (ALITEs) were used to mimic the injured lung microenvironment. The addition of ALITEs significantly improved the differentiation efficiency of BMSCs into AT2 cells along with activation of the Shh pathway. The inhibition of the Shh pathway not only reduced the differentiation rate of BMSCs but also failed to mitigate lung injury and regenerate AT2 cells. The results confirmed that promoting AT2 cell regeneration through the differentiation of BMSCs into AT2 cells is one of the important therapeutic mechanisms for the treatment of ALI with BMSCs. This differentiation process is highly dependent on Shh pathway activation in BMSCs in the injured lung microenvironment.
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Affiliation(s)
- Mengyu Wu
- Department of Trauma Medical CenterDaping HospitalState Key Laboratory of Trauma and Chemical PoisoningArmy Medical University, Chongqing 400042, China
- College of BioengineeringChongqing University, Chongqing 400044, China
| | - Jing Liu
- Department of Trauma Medical CenterDaping HospitalState Key Laboratory of Trauma and Chemical PoisoningArmy Medical University, Chongqing 400042, China
| | - Shu Zhang
- Department of Trauma Medical CenterDaping HospitalState Key Laboratory of Trauma and Chemical PoisoningArmy Medical University, Chongqing 400042, China
| | - Yi Jian
- Department of Trauma Medical CenterDaping HospitalState Key Laboratory of Trauma and Chemical PoisoningArmy Medical University, Chongqing 400042, China
- College of BioengineeringChongqing University, Chongqing 400044, China
| | - Ling Guo
- Department of Trauma Medical CenterDaping HospitalState Key Laboratory of Trauma and Chemical PoisoningArmy Medical University, Chongqing 400042, China
| | - Huacai Zhang
- Department of Trauma Medical CenterDaping HospitalState Key Laboratory of Trauma and Chemical PoisoningArmy Medical University, Chongqing 400042, China
| | - Junwei Mi
- Department of Trauma Medical CenterDaping HospitalState Key Laboratory of Trauma and Chemical PoisoningArmy Medical University, Chongqing 400042, China
| | - Guoxin Qu
- Department of Orthopedic SurgeryThe First Affiliated Hospital of Hainan Medical University, Haikou 570100, Hainan Province, China
| | - Yaojun Liu
- Department of Trauma Medical CenterDaping HospitalState Key Laboratory of Trauma and Chemical PoisoningArmy Medical University, Chongqing 400042, China
| | - Chu Gao
- Department of Trauma Medical CenterDaping HospitalState Key Laboratory of Trauma and Chemical PoisoningArmy Medical University, Chongqing 400042, China
| | - Qingli Cai
- Department of Trauma Medical CenterDaping HospitalState Key Laboratory of Trauma and Chemical PoisoningArmy Medical University, Chongqing 400042, China
| | - Dalin Wen
- Department of Trauma Medical CenterDaping HospitalState Key Laboratory of Trauma and Chemical PoisoningArmy Medical University, Chongqing 400042, China
| | - Di Liu
- Department of Trauma Medical CenterDaping HospitalState Key Laboratory of Trauma and Chemical PoisoningArmy Medical University, Chongqing 400042, China
| | - Jianhui Sun
- Department of Trauma Medical CenterDaping HospitalState Key Laboratory of Trauma and Chemical PoisoningArmy Medical University, Chongqing 400042, China
| | - Jianxin Jiang
- Department of Trauma Medical CenterDaping HospitalState Key Laboratory of Trauma and Chemical PoisoningArmy Medical University, Chongqing 400042, China
| | - Hong Huang
- Department of Trauma Medical CenterDaping HospitalState Key Laboratory of Trauma and Chemical PoisoningArmy Medical University, Chongqing 400042, China
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Wei C, Chan SF, Saguner AM, Brunckhorst C, Duru F, Marine JE, James CA, Calkins H, Judge DP, Shou W, Chen HSV. Desmoplakin mutations in cardiac fibroblasts cause TGFβ1-mediated pathological fibrogenesis in desmoplakin cardiomyopathy via beclin-1 regulation. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.09.09.612149. [PMID: 39314404 PMCID: PMC11418989 DOI: 10.1101/2024.09.09.612149] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 09/25/2024]
Abstract
Background Pathological fibrosis is a major finding in cardiovascular diseases and can result in arrhythmia and heart failure. Desmosome gene mutations can lead to arrhythmogenic cardiomyopathy (ACM). Among ACM, pathogenic desmoplakin ( DSP ) variants cause a distinctive cardiomyopathy with excessive cardiac fibrosis that could precede ventricular dysfunction. DSP variants are also linked to other fibrotic diseases. Whether DSP plays any role in pathological fibrosis remain unknown. Methods Mesenchymal stromal cells (MSCs) are resident fibroblast-like cells that are responsible for fibrogenesis in most organs, including hearts. We first used unbiased genome-wide analyses to generate cardiac fibroblasts-like, induced pluripotent stem cell-derived MSCs from normal donors and ACM patients with DSP mutations. We then studied the fibrogenic responses of cardiac MSCs to transforming growth factor beta-1 (TGF-β1) using Western/Co-IP, autophagy assay, gene knockdowns/over-expressions, genomic analyses, mouse DSP knockdown models, immunostaining, and qPCR. Results TGFβ1 induced excessive accumulations of vimentin (VIM)/fibrillar collagens, and over-activated fibrotic genes in DSP- mutant MSCs when compared to normal MSCs. In normal MSCs, VIMs bind to wild-type DSP during normal fibrogenesis after TGFβ1. DSP- mutant MSCs exhibited a haplo-insufficient phenotype with increased DSP-unbound VIMs that sequestered beclin-1 (BECN1) from activating autophagy and caveolin-1 (CAV1)-mediated endocytosis. Decreased autophagy caused collagen accumulations and diminished CAV1 endocytosis resulted in abnormal CAV1 plaque formation that over-activated fibrotic genes [ COL1A1, COL3A1, and fibronectin ( FN )] via heightened p38 activities after TGFβ1. Genome-wide analysis and DSP knockdown in mouse fibroblasts confirmed this novel role of DSP mutations in pathological fibrosis. Overexpression of VIM-binding domains of DSP could suppress pathological fibrosis by increasing collagen autophagic degradation and decreasing fibrotic gene expressions. Conclusions Our data reveal that DSP deficiency in MSCs/fibroblasts leads to exaggerated fibrogenesis in DSP-cardiomyopathy by decreasing BECN1 availability for autophagy and CAV1-endocytosis. Overexpression of VIM binding domains of DSP could be a new strategy to treat pathological fibrosis.
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25
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Bao H, Wu M, Xing J, Li Z, Zhang Y, Wu A, Li J. Enzyme-like nanoparticle-engineered mesenchymal stem cell secreting HGF promotes visualized therapy for idiopathic pulmonary fibrosis in vivo. SCIENCE ADVANCES 2024; 10:eadq0703. [PMID: 39167646 PMCID: PMC11338238 DOI: 10.1126/sciadv.adq0703] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/25/2024] [Accepted: 07/17/2024] [Indexed: 08/23/2024]
Abstract
Stem cell therapy is being explored as a potential treatment for idiopathic pulmonary fibrosis (IPF), but its effectiveness is hindered by factors like reactive oxygen species (ROS) and inflammation in fibrotic lungs. Moreover, the distribution, migration, and survival of transplanted stem cells are still unclear, impeding the clinical advancement of stem cell therapy. To tackle these challenges, we fabricate AuPtCoPS trimetallic-based nanocarriers (TBNCs), with enzyme-like activity and plasmid loading capabilities, aiming to efficiently eradicate ROS, facilitate delivery of therapeutic genes, and ultimately improve the therapeutic efficacy. TBNCs also function as a computed tomography contrast agent for tracking mesenchymal stem cells (MSCs) during therapy. Accordingly, we enhanced the antioxidant stress and anti-inflammatory capabilities of engineered MSCs and successfully visualized their biological behavior in IPF mice in vivo. Overall, this study provides an efficient and forward-looking treatment approach for IPF and establishes a framework for a stem cell-based therapeutic system aimed at addressing lung disease.
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Affiliation(s)
- Hongying Bao
- Ningbo Key Laboratory of Biomedical Imaging Probe Materials and Technology, CAS Key Laboratory of Magnetic Materials and Devices, Laboratory of Advanced Theranostic Materials and Technology, Ningbo Institute of Materials Technology and Engineering, Chinese Academy of Sciences, Ningbo 315201, China
- Zhejiang International Cooperation Base of Biomedical Materials Technology and Application, Zhejiang Engineering Research Center for Biomedical Materials, Ningbo Cixi Institute of Biomedical Engineering, Cixi 315300, China
| | - Manxiang Wu
- Ningbo Key Laboratory of Biomedical Imaging Probe Materials and Technology, CAS Key Laboratory of Magnetic Materials and Devices, Laboratory of Advanced Theranostic Materials and Technology, Ningbo Institute of Materials Technology and Engineering, Chinese Academy of Sciences, Ningbo 315201, China
| | - Jie Xing
- Ningbo Key Laboratory of Biomedical Imaging Probe Materials and Technology, CAS Key Laboratory of Magnetic Materials and Devices, Laboratory of Advanced Theranostic Materials and Technology, Ningbo Institute of Materials Technology and Engineering, Chinese Academy of Sciences, Ningbo 315201, China
- Zhejiang International Cooperation Base of Biomedical Materials Technology and Application, Zhejiang Engineering Research Center for Biomedical Materials, Ningbo Cixi Institute of Biomedical Engineering, Cixi 315300, China
| | - Zihou Li
- Ningbo Key Laboratory of Biomedical Imaging Probe Materials and Technology, CAS Key Laboratory of Magnetic Materials and Devices, Laboratory of Advanced Theranostic Materials and Technology, Ningbo Institute of Materials Technology and Engineering, Chinese Academy of Sciences, Ningbo 315201, China
- Zhejiang International Cooperation Base of Biomedical Materials Technology and Application, Zhejiang Engineering Research Center for Biomedical Materials, Ningbo Cixi Institute of Biomedical Engineering, Cixi 315300, China
| | - Yuenan Zhang
- Ningbo Key Laboratory of Biomedical Imaging Probe Materials and Technology, CAS Key Laboratory of Magnetic Materials and Devices, Laboratory of Advanced Theranostic Materials and Technology, Ningbo Institute of Materials Technology and Engineering, Chinese Academy of Sciences, Ningbo 315201, China
- Zhejiang International Cooperation Base of Biomedical Materials Technology and Application, Zhejiang Engineering Research Center for Biomedical Materials, Ningbo Cixi Institute of Biomedical Engineering, Cixi 315300, China
| | - Aiguo Wu
- Ningbo Key Laboratory of Biomedical Imaging Probe Materials and Technology, CAS Key Laboratory of Magnetic Materials and Devices, Laboratory of Advanced Theranostic Materials and Technology, Ningbo Institute of Materials Technology and Engineering, Chinese Academy of Sciences, Ningbo 315201, China
- Zhejiang International Cooperation Base of Biomedical Materials Technology and Application, Zhejiang Engineering Research Center for Biomedical Materials, Ningbo Cixi Institute of Biomedical Engineering, Cixi 315300, China
| | - Juan Li
- Ningbo Key Laboratory of Biomedical Imaging Probe Materials and Technology, CAS Key Laboratory of Magnetic Materials and Devices, Laboratory of Advanced Theranostic Materials and Technology, Ningbo Institute of Materials Technology and Engineering, Chinese Academy of Sciences, Ningbo 315201, China
- Zhejiang International Cooperation Base of Biomedical Materials Technology and Application, Zhejiang Engineering Research Center for Biomedical Materials, Ningbo Cixi Institute of Biomedical Engineering, Cixi 315300, China
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Sun J, Shi M, Song Z, Hua F, Yan X, Zhang M, Duan H, Liu J. CD146-dependent macrophage infiltration promotes epidural fibrosis via the Erdr1/ERK/CCR2 pathway. Int Immunopharmacol 2024; 137:112528. [PMID: 38908086 DOI: 10.1016/j.intimp.2024.112528] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2024] [Revised: 06/14/2024] [Accepted: 06/17/2024] [Indexed: 06/24/2024]
Abstract
Low back pain due to epidural fibrosis is a major complication after spine surgery. Macrophages infiltrate the wound area post laminectomy, but the role of macrophages in epidural fibrosis remains largely elusive. In a mouse model of laminectomy, macrophage depletion decreased epidural fibrosis. CD146, an adhesion molecule involved in cell migration, is expressed by macrophages. CD146-defective macrophages exhibited impaired migration, which was mediated by reduced expression of CCR2 and suppression of the MAPK/ERK signaling pathway. CD146-defective macrophages suppress the MAPK/ERK signaling pathway by increasing Erdr1. In vivo, CD146 deficiency decreased macrophage infiltration and reduced extracellular matrix deposition in wound tissues. Moreover, the anti-CD146 antibody AA98 suppressed macrophage infiltration and epidural fibrosis. Taken together, these findings demonstrated that CD146 deficiency alleviates epidural fibrosis by decreasing the migration of macrophages via the Erdr1/ERK/CCR2 pathway. Blocking CD146 and macrophage infiltration may help alleviate epidural fibrosis.
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Affiliation(s)
- Jinpeng Sun
- Department of Orthopedics, The Second Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Mohan Shi
- Department of Orthopedics, The Second Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Zeyuan Song
- Department of Orthopedics, The Second Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Feng Hua
- Department of Orthopedics, The Second Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Xiyun Yan
- Key Laboratory of Protein and Peptide Pharmaceutical, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China; Nanozyme Laboratory in Zhongyuan, Henan Academy of Innovations in Medical Science, Zhengzhou, Henan 451163, China
| | - Mingshun Zhang
- NHC Key Laboratory of Antibody Technique, Jiangsu Province Engineering Research Center of Antibody Drug, Department of Immunology, Nanjing Medical University, Nanjing, China.
| | - Hongxia Duan
- Key Laboratory of Protein and Peptide Pharmaceutical, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China.
| | - Jun Liu
- Department of Orthopedics, The Second Affiliated Hospital of Nanjing Medical University, Nanjing, China.
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Younesi FS, Hinz B. The Myofibroblast Fate of Therapeutic Mesenchymal Stromal Cells: Regeneration, Repair, or Despair? Int J Mol Sci 2024; 25:8712. [PMID: 39201399 PMCID: PMC11354465 DOI: 10.3390/ijms25168712] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2024] [Revised: 07/31/2024] [Accepted: 08/06/2024] [Indexed: 09/02/2024] Open
Abstract
Mesenchymal stromal cells (MSCs) can be isolated from various tissues of healthy or patient donors to be retransplanted in cell therapies. Because the number of MSCs obtained from biopsies is typically too low for direct clinical application, MSC expansion in cell culture is required. However, ex vivo amplification often reduces the desired MSC regenerative potential and enhances undesired traits, such as activation into fibrogenic myofibroblasts. Transiently activated myofibroblasts restore tissue integrity after organ injury by producing and contracting extracellular matrix into scar tissue. In contrast, persistent myofibroblasts cause excessive scarring-called fibrosis-that destroys organ function. In this review, we focus on the relevance and molecular mechanisms of myofibroblast activation upon contact with stiff cell culture plastic or recipient scar tissue, such as hypertrophic scars of large skin burns. We discuss cell mechanoperception mechanisms such as integrins and stretch-activated channels, mechanotransduction through the contractile actin cytoskeleton, and conversion of mechanical signals into transcriptional programs via mechanosensitive co-transcription factors, such as YAP, TAZ, and MRTF. We further elaborate how prolonged mechanical stress can create persistent myofibroblast memory by direct mechanotransduction to the nucleus that can evoke lasting epigenetic modifications at the DNA level, such as histone methylation and acetylation. We conclude by projecting how cell culture mechanics can be modulated to generate MSCs, which epigenetically protected against myofibroblast activation and transport desired regeneration potential to the recipient tissue environment in clinical therapies.
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Affiliation(s)
- Fereshteh Sadat Younesi
- Faculty of Dentistry, University of Toronto, Toronto, ON M5G 1G6, Canada;
- Keenan Research Institute for Biomedical Science, St. Michael’s Hospital, Toronto, ON M5B 1T8, Canada
| | - Boris Hinz
- Faculty of Dentistry, University of Toronto, Toronto, ON M5G 1G6, Canada;
- Keenan Research Institute for Biomedical Science, St. Michael’s Hospital, Toronto, ON M5B 1T8, Canada
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28
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Lian Z, Kuerban R, Niu Z, Aisaiti P, Wu C, Yang X. Notch Signaling Is Associated with Pulmonary Fibrosis in Patients with Pigeon Breeder's Lung by Regulating Oxidative Stress. Emerg Med Int 2024; 2024:7610032. [PMID: 39139588 PMCID: PMC11321885 DOI: 10.1155/2024/7610032] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2024] [Revised: 05/03/2024] [Accepted: 07/17/2024] [Indexed: 08/15/2024] Open
Abstract
This study explored the molecular mechanism underlying the association of Notch signaling and oxidative stress with the occurrence of pulmonary fibrosis in patients with pigeon breeder's lung (PBL). Rat models of fibrotic PBL were constructed with freeze-dried protein powder, and the animals were divided into the control (intratracheal instillation of normal saline; n = 9), M (PBL model; intratracheal instillation of freeze-dried protein powder; n = 9), and M + D (PBL+ the Notch inhibitor DAPT; n = 9) groups. Immunohistochemistry was employed to observe the protein levels of pathway factors and α-SMA, and the levels of ROS, GSH-PX, SOD, and MDA were observed using ELISA. To verify the results of the animal experiment, cytological models were constructed. The M group and the M + D group had significantly increased α-SMA levels (P < 0.05). Although both groups had significantly higher key protein levels in the Notch channel, the M + D group had significantly lower levels relative to the M group (P < 0.05). Oxidative stress products were examined, and the levels of MDA and ROS were significantly increased, while those of GSH-PX and SOD were significantly decreased in the M and M + D groups as compared to the control, but the M group and the M + D group significantly differed (P < 0.05). These findings were further validated by the cytological experiment. Notch signaling is associated with pulmonary fibrosis in PBL by regulating cellular oxidative stress, and inhibiting this pathway can slow down pulmonary fibrosis progression.
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Affiliation(s)
- Zhichuang Lian
- Graduate SchoolXinjiang Medical University, Urumqi 830001, China
| | - Remila Kuerban
- Department of Respiratory and Critical Care MedicinePeople's Hospital of Xinjiang Uygur Autonomous Region, Urumqi 830001, China
| | - Zongxin Niu
- Department of Respiratory and Critical Care MedicinePeople's Hospital of Xinjiang Uygur Autonomous Region, Urumqi 830001, China
| | - Paruzha Aisaiti
- Department of Respiratory and Critical Care MedicinePeople's Hospital of Xinjiang Uygur Autonomous Region, Urumqi 830001, China
| | - Chao Wu
- Graduate SchoolXinjiang Medical University, Urumqi 830001, China
| | - Xiaohong Yang
- Graduate SchoolXinjiang Medical University, Urumqi 830001, China
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29
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Younesi FS, Miller AE, Barker TH, Rossi FMV, Hinz B. Fibroblast and myofibroblast activation in normal tissue repair and fibrosis. Nat Rev Mol Cell Biol 2024; 25:617-638. [PMID: 38589640 DOI: 10.1038/s41580-024-00716-0] [Citation(s) in RCA: 123] [Impact Index Per Article: 123.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 02/21/2024] [Indexed: 04/10/2024]
Abstract
The term 'fibroblast' often serves as a catch-all for a diverse array of mesenchymal cells, including perivascular cells, stromal progenitor cells and bona fide fibroblasts. Although phenotypically similar, these subpopulations are functionally distinct, maintaining tissue integrity and serving as local progenitor reservoirs. In response to tissue injury, these cells undergo a dynamic fibroblast-myofibroblast transition, marked by extracellular matrix secretion and contraction of actomyosin-based stress fibres. Importantly, whereas transient activation into myofibroblasts aids in tissue repair, persistent activation triggers pathological fibrosis. In this Review, we discuss the roles of mechanical cues, such as tissue stiffness and strain, alongside cell signalling pathways and extracellular matrix ligands in modulating myofibroblast activation and survival. We also highlight the role of epigenetic modifications and myofibroblast memory in physiological and pathological processes. Finally, we discuss potential strategies for therapeutically interfering with these factors and the associated signal transduction pathways to improve the outcome of dysregulated healing.
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Affiliation(s)
- Fereshteh Sadat Younesi
- Keenan Research Institute for Biomedical Science of the St. Michael's Hospital, Toronto, Ontario, Canada
- Faculty of Dentistry, University of Toronto, Toronto, Ontario, Canada
| | - Andrew E Miller
- Department of Biomedical Engineering, School of Engineering and Applied Science, University of Virginia, Charlottesville, VA, USA
| | - Thomas H Barker
- Department of Biomedical Engineering, School of Engineering and Applied Science, University of Virginia, Charlottesville, VA, USA
| | - Fabio M V Rossi
- School of Biomedical Engineering and Department of Medical Genetics, University of British Columbia, Vancouver, British Columbia, Canada
| | - Boris Hinz
- Keenan Research Institute for Biomedical Science of the St. Michael's Hospital, Toronto, Ontario, Canada.
- Faculty of Dentistry, University of Toronto, Toronto, Ontario, Canada.
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30
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Chen L, Huang Y, Zhang N, Qu J, Fang Y, Fu J, Yuan Y, Zhang Q, Li H, Wen Z, Yuan L, Chen L, Xu Z, Li Y, Yan H, Izawa H, Li L, Xiang C. Single-cell RNA sequencing reveals reduced intercellular adhesion molecule crosstalk between activated hepatic stellate cells and neutrophils alleviating liver fibrosis in hepatitis B virus transgenic mice post menstrual blood-derived mesenchymal stem cell transplantation. MedComm (Beijing) 2024; 5:e654. [PMID: 39040848 PMCID: PMC11261812 DOI: 10.1002/mco2.654] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2024] [Revised: 06/03/2024] [Accepted: 06/10/2024] [Indexed: 07/24/2024] Open
Abstract
Liver fibrosis can cause hepatitis B virus (HBV)-associated hepatocellular carcinoma. Menstrual blood-derived mesenchymal stem cells (MenSCs) can ameliorate liver fibrosis through paracrine. Single-cell RNA sequencing (scRNA-seq) may be used to explore the roadmap of activated hepatic stellate cell (aHSC) inactivation to target liver fibrosis. This study established HBV transgenic (HBV-Tg) mouse model of carbon tetrachloride (CCl4)-induced liver fibrosis and demonstrated that MenSCs migrated to the injured liver to improve serological indices and reduce fibrotic accumulation. RNA-bulk analysis revealed that MenSCs mediated extracellular matrix accumulation and cell adhesion. Liver parenchymal cells and nonparenchymal cells were identified by scRNA-seq in the control, CCl4, and MenSC groups, revealing the heterogeneity of fibroblasts/HSCs. A CellChat analysis revealed that diminished intercellular adhesion molecule (ICAM) signaling is vital for MenSC therapy. Specifically, Icam1 in aHSCs acted on Itgal/Itgb2 and Itgam/Itgb2 in neutrophils, causing decreased adhesion. The expression of Itgal, Itgam, and Itgb2 was higher in CCl4 group than in the control group and decreased after MenSC therapy in neutrophil clusters. The Lcn2, Pglyrp1, Wfdc21, and Mmp8 had high expression and may be potential targets in neutrophils. This study highlights interacting cells, corresponding molecules, and underlying targets for MenSCs in treating HBV-associated liver fibrosis.
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Affiliation(s)
- Lijun Chen
- State Key Laboratory for Diagnosis and Treatment of Infectious DiseasesNational Clinical Research Center for Infectious DiseasesNational Medical Center for Infectious DiseasesCollaborative Innovation Center for Diagnosis and Treatment of Infectious DiseasesThe First Affiliated HospitalZhejiang University School of MedicineHangzhouChina
- Research Units of Infectious Disease and MicroecologyChinese Academy of Medical SciencesBeijingChina
| | - Yuqi Huang
- State Key Laboratory for Diagnosis and Treatment of Infectious DiseasesNational Clinical Research Center for Infectious DiseasesNational Medical Center for Infectious DiseasesCollaborative Innovation Center for Diagnosis and Treatment of Infectious DiseasesThe First Affiliated HospitalZhejiang University School of MedicineHangzhouChina
| | - Ning Zhang
- State Key Laboratory for Diagnosis and Treatment of Infectious DiseasesNational Clinical Research Center for Infectious DiseasesNational Medical Center for Infectious DiseasesCollaborative Innovation Center for Diagnosis and Treatment of Infectious DiseasesThe First Affiliated HospitalZhejiang University School of MedicineHangzhouChina
| | - Jingjing Qu
- Department of Respiratory DiseaseThoracic Disease CentreThe First Affiliated HospitalZhejiang University School of MedicineHangzhouChina
| | - Yangxin Fang
- State Key Laboratory for Diagnosis and Treatment of Infectious DiseasesNational Clinical Research Center for Infectious DiseasesNational Medical Center for Infectious DiseasesCollaborative Innovation Center for Diagnosis and Treatment of Infectious DiseasesThe First Affiliated HospitalZhejiang University School of MedicineHangzhouChina
| | - Jiamin Fu
- State Key Laboratory for Diagnosis and Treatment of Infectious DiseasesNational Clinical Research Center for Infectious DiseasesNational Medical Center for Infectious DiseasesCollaborative Innovation Center for Diagnosis and Treatment of Infectious DiseasesThe First Affiliated HospitalZhejiang University School of MedicineHangzhouChina
| | - Yin Yuan
- State Key Laboratory for Diagnosis and Treatment of Infectious DiseasesNational Clinical Research Center for Infectious DiseasesNational Medical Center for Infectious DiseasesCollaborative Innovation Center for Diagnosis and Treatment of Infectious DiseasesThe First Affiliated HospitalZhejiang University School of MedicineHangzhouChina
| | - Qi Zhang
- State Key Laboratory for Diagnosis and Treatment of Infectious DiseasesNational Clinical Research Center for Infectious DiseasesNational Medical Center for Infectious DiseasesCollaborative Innovation Center for Diagnosis and Treatment of Infectious DiseasesThe First Affiliated HospitalZhejiang University School of MedicineHangzhouChina
| | - Hang Li
- Innovative Precision Medicine (IPM) GroupHangzhouChina
| | - Zuoshi Wen
- Department of CardiologyThe First Affiliated HospitalZhejiang University School of MedicineHangzhouChina
| | - Li Yuan
- Innovative Precision Medicine (IPM) GroupHangzhouChina
| | - Lu Chen
- Innovative Precision Medicine (IPM) GroupHangzhouChina
| | - Zhenyu Xu
- Innovative Precision Medicine (IPM) GroupHangzhouChina
| | - Yifei Li
- State Key Laboratory for Diagnosis and Treatment of Infectious DiseasesNational Clinical Research Center for Infectious DiseasesNational Medical Center for Infectious DiseasesCollaborative Innovation Center for Diagnosis and Treatment of Infectious DiseasesThe First Affiliated HospitalZhejiang University School of MedicineHangzhouChina
- Research Units of Infectious Disease and MicroecologyChinese Academy of Medical SciencesBeijingChina
| | - Huadong Yan
- Infectious Disease DepartmentShulan (Hangzhou) Hospital Affiliated to Zhejiang Shuren University Shulan International Medical CollegeHangzhouChina
| | | | - Lanjuan Li
- State Key Laboratory for Diagnosis and Treatment of Infectious DiseasesNational Clinical Research Center for Infectious DiseasesNational Medical Center for Infectious DiseasesCollaborative Innovation Center for Diagnosis and Treatment of Infectious DiseasesThe First Affiliated HospitalZhejiang University School of MedicineHangzhouChina
- Research Units of Infectious Disease and MicroecologyChinese Academy of Medical SciencesBeijingChina
- Jinan Microecological Biomedicine Shandong LaboratoryJinanChina
| | - Charlie Xiang
- State Key Laboratory for Diagnosis and Treatment of Infectious DiseasesNational Clinical Research Center for Infectious DiseasesNational Medical Center for Infectious DiseasesCollaborative Innovation Center for Diagnosis and Treatment of Infectious DiseasesThe First Affiliated HospitalZhejiang University School of MedicineHangzhouChina
- Research Units of Infectious Disease and MicroecologyChinese Academy of Medical SciencesBeijingChina
- Jinan Microecological Biomedicine Shandong LaboratoryJinanChina
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31
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Shi L, Hu Y, Zeng H, Shi H, Xu W, Sun Y, Chu H, Ji C, Qian H. Mesenchymal stem cell-derived extracellular vesicles ameliorate renal interstitial fibrosis via the miR-13474/ADAM17 axis. Sci Rep 2024; 14:17703. [PMID: 39085289 PMCID: PMC11291924 DOI: 10.1038/s41598-024-67339-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2024] [Accepted: 07/10/2024] [Indexed: 08/02/2024] Open
Abstract
Renal interstitial fibrosis (RIF) is a prevalent consequence of chronic renal diseases, characterized by excessive extracellular matrix (ECM) deposition. A Disintegrin and Metalloprotease 17 (ADAM17), a transmembrane metalloproteinase, plays a central role in driving renal fibrosis progression by activating Notch 1 protein and the downstream TGF-β signaling pathway. Our study investigated potential therapeutic interventions for renal fibrosis, focusing on human umbilical cord mesenchymal stem cell-derived extracellular vesicles (hucMSC-EVs). We found that hucMSC-EVs inhibit ADAM17, thereby impeding renal fibrosis progression. Analysis of hucMSC-EVs miRNA profiles revealed significant enrichment of miR-13474, which effectively targeted and inhibited ADAM17 mRNA expression, subsequently suppressing Notch1 activation, TGF-β signaling, and collagen deposition. Overexpression of miR-13474 enhanced hucMSC-EVs' inhibitory effect on renal fibrosis, while its downregulation abolished this protective effect. Our findings highlight the efficacy of hucMSC-EVs overexpressing miR-13474 in mitigating renal fibrosis via ADAM17 targeting. These insights offer potential therapeutic strategies for managing renal fibrosis.
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Affiliation(s)
- Linru Shi
- Center for Molecular & Imageology of Jiangsu University, Division of Nephrology, The Affiliated Yixing Hospital of Jiangsu University, Yixing, 214200, Jiangsu, China
- Jiangsu Key Laboratory of Medical Science and Laboratory Medicine, Department of Laboratory Medicine, School of Medicine, Jiangsu University, 301 Xuefu Road, Zhenjiang, 212013, Jiangsu, China
| | - Yuyan Hu
- Jiangsu Key Laboratory of Medical Science and Laboratory Medicine, Department of Laboratory Medicine, School of Medicine, Jiangsu University, 301 Xuefu Road, Zhenjiang, 212013, Jiangsu, China
- Shaoxing Central Hospital Medical Alliance General Hospital, The Department of Laboratory, Shaoxing, 312030, Zhejiang, China
| | - Houcheng Zeng
- Jiangsu Key Laboratory of Medical Science and Laboratory Medicine, Department of Laboratory Medicine, School of Medicine, Jiangsu University, 301 Xuefu Road, Zhenjiang, 212013, Jiangsu, China
| | - Hui Shi
- Jiangsu Key Laboratory of Medical Science and Laboratory Medicine, Department of Laboratory Medicine, School of Medicine, Jiangsu University, 301 Xuefu Road, Zhenjiang, 212013, Jiangsu, China
| | - Wenrong Xu
- Jiangsu Key Laboratory of Medical Science and Laboratory Medicine, Department of Laboratory Medicine, School of Medicine, Jiangsu University, 301 Xuefu Road, Zhenjiang, 212013, Jiangsu, China
| | - Yaoxiang Sun
- Center for Molecular & Imageology of Jiangsu University, Division of Nephrology, The Affiliated Yixing Hospital of Jiangsu University, Yixing, 214200, Jiangsu, China
| | - Hong Chu
- Center for Molecular & Imageology of Jiangsu University, Division of Nephrology, The Affiliated Yixing Hospital of Jiangsu University, Yixing, 214200, Jiangsu, China.
| | - Cheng Ji
- Jiangsu Key Laboratory of Medical Science and Laboratory Medicine, Department of Laboratory Medicine, School of Medicine, Jiangsu University, 301 Xuefu Road, Zhenjiang, 212013, Jiangsu, China.
| | - Hui Qian
- Center for Molecular & Imageology of Jiangsu University, Division of Nephrology, The Affiliated Yixing Hospital of Jiangsu University, Yixing, 214200, Jiangsu, China.
- Jiangsu Key Laboratory of Medical Science and Laboratory Medicine, Department of Laboratory Medicine, School of Medicine, Jiangsu University, 301 Xuefu Road, Zhenjiang, 212013, Jiangsu, China.
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32
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Mei R, Wan Z, Yang C, Shen X, Wang R, Zhang H, Yang R, Li J, Song Y, Su H. Advances and clinical challenges of mesenchymal stem cell therapy. Front Immunol 2024; 15:1421854. [PMID: 39100671 PMCID: PMC11294097 DOI: 10.3389/fimmu.2024.1421854] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2024] [Accepted: 07/02/2024] [Indexed: 08/06/2024] Open
Abstract
In recent years, cell therapy has provided desirable properties for promising new drugs. Mesenchymal stem cells are promising candidates for developing genetic engineering and drug delivery strategies due to their inherent properties, including immune regulation, homing ability and tumor tropism. The therapeutic potential of mesenchymal stem cells is being investigated for cancer therapy, inflammatory and fibrotic diseases, among others. Mesenchymal stem cells are attractive cellular carriers for synthetic nanoparticles for drug delivery due to their inherent homing ability. In this review, we comprehensively discuss the various genetic and non-genetic strategies of mesenchymal stem cells and their derivatives in drug delivery, tumor therapy, immune regulation, tissue regeneration and other fields. In addition, we discuss the current limitations of stem cell therapy and the challenges in clinical translation, aiming to identify important development areas and potential future directions.
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Affiliation(s)
- Ruiyan Mei
- Department of Oncology, Tangdu Hospital, Air Force Medical University, Xi’an, China
| | - Zhuo Wan
- Department of Hematology, Tangdu Hospital, Air Force Medical University, Xi’an, China
| | - Cheng Yang
- Department of Oncology, Tangdu Hospital, Air Force Medical University, Xi’an, China
| | - Xiangjing Shen
- Department of Oncology, Tangdu Hospital, Air Force Medical University, Xi’an, China
| | - Ronglin Wang
- Department of Oncology, Tangdu Hospital, Air Force Medical University, Xi’an, China
| | - Haihua Zhang
- Department of Oncology, Tangdu Hospital, Air Force Medical University, Xi’an, China
| | - Rui Yang
- Department of Oncology, Tangdu Hospital, Air Force Medical University, Xi’an, China
| | - Junqiang Li
- Department of Oncology, Tangdu Hospital, Air Force Medical University, Xi’an, China
| | - Yang Song
- Department of Oncology, Tangdu Hospital, Air Force Medical University, Xi’an, China
| | - Haichuan Su
- Department of Oncology, Tangdu Hospital, Air Force Medical University, Xi’an, China
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33
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Chang Z, Li LY, Shi ZJ, Liu W, Xu GK. Beyond stiffness: Multiscale viscoelastic features as biomechanical markers for assessing cell types and states. Biophys J 2024; 123:1869-1881. [PMID: 38835167 PMCID: PMC11267428 DOI: 10.1016/j.bpj.2024.05.033] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2024] [Revised: 05/14/2024] [Accepted: 05/30/2024] [Indexed: 06/06/2024] Open
Abstract
Cell mechanics are pivotal in regulating cellular activities, diseases progression, and cancer development. However, the understanding of how cellular viscoelastic properties vary in physiological and pathological stimuli remains scarce. Here, we develop a hybrid self-similar hierarchical theory-microrheology approach to accurately and efficiently characterize cellular viscoelasticity. Focusing on two key cell types associated with livers fibrosis-the capillarized liver sinusoidal endothelial cells and activated hepatic stellate cells-we uncover a universal two-stage power-law rheology characterized by two distinct exponents, αshort and αlong. The mechanical profiles derived from both exponents exhibit significant potential for discriminating among diverse cells. This finding suggests a potential common dynamic creep characteristic across biological systems, extending our earlier observations in soft tissues. Using a tailored hierarchical model for cellular mechanical structures, we discern significant variations in the viscoelastic properties and their distribution profiles across different cell types and states from the cytoplasm (elastic stiffness E1 and viscosity η), to a single cytoskeleton fiber (elastic stiffness E2), and then to the cell level (transverse expansion stiffness E3). Importantly, we construct a logistic-regression-based machine-learning model using the dynamic parameters that outperforms conventional cell-stiffness-based classifiers in assessing cell states, achieving an area under the curve of 97% vs. 78%. Our findings not only advance a robust framework for monitoring intricate cell dynamics but also highlight the crucial role of cellular viscoelasticity in discerning cell states across a spectrum of liver diseases and prognosis, offering new avenues for developing diagnostic and therapeutic strategies based on cellular viscoelasticity.
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Affiliation(s)
- Zhuo Chang
- Laboratory for Multiscale Mechanics and Medical Science, Department of Engineering Mechanics, State Key Laboratory for Strength and Vibration of Mechanical Structures, School of Aerospace Engineering, Xi'an Jiaotong University, Xi'an, China
| | - Li-Ya Li
- Institute for Stem Cell & Regenerative Medicine, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Zhi-Jun Shi
- Laboratory for Multiscale Mechanics and Medical Science, Department of Engineering Mechanics, State Key Laboratory for Strength and Vibration of Mechanical Structures, School of Aerospace Engineering, Xi'an Jiaotong University, Xi'an, China
| | - Wenjia Liu
- Institute for Stem Cell & Regenerative Medicine, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China.
| | - Guang-Kui Xu
- Laboratory for Multiscale Mechanics and Medical Science, Department of Engineering Mechanics, State Key Laboratory for Strength and Vibration of Mechanical Structures, School of Aerospace Engineering, Xi'an Jiaotong University, Xi'an, China.
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34
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Sun L, Rao S, Kerim K, Lu J, Li H, Zhao S, Shen P, Sun W. A chemically adjustable BMP6-IL6 axis in mesenchymal stem cells drives acute myeloid leukemia cell differentiation. Biochem Pharmacol 2024; 225:116262. [PMID: 38705535 DOI: 10.1016/j.bcp.2024.116262] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2023] [Revised: 04/29/2024] [Accepted: 05/02/2024] [Indexed: 05/07/2024]
Abstract
Chemotherapy alone or in combination with allogeneic stem cell transplantation has been the standard of care for acute myeloid leukemia (AML) for decades. Leukemia relapse with limited treatment options remains the main cause of treatment failure. Therefore, an effective and safe approach to improve treatment outcomes is urgently needed for most AML patients. Mesenchymal stem cells (MSCs) have been reported to efficiently induce apoptosis and shape the fate of acute myeloid leukemia cells. Here, we identified LG190155 as a potent compound that enhances the antileukemia efficiency of MSCs. Pretreatment of MSCs with LG190155 significantly provoked differentiation in both AML patient-derived primary leukemia cells and AML cell lines and reduced the tumor burden in the AML mouse model. Using the quantitative proteomic technique, we discovered a pivotal mechanism that mediates AML cell differentiation, in which autocrine bone morphogenetic protein 6 (BMP6) in MSCs boosted IL-6 secretion and further acted on leukemic cells to trigger differentiation. Furthermore, the activity of the BMP6-IL6 axis was dramatically enhanced by activating vitamin D receptor (VDR) in MSCs. Our data illustrated an effective preactivated approach to reinforcing the antileukemia effect of MSCs, which could serve as an effective therapeutic strategy for AML.
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Affiliation(s)
- Luchen Sun
- The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou 325000, China
| | - Shangrui Rao
- The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou 325000, China
| | - Kamran Kerim
- State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing 210023, China
| | - Jianhua Lu
- The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou 325000, China
| | - Hongzheng Li
- The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou 325000, China
| | - Shengsheng Zhao
- The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou 325000, China
| | - Pingping Shen
- The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou 325000, China; State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing 210023, China; Shenzhen Research Institute of NanJing University, Shenzhen 518000, China.
| | - Weijian Sun
- The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou 325000, China.
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Gao Y, Liu MF, Li Y, Liu X, Cao YJ, Long QF, Yu J, Li JY. Mesenchymal stem cells-extracellular vesicles alleviate pulmonary fibrosis by regulating immunomodulators. World J Stem Cells 2024; 16:670-689. [PMID: 38948098 PMCID: PMC11212550 DOI: 10.4252/wjsc.v16.i6.670] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/06/2024] [Revised: 03/22/2024] [Accepted: 05/11/2024] [Indexed: 06/25/2024] Open
Abstract
BACKGROUND Pulmonary fibrosis (PF) is a chronic interstitial lung disease characterized by fibroblast proliferation and extracellular matrix formation, causing structural damage and lung failure. Stem cell therapy and mesenchymal stem cells-extracellular vesicles (MSC-EVs) offer new hope for PF treatment. AIM To investigate the therapeutic potential of MSC-EVs in alleviating fibrosis, oxidative stress, and immune inflammation in A549 cells and bleomycin (BLM)-induced mouse model. METHODS The effect of MSC-EVs on A549 cells was assessed by fibrosis markers [collagen I and α-smooth muscle actin (α-SMA), oxidative stress regulators [nuclear factor E2-related factor 2 (Nrf2) and heme oxygenase-1 (HO-1), and inflammatory regulators [nuclear factor-kappaB (NF-κB) p65, interleukin (IL)-1β, and IL-2]. Similarly, they were assessed in the lungs of mice where PF was induced by BLM after MSC-EV transfection. MSC-EVs ion PF mice were detected by pathological staining and western blot. Single-cell RNA sequencing was performed to investigate the effects of the MSC-EVs on gene expression profiles of macrophages after modeling in mice. RESULTS Transforming growth factor (TGF)-β1 enhanced fibrosis in A549 cells, significantly increasing collagen I and α-SMA levels. Notably, treatment with MSC-EVs demonstrated a remarkable alleviation of these effects. Similarly, the expression of oxidative stress regulators, such as Nrf2 and HO-1, along with inflammatory regulators, including NF-κB p65 and IL-1β, were mitigated by MSC-EV treatment. Furthermore, in a parallel manner, MSC-EVs exhibited a downregulatory impact on collagen deposition, oxidative stress injuries, and inflammatory-related cytokines in the lungs of mice with PF. Additionally, the mRNA sequencing results suggested that BLM may induce PF in mice by upregulating pulmonary collagen fiber deposition and triggering an immune inflammatory response. The findings collectively highlight the potential therapeutic efficacy of MSC-EVs in ameliorating fibrotic processes, oxidative stress, and inflammatory responses associated with PF. CONCLUSION MSC-EVs could ameliorate fibrosis in vitro and in vivo by downregulating collagen deposition, oxidative stress, and immune-inflammatory responses.
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Affiliation(s)
- Ying Gao
- Department of Respiratory and Critical Care Medicine, Shaanxi Provincial Rehabilitation Hospital, Xi'an 710000, Shaanxi Province, China
| | - Mei-Fang Liu
- Department of Respiratory and Critical Care Medicine, Second Affiliated Hospital of Ningxia Medical University (The First People's Hospital of Yinchuan), Yinchuan 750001, Ningxia Hui Autonomous Region, China
| | - Yang Li
- School of Clinical Medicine, Xi'an Medical University, Xi'an 710021, Shaanxi Province, China
| | - Xi Liu
- Department of Respiratory and Critical Care Medicine, Xi'an Central Hospital, Xi'an 710000, Shaanxi Province, China
| | - Yu-Jie Cao
- Department of Respiratory and Critical Care Medicine, Xi'an Central Hospital, Xi'an 710000, Shaanxi Province, China
| | - Qian-Fa Long
- Department of Neurosurgery, Xi'an Central Hospital, Xi'an 710000, Shaanxi Province, China
| | - Jun Yu
- Department of Emergency, Xi'an Central Hospital, Xi'an 710000, Shaanxi Province, China
| | - Jian-Ying Li
- Department of Respiratory and Critical Care Medicine, Xi'an Central Hospital, Xi'an 710000, Shaanxi Province, China.
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Gao Y, Liu MF, Li Y, Liu X, Cao YJ, Long QF, Yu J, Li JY. Mesenchymal stem cells-extracellular vesicles alleviate pulmonary fibrosis by regulating immunomodulators. World J Stem Cells 2024; 16:669-688. [DOI: 10.4252/wjsc.v16.i6.669] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/06/2024] [Revised: 03/22/2024] [Accepted: 05/11/2024] [Indexed: 06/25/2024] Open
Abstract
BACKGROUND Pulmonary fibrosis (PF) is a chronic interstitial lung disease characterized by fibroblast proliferation and extracellular matrix formation, causing structural damage and lung failure. Stem cell therapy and mesenchymal stem cells-extracellular vesicles (MSC-EVs) offer new hope for PF treatment.
AIM To investigate the therapeutic potential of MSC-EVs in alleviating fibrosis, oxidative stress, and immune inflammation in A549 cells and bleomycin (BLM)-induced mouse model.
METHODS The effect of MSC-EVs on A549 cells was assessed by fibrosis markers [collagen I and α-smooth muscle actin (α-SMA), oxidative stress regulators [nuclear factor E2-related factor 2 (Nrf2) and heme oxygenase-1 (HO-1), and inflammatory regulators [nuclear factor-kappaB (NF-κB) p65, interleukin (IL)-1β, and IL-2]. Similarly, they were assessed in the lungs of mice where PF was induced by BLM after MSC-EV transfection. MSC-EVs ion PF mice were detected by pathological staining and western blot. Single-cell RNA sequencing was performed to investigate the effects of the MSC-EVs on gene expression profiles of macrophages after modeling in mice.
RESULTS Transforming growth factor (TGF)-β1 enhanced fibrosis in A549 cells, significantly increasing collagen I and α-SMA levels. Notably, treatment with MSC-EVs demonstrated a remarkable alleviation of these effects. Similarly, the expression of oxidative stress regulators, such as Nrf2 and HO-1, along with inflammatory regulators, including NF-κB p65 and IL-1β, were mitigated by MSC-EV treatment. Furthermore, in a parallel manner, MSC-EVs exhibited a downregulatory impact on collagen deposition, oxidative stress injuries, and inflammatory-related cytokines in the lungs of mice with PF. Additionally, the mRNA sequencing results suggested that BLM may induce PF in mice by upregulating pulmonary collagen fiber deposition and triggering an immune inflammatory response. The findings collectively highlight the potential therapeutic efficacy of MSC-EVs in ameliorating fibrotic processes, oxidative stress, and inflammatory responses associated with PF.
CONCLUSION MSC-EVs could ameliorate fibrosis in vitro and in vivo by downregulating collagen deposition, oxidative stress, and immune-inflammatory responses.
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Affiliation(s)
- Ying Gao
- Department of Respiratory and Critical Care Medicine, Shaanxi Provincial Rehabilitation Hospital, Xi’an 710000, Shaanxi Province, China
| | - Mei-Fang Liu
- Department of Respiratory and Critical Care Medicine, Second Affiliated Hospital of Ningxia Medical University (The First People’s Hospital of Yinchuan), Yinchuan 750001, Ningxia Hui Autonomous Region, China
| | - Yang Li
- School of Clinical Medicine, Xi’an Medical University, Xi’an 710021, Shaanxi Province, China
| | - Xi Liu
- Department of Respiratory and Critical Care Medicine, Xi’an Central Hospital, Xi’an 710000, Shaanxi Province, China
| | - Yu-Jie Cao
- Department of Respiratory and Critical Care Medicine, Xi’an Central Hospital, Xi’an 710000, Shaanxi Province, China
| | - Qian-Fa Long
- Department of Neurosurgery, Xi’an Central Hospital, Xi’an 710000, Shaanxi Province, China
| | - Jun Yu
- Department of Emergency, Xi’an Central Hospital, Xi’an 710000, Shaanxi Province, China
| | - Jian-Ying Li
- Department of Respiratory and Critical Care Medicine, Xi’an Central Hospital, Xi’an 710000, Shaanxi Province, China
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Wang Y, Li M, Yang T, Xie Y, Wang FS, Hu J, Shi M. Human umbilical cord mesenchymal stem cell transplantation for the treatment of acute-on-chronic liver failure: protocol for a multicentre random double-blind placebo-controlled trial. BMJ Open 2024; 14:e084237. [PMID: 38925694 PMCID: PMC11202670 DOI: 10.1136/bmjopen-2024-084237] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/13/2024] [Accepted: 05/31/2024] [Indexed: 06/28/2024] Open
Abstract
INTRODUCTION Acute-on-chronic liver failure (ACLF) is a prevalent and life-threatening liver disease with high short-term mortality. Although recent clinical trials on the use of mesenchymal stem cells (MSCs) for ACLF treatment have shown promising results, multicentre randomised controlled phase II clinical trials remain uncommon. The primary aim of this trial is to assess the safety and efficacy of different MSCs treatment courses for ACLF. METHODS AND ANALYSIS This is a multicentre, double-blind, two-stage, randomised and placebo-controlled clinical trial. In the first stage, 150 patients with ACLF will be enrolled and randomly assigned to either a control group (50 cases) or an MSCs treatment group (100 cases). They will receive either a placebo or umbilical cord-derived MSCs (UC-MSCs) treatment three times (at weeks 0, 1 and 2). In the second stage, 28 days after the first UC-MSCs infusion, surviving patients in the MSCs treatment group will be further randomly divided into MSCs-short and MSCs-prolonged groups at a 1:1 ratio. They will receive two additional rounds of placebo or UC-MSCs treatment at weeks 4 and 5. The primary endpoints are the transplant-free survival rate and the incidence of treatment-related adverse events. Secondary endpoints include international normalised ratio, total bilirubin, serum albumin, blood urea nitrogen, model for end-stage liver disease score and Child-Turcotte-Pugh score. ETHICS AND DISSEMINATION Ethical approval of this study has been obtained from the Fifth Medical Center of the Chinese PLA General Hospital (KY-2023-3-19-1). All results of the study will be submitted to international journals and international conferences for publication on completion of the study. TRIAL REGISTRATION NUMBER NCT05985863.
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Affiliation(s)
- Yanhu Wang
- Chinese PLA Medical School, Chinese PLA General Hospital, Beijing, China
- Senior Department of Infectious Diseases, The Fifth Medical Center of Chinese PLA General Hospital, National Clinical Research Center for Infectious Diseases, Beijing, China
| | - Mengyao Li
- Peking University 302 Clinical Medical School, Beijing, China
| | - Tao Yang
- Chinese PLA Medical School, Chinese PLA General Hospital, Beijing, China
- Senior Department of Infectious Diseases, The Fifth Medical Center of Chinese PLA General Hospital, National Clinical Research Center for Infectious Diseases, Beijing, China
| | - Yunbo Xie
- Chinese PLA Medical School, Chinese PLA General Hospital, Beijing, China
- Senior Department of Infectious Diseases, The Fifth Medical Center of Chinese PLA General Hospital, National Clinical Research Center for Infectious Diseases, Beijing, China
| | - Fu-Sheng Wang
- Senior Department of Infectious Diseases, The Fifth Medical Center of Chinese PLA General Hospital, National Clinical Research Center for Infectious Diseases, Beijing, China
| | - Jinhua Hu
- Senior Department of Hepatology, The Fifth Medical Center of Chinese PLA General Hospital, Beijing, China
| | - Ming Shi
- Senior Department of Infectious Diseases, The Fifth Medical Center of Chinese PLA General Hospital, National Clinical Research Center for Infectious Diseases, Beijing, China
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38
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Taherian M, Bayati P, Mojtabavi N. Stem cell-based therapy for fibrotic diseases: mechanisms and pathways. Stem Cell Res Ther 2024; 15:170. [PMID: 38886859 PMCID: PMC11184790 DOI: 10.1186/s13287-024-03782-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2024] [Accepted: 06/04/2024] [Indexed: 06/20/2024] Open
Abstract
Fibrosis is a pathological process, that could result in permanent scarring and impairment of the physiological function of the affected organ; this condition which is categorized under the term organ failure could affect various organs in different situations. The involvement of the major organs, such as the lungs, liver, kidney, heart, and skin, is associated with a high rate of morbidity and mortality across the world. Fibrotic disorders encompass a broad range of complications and could be traced to various illnesses and impairments; these could range from simple skin scars with beauty issues to severe rheumatologic or inflammatory disorders such as systemic sclerosis as well as idiopathic pulmonary fibrosis. Besides, the overactivation of immune responses during any inflammatory condition causing tissue damage could contribute to the pathogenic fibrotic events accompanying the healing response; for instance, the inflammation resulting from tissue engraftment could cause the formation of fibrotic scars in the grafted tissue, even in cases where the immune system deals with hard to clear infections, fibrotic scars could follow and cause severe adverse effects. A good example of such a complication is post-Covid19 lung fibrosis which could impair the life of the affected individuals with extensive lung involvement. However, effective therapies that halt or slow down the progression of fibrosis are missing in the current clinical settings. Considering the immunomodulatory and regenerative potential of distinct stem cell types, their application as an anti-fibrotic agent, capable of attenuating tissue fibrosis has been investigated by many researchers. Although the majority of the studies addressing the anti-fibrotic effects of stem cells indicated their potent capabilities, the underlying mechanisms, and pathways by which these cells could impact fibrotic processes remain poorly understood. Here, we first, review the properties of various stem cell types utilized so far as anti-fibrotic treatments and discuss the challenges and limitations associated with their applications in clinical settings; then, we will summarize the general and organ-specific mechanisms and pathways contributing to tissue fibrosis; finally, we will describe the mechanisms and pathways considered to be employed by distinct stem cell types for exerting anti-fibrotic events.
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Affiliation(s)
- Marjan Taherian
- Department of Immunology, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
- Immunology Research Center, Institute of Immunology and Infectious Diseases, Iran University of Medical Sciences, Tehran, Iran
| | - Paria Bayati
- Department of Immunology, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
- Immunology Research Center, Institute of Immunology and Infectious Diseases, Iran University of Medical Sciences, Tehran, Iran
| | - Nazanin Mojtabavi
- Department of Immunology, School of Medicine, Iran University of Medical Sciences, Tehran, Iran.
- Immunology Research Center, Institute of Immunology and Infectious Diseases, Iran University of Medical Sciences, Tehran, Iran.
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Xu Y, Huang L, Qiu Z, Zhang J, Xue X, Lin J. Overexpressed miR-486 in bone marrow mesenchymal stem cells represses urethral fibrosis and targets Col13a1 in urethral stricture rats. J Cell Commun Signal 2024; 18:e12028. [PMID: 38946723 PMCID: PMC11208119 DOI: 10.1002/ccs3.12028] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2023] [Revised: 04/01/2024] [Accepted: 04/01/2024] [Indexed: 07/02/2024] Open
Abstract
Urethral stricture (US) is a challenging problem in urology and its pathogenesis of US is closely related to the fibrotic process. Previous evidence has indicated the downregulation of microRNA (miR)-486 in injured urethral specimens of rats. This study aimed to explore the effects of miR-486-overexpressed bone marrow mesenchymal stem cells (BMSCs) on US. BMSCs were identified by detecting their multipotency and surface antigens. Lentivirus virus expressing miR-486 was transduced into rat BMSCs to overexpress miR-486. Transforming growth factor (TGF)-β1 induced fibrotic phenotypes in urethral fibroblasts (UFs) and rat models. Western blotting showed protein levels of collagen I/III and collagen type XIII alpha 1 chain (Col13a1). Real time quantitative polymerase chain reaction was utilized for messenger RNA level evaluation. Hematoxylin-eosin, Masson's trichrome, and Von Willebrand Factor staining were conducted for histopathological analysis. Immunofluorescence staining was employed for detecting alpha smooth muscle actin (α-SMA) expression. Luciferase reporter assay verified the interaction between miR-486 and Col13a1. The results showed that miR-486-overexpressed BMSCs suppressed collagen I/III and α-SMA expression in TGF-β1-stimulated UFs. miR-486-overexpressed BMSCs alleviated urethral fibrosis, collagen deposition, and epithelial injury in the urethral tissue of US rats. miR-486 targeted and negatively regulated Col13a1 in US rats. In conclusion, overexpression of miR-486 in BMSCs targets Col13a1 and attenuates urethral fibrosis in TGF-β1-triggered UFs and US rats.
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Affiliation(s)
- Yali Xu
- Department of Pediatric Surgery The First Affiliated Hospital Fujian Medical University Fuzhou China
| | - Lihong Huang
- The First Clinical Medical School Fujian Medical University Fuzhou China
| | - Zhixin Qiu
- Department of Pediatric Surgery The First Affiliated Hospital Fujian Medical University Fuzhou China
| | - Jiaqi Zhang
- The First Clinical Medical School Fujian Medical University Fuzhou China
| | - Xueyi Xue
- Department of Urology The First Affiliated Hospital Fujian Medical University Fuzhou China
| | - Junshan Lin
- Department of Pediatric Surgery The First Affiliated Hospital Fujian Medical University Fuzhou China
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40
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Zhang H, Li M, Hu CJ, Stenmark KR. Fibroblasts in Pulmonary Hypertension: Roles and Molecular Mechanisms. Cells 2024; 13:914. [PMID: 38891046 PMCID: PMC11171669 DOI: 10.3390/cells13110914] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2024] [Revised: 05/17/2024] [Accepted: 05/22/2024] [Indexed: 06/20/2024] Open
Abstract
Fibroblasts, among the most prevalent and widely distributed cell types in the human body, play a crucial role in defining tissue structure. They do this by depositing and remodeling extracellular matrixes and organizing functional tissue networks, which are essential for tissue homeostasis and various human diseases. Pulmonary hypertension (PH) is a devastating syndrome with high mortality, characterized by remodeling of the pulmonary vasculature and significant cellular and structural changes within the intima, media, and adventitia layers. Most research on PH has focused on alterations in the intima (endothelial cells) and media (smooth muscle cells). However, research over the past decade has provided strong evidence of the critical role played by pulmonary artery adventitial fibroblasts in PH. These fibroblasts exhibit the earliest, most dramatic, and most sustained proliferative, apoptosis-resistant, and inflammatory responses to vascular stress. This review examines the aberrant phenotypes of PH fibroblasts and their role in the pathogenesis of PH, discusses potential molecular signaling pathways underlying these activated phenotypes, and highlights areas of research that merit further study to identify promising targets for the prevention and treatment of PH.
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Affiliation(s)
- Hui Zhang
- Cardiovascular Pulmonary Research Laboratories, Departments of Pediatrics and Medicine, University of Colorado School of Medicine, Anschutz Medical Campus, Aurora, CO 80045, USA
| | - Min Li
- Cardiovascular Pulmonary Research Laboratories, Departments of Pediatrics and Medicine, University of Colorado School of Medicine, Anschutz Medical Campus, Aurora, CO 80045, USA
| | - Cheng-Jun Hu
- Cardiovascular Pulmonary Research Laboratories, Departments of Pediatrics and Medicine, University of Colorado School of Medicine, Anschutz Medical Campus, Aurora, CO 80045, USA
- Department of Craniofacial Biology, University of Colorado School of Dental Medicine, Anschutz Medical Campus, Aurora, CO 80045, USA
| | - Kurt R. Stenmark
- Cardiovascular Pulmonary Research Laboratories, Departments of Pediatrics and Medicine, University of Colorado School of Medicine, Anschutz Medical Campus, Aurora, CO 80045, USA
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41
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Chu X, Kheirollahi V, Lingampally A, Chelladurai P, Valasarajan C, Vazquez-Armendariz AI, Hadzic S, Khadim A, Pak O, Rivetti S, Wilhelm J, Bartkuhn M, Crnkovic S, Moiseenko A, Heiner M, Kraut S, Atefi LS, Koepke J, Valente G, Ruppert C, Braun T, Samakovlis C, Alexopoulos I, Looso M, Chao CM, Herold S, Seeger W, Kwapiszewska G, Huang X, Zhang JS, Pullamsetti SS, Weissmann N, Li X, El Agha E, Bellusci S. GLI1+ Cells Contribute to Vascular Remodeling in Pulmonary Hypertension. Circ Res 2024; 134:e133-e149. [PMID: 38639105 DOI: 10.1161/circresaha.123.323736] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/27/2023] [Accepted: 04/01/2024] [Indexed: 04/20/2024]
Abstract
BACKGROUND The precise origin of newly formed ACTA2+ (alpha smooth muscle actin-positive) cells appearing in nonmuscularized vessels in the context of pulmonary hypertension is still debatable although it is believed that they predominantly derive from preexisting vascular smooth muscle cells (VSMCs). METHODS Gli1Cre-ERT2; tdTomatoflox mice were used to lineage trace GLI1+ (glioma-associated oncogene homolog 1-positive) cells in the context of pulmonary hypertension using 2 independent models of vascular remodeling and reverse remodeling: hypoxia and cigarette smoke exposure. Hemodynamic measurements, right ventricular hypertrophy assessment, flow cytometry, and histological analysis of thick lung sections followed by state-of-the-art 3-dimensional reconstruction and quantification using Imaris software were used to investigate the contribution of GLI1+ cells to neomuscularization of the pulmonary vasculature. RESULTS The data show that GLI1+ cells are abundant around distal, nonmuscularized vessels during steady state, and this lineage contributes to around 50% of newly formed ACTA2+ cells around these normally nonmuscularized vessels. During reverse remodeling, cells derived from the GLI1+ lineage are largely cleared in parallel to the reversal of muscularization. Partial ablation of GLI1+ cells greatly prevented vascular remodeling in response to hypoxia and attenuated the increase in right ventricular systolic pressure and right heart hypertrophy. Single-cell RNA sequencing on sorted lineage-labeled GLI1+ cells revealed an Acta2high fraction of cells with pathways in cancer and MAPK (mitogen-activated protein kinase) signaling as potential players in reprogramming these cells during vascular remodeling. Analysis of human lung-derived material suggests that GLI1 signaling is overactivated in both group 1 and group 3 pulmonary hypertension and can promote proliferation and myogenic differentiation. CONCLUSIONS Our data highlight GLI1+ cells as an alternative cellular source of VSMCs in pulmonary hypertension and suggest that these cells and the associated signaling pathways represent an important therapeutic target for further studies.
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MESH Headings
- Animals
- Zinc Finger Protein GLI1/metabolism
- Zinc Finger Protein GLI1/genetics
- Mice
- Vascular Remodeling
- Hypertension, Pulmonary/metabolism
- Hypertension, Pulmonary/physiopathology
- Hypertension, Pulmonary/pathology
- Muscle, Smooth, Vascular/metabolism
- Muscle, Smooth, Vascular/pathology
- Myocytes, Smooth Muscle/metabolism
- Myocytes, Smooth Muscle/pathology
- Mice, Inbred C57BL
- Pulmonary Artery/metabolism
- Pulmonary Artery/pathology
- Pulmonary Artery/physiopathology
- Mice, Transgenic
- Male
- Humans
- Hypoxia/metabolism
- Hypoxia/physiopathology
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Affiliation(s)
- Xuran Chu
- Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision and Brain Health) (X.C., S.B.), Wenzhou Medical University, China
- School of Pharmaceutical Sciences (X.C., X.L.), Wenzhou Medical University, China
- Cardio-Pulmonary Institute (X.C., V.K., A.L., P.C., C.V., A.I.V.-A., S. Hadzic, A.K., O.P., S.R., J.W., M.B., A.M., M.H., S.K., L.S., J.K., C.R., C.S., I.A., C.-M.C., S. Herold, W.S., G.K., S.S.P., N.W., E.E.A., S.B.), Universities of Giessen and Marburg Lung Center, German Center for Lung Research (DZL), Justus Liebig University Giessen, Germany
| | - Vahid Kheirollahi
- Cardio-Pulmonary Institute (X.C., V.K., A.L., P.C., C.V., A.I.V.-A., S. Hadzic, A.K., O.P., S.R., J.W., M.B., A.M., M.H., S.K., L.S., J.K., C.R., C.S., I.A., C.-M.C., S. Herold, W.S., G.K., S.S.P., N.W., E.E.A., S.B.), Universities of Giessen and Marburg Lung Center, German Center for Lung Research (DZL), Justus Liebig University Giessen, Germany
| | - Arun Lingampally
- Cardio-Pulmonary Institute (X.C., V.K., A.L., P.C., C.V., A.I.V.-A., S. Hadzic, A.K., O.P., S.R., J.W., M.B., A.M., M.H., S.K., L.S., J.K., C.R., C.S., I.A., C.-M.C., S. Herold, W.S., G.K., S.S.P., N.W., E.E.A., S.B.), Universities of Giessen and Marburg Lung Center, German Center for Lung Research (DZL), Justus Liebig University Giessen, Germany
- Department of Medicine V, Internal Medicine, Infectious Diseases and Infection Control (A.L., A.I.V.-A., A.K., M.H., I.A., S. Herold, E.E.A.), Universities of Giessen and Marburg Lung Center, German Center for Lung Research (DZL), Justus Liebig University Giessen, Germany
| | - Prakash Chelladurai
- Cardio-Pulmonary Institute (X.C., V.K., A.L., P.C., C.V., A.I.V.-A., S. Hadzic, A.K., O.P., S.R., J.W., M.B., A.M., M.H., S.K., L.S., J.K., C.R., C.S., I.A., C.-M.C., S. Herold, W.S., G.K., S.S.P., N.W., E.E.A., S.B.), Universities of Giessen and Marburg Lung Center, German Center for Lung Research (DZL), Justus Liebig University Giessen, Germany
- Institute for Lung Health, Giessen, Germany (P.C., C.V., A.I.V.-A., A.K., J.W., M.B., J.K., C.S., I.A., S. Herold, W.S., G.K., S.S.P., E.E.A., S.B.)
| | - Chanil Valasarajan
- Cardio-Pulmonary Institute (X.C., V.K., A.L., P.C., C.V., A.I.V.-A., S. Hadzic, A.K., O.P., S.R., J.W., M.B., A.M., M.H., S.K., L.S., J.K., C.R., C.S., I.A., C.-M.C., S. Herold, W.S., G.K., S.S.P., N.W., E.E.A., S.B.), Universities of Giessen and Marburg Lung Center, German Center for Lung Research (DZL), Justus Liebig University Giessen, Germany
- Institute for Lung Health, Giessen, Germany (P.C., C.V., A.I.V.-A., A.K., J.W., M.B., J.K., C.S., I.A., S. Herold, W.S., G.K., S.S.P., E.E.A., S.B.)
| | - Ana Ivonne Vazquez-Armendariz
- Cardio-Pulmonary Institute (X.C., V.K., A.L., P.C., C.V., A.I.V.-A., S. Hadzic, A.K., O.P., S.R., J.W., M.B., A.M., M.H., S.K., L.S., J.K., C.R., C.S., I.A., C.-M.C., S. Herold, W.S., G.K., S.S.P., N.W., E.E.A., S.B.), Universities of Giessen and Marburg Lung Center, German Center for Lung Research (DZL), Justus Liebig University Giessen, Germany
- Department of Medicine V, Internal Medicine, Infectious Diseases and Infection Control (A.L., A.I.V.-A., A.K., M.H., I.A., S. Herold, E.E.A.), Universities of Giessen and Marburg Lung Center, German Center for Lung Research (DZL), Justus Liebig University Giessen, Germany
- Institute for Lung Health, Giessen, Germany (P.C., C.V., A.I.V.-A., A.K., J.W., M.B., J.K., C.S., I.A., S. Herold, W.S., G.K., S.S.P., E.E.A., S.B.)
| | - Stefan Hadzic
- Cardio-Pulmonary Institute (X.C., V.K., A.L., P.C., C.V., A.I.V.-A., S. Hadzic, A.K., O.P., S.R., J.W., M.B., A.M., M.H., S.K., L.S., J.K., C.R., C.S., I.A., C.-M.C., S. Herold, W.S., G.K., S.S.P., N.W., E.E.A., S.B.), Universities of Giessen and Marburg Lung Center, German Center for Lung Research (DZL), Justus Liebig University Giessen, Germany
| | - Ali Khadim
- Cardio-Pulmonary Institute (X.C., V.K., A.L., P.C., C.V., A.I.V.-A., S. Hadzic, A.K., O.P., S.R., J.W., M.B., A.M., M.H., S.K., L.S., J.K., C.R., C.S., I.A., C.-M.C., S. Herold, W.S., G.K., S.S.P., N.W., E.E.A., S.B.), Universities of Giessen and Marburg Lung Center, German Center for Lung Research (DZL), Justus Liebig University Giessen, Germany
- Department of Medicine V, Internal Medicine, Infectious Diseases and Infection Control (A.L., A.I.V.-A., A.K., M.H., I.A., S. Herold, E.E.A.), Universities of Giessen and Marburg Lung Center, German Center for Lung Research (DZL), Justus Liebig University Giessen, Germany
- Institute for Lung Health, Giessen, Germany (P.C., C.V., A.I.V.-A., A.K., J.W., M.B., J.K., C.S., I.A., S. Herold, W.S., G.K., S.S.P., E.E.A., S.B.)
| | - Oleg Pak
- Cardio-Pulmonary Institute (X.C., V.K., A.L., P.C., C.V., A.I.V.-A., S. Hadzic, A.K., O.P., S.R., J.W., M.B., A.M., M.H., S.K., L.S., J.K., C.R., C.S., I.A., C.-M.C., S. Herold, W.S., G.K., S.S.P., N.W., E.E.A., S.B.), Universities of Giessen and Marburg Lung Center, German Center for Lung Research (DZL), Justus Liebig University Giessen, Germany
| | - Stefano Rivetti
- Cardio-Pulmonary Institute (X.C., V.K., A.L., P.C., C.V., A.I.V.-A., S. Hadzic, A.K., O.P., S.R., J.W., M.B., A.M., M.H., S.K., L.S., J.K., C.R., C.S., I.A., C.-M.C., S. Herold, W.S., G.K., S.S.P., N.W., E.E.A., S.B.), Universities of Giessen and Marburg Lung Center, German Center for Lung Research (DZL), Justus Liebig University Giessen, Germany
| | - Jochen Wilhelm
- Cardio-Pulmonary Institute (X.C., V.K., A.L., P.C., C.V., A.I.V.-A., S. Hadzic, A.K., O.P., S.R., J.W., M.B., A.M., M.H., S.K., L.S., J.K., C.R., C.S., I.A., C.-M.C., S. Herold, W.S., G.K., S.S.P., N.W., E.E.A., S.B.), Universities of Giessen and Marburg Lung Center, German Center for Lung Research (DZL), Justus Liebig University Giessen, Germany
- Institute for Lung Health, Giessen, Germany (P.C., C.V., A.I.V.-A., A.K., J.W., M.B., J.K., C.S., I.A., S. Herold, W.S., G.K., S.S.P., E.E.A., S.B.)
| | - Marek Bartkuhn
- Cardio-Pulmonary Institute (X.C., V.K., A.L., P.C., C.V., A.I.V.-A., S. Hadzic, A.K., O.P., S.R., J.W., M.B., A.M., M.H., S.K., L.S., J.K., C.R., C.S., I.A., C.-M.C., S. Herold, W.S., G.K., S.S.P., N.W., E.E.A., S.B.), Universities of Giessen and Marburg Lung Center, German Center for Lung Research (DZL), Justus Liebig University Giessen, Germany
- Institute for Lung Health, Giessen, Germany (P.C., C.V., A.I.V.-A., A.K., J.W., M.B., J.K., C.S., I.A., S. Herold, W.S., G.K., S.S.P., E.E.A., S.B.)
| | - Slaven Crnkovic
- Ludwig Boltzmann Institute for Lung Vascular Research, Medical University Graz, Austria (S.C., G.K.)
| | - Alena Moiseenko
- Cardio-Pulmonary Institute (X.C., V.K., A.L., P.C., C.V., A.I.V.-A., S. Hadzic, A.K., O.P., S.R., J.W., M.B., A.M., M.H., S.K., L.S., J.K., C.R., C.S., I.A., C.-M.C., S. Herold, W.S., G.K., S.S.P., N.W., E.E.A., S.B.), Universities of Giessen and Marburg Lung Center, German Center for Lung Research (DZL), Justus Liebig University Giessen, Germany
| | - Monika Heiner
- Cardio-Pulmonary Institute (X.C., V.K., A.L., P.C., C.V., A.I.V.-A., S. Hadzic, A.K., O.P., S.R., J.W., M.B., A.M., M.H., S.K., L.S., J.K., C.R., C.S., I.A., C.-M.C., S. Herold, W.S., G.K., S.S.P., N.W., E.E.A., S.B.), Universities of Giessen and Marburg Lung Center, German Center for Lung Research (DZL), Justus Liebig University Giessen, Germany
- Department of Medicine V, Internal Medicine, Infectious Diseases and Infection Control (A.L., A.I.V.-A., A.K., M.H., I.A., S. Herold, E.E.A.), Universities of Giessen and Marburg Lung Center, German Center for Lung Research (DZL), Justus Liebig University Giessen, Germany
| | - Simone Kraut
- Cardio-Pulmonary Institute (X.C., V.K., A.L., P.C., C.V., A.I.V.-A., S. Hadzic, A.K., O.P., S.R., J.W., M.B., A.M., M.H., S.K., L.S., J.K., C.R., C.S., I.A., C.-M.C., S. Herold, W.S., G.K., S.S.P., N.W., E.E.A., S.B.), Universities of Giessen and Marburg Lung Center, German Center for Lung Research (DZL), Justus Liebig University Giessen, Germany
| | | | - Janine Koepke
- Cardio-Pulmonary Institute (X.C., V.K., A.L., P.C., C.V., A.I.V.-A., S. Hadzic, A.K., O.P., S.R., J.W., M.B., A.M., M.H., S.K., L.S., J.K., C.R., C.S., I.A., C.-M.C., S. Herold, W.S., G.K., S.S.P., N.W., E.E.A., S.B.), Universities of Giessen and Marburg Lung Center, German Center for Lung Research (DZL), Justus Liebig University Giessen, Germany
- Institute for Lung Health, Giessen, Germany (P.C., C.V., A.I.V.-A., A.K., J.W., M.B., J.K., C.S., I.A., S. Herold, W.S., G.K., S.S.P., E.E.A., S.B.)
| | - Guilherme Valente
- Max Planck Institute for Lung and Heart, Bad Nauheim, Germany (G.V., T.B., M.L., W.S.)
| | - Clemens Ruppert
- Cardio-Pulmonary Institute (X.C., V.K., A.L., P.C., C.V., A.I.V.-A., S. Hadzic, A.K., O.P., S.R., J.W., M.B., A.M., M.H., S.K., L.S., J.K., C.R., C.S., I.A., C.-M.C., S. Herold, W.S., G.K., S.S.P., N.W., E.E.A., S.B.), Universities of Giessen and Marburg Lung Center, German Center for Lung Research (DZL), Justus Liebig University Giessen, Germany
| | - Thomas Braun
- Max Planck Institute for Lung and Heart, Bad Nauheim, Germany (G.V., T.B., M.L., W.S.)
| | - Christos Samakovlis
- Cardio-Pulmonary Institute (X.C., V.K., A.L., P.C., C.V., A.I.V.-A., S. Hadzic, A.K., O.P., S.R., J.W., M.B., A.M., M.H., S.K., L.S., J.K., C.R., C.S., I.A., C.-M.C., S. Herold, W.S., G.K., S.S.P., N.W., E.E.A., S.B.), Universities of Giessen and Marburg Lung Center, German Center for Lung Research (DZL), Justus Liebig University Giessen, Germany
- Institute for Lung Health, Giessen, Germany (P.C., C.V., A.I.V.-A., A.K., J.W., M.B., J.K., C.S., I.A., S. Herold, W.S., G.K., S.S.P., E.E.A., S.B.)
| | - Ioannis Alexopoulos
- Cardio-Pulmonary Institute (X.C., V.K., A.L., P.C., C.V., A.I.V.-A., S. Hadzic, A.K., O.P., S.R., J.W., M.B., A.M., M.H., S.K., L.S., J.K., C.R., C.S., I.A., C.-M.C., S. Herold, W.S., G.K., S.S.P., N.W., E.E.A., S.B.), Universities of Giessen and Marburg Lung Center, German Center for Lung Research (DZL), Justus Liebig University Giessen, Germany
- Department of Medicine V, Internal Medicine, Infectious Diseases and Infection Control (A.L., A.I.V.-A., A.K., M.H., I.A., S. Herold, E.E.A.), Universities of Giessen and Marburg Lung Center, German Center for Lung Research (DZL), Justus Liebig University Giessen, Germany
- Institute for Lung Health, Giessen, Germany (P.C., C.V., A.I.V.-A., A.K., J.W., M.B., J.K., C.S., I.A., S. Herold, W.S., G.K., S.S.P., E.E.A., S.B.)
| | - Mario Looso
- Max Planck Institute for Lung and Heart, Bad Nauheim, Germany (G.V., T.B., M.L., W.S.)
| | - Cho-Ming Chao
- Cardio-Pulmonary Institute (X.C., V.K., A.L., P.C., C.V., A.I.V.-A., S. Hadzic, A.K., O.P., S.R., J.W., M.B., A.M., M.H., S.K., L.S., J.K., C.R., C.S., I.A., C.-M.C., S. Herold, W.S., G.K., S.S.P., N.W., E.E.A., S.B.), Universities of Giessen and Marburg Lung Center, German Center for Lung Research (DZL), Justus Liebig University Giessen, Germany
- Department of Pediatrics, HELIOS University Medical Center, Witten/Herdecke University, Wuppertal, Germany (C.-M.C.)
| | - Susanne Herold
- Cardio-Pulmonary Institute (X.C., V.K., A.L., P.C., C.V., A.I.V.-A., S. Hadzic, A.K., O.P., S.R., J.W., M.B., A.M., M.H., S.K., L.S., J.K., C.R., C.S., I.A., C.-M.C., S. Herold, W.S., G.K., S.S.P., N.W., E.E.A., S.B.), Universities of Giessen and Marburg Lung Center, German Center for Lung Research (DZL), Justus Liebig University Giessen, Germany
- Department of Medicine V, Internal Medicine, Infectious Diseases and Infection Control (A.L., A.I.V.-A., A.K., M.H., I.A., S. Herold, E.E.A.), Universities of Giessen and Marburg Lung Center, German Center for Lung Research (DZL), Justus Liebig University Giessen, Germany
- Institute for Lung Health, Giessen, Germany (P.C., C.V., A.I.V.-A., A.K., J.W., M.B., J.K., C.S., I.A., S. Herold, W.S., G.K., S.S.P., E.E.A., S.B.)
| | - Werner Seeger
- Cardio-Pulmonary Institute (X.C., V.K., A.L., P.C., C.V., A.I.V.-A., S. Hadzic, A.K., O.P., S.R., J.W., M.B., A.M., M.H., S.K., L.S., J.K., C.R., C.S., I.A., C.-M.C., S. Herold, W.S., G.K., S.S.P., N.W., E.E.A., S.B.), Universities of Giessen and Marburg Lung Center, German Center for Lung Research (DZL), Justus Liebig University Giessen, Germany
- Institute for Lung Health, Giessen, Germany (P.C., C.V., A.I.V.-A., A.K., J.W., M.B., J.K., C.S., I.A., S. Herold, W.S., G.K., S.S.P., E.E.A., S.B.)
- Max Planck Institute for Lung and Heart, Bad Nauheim, Germany (G.V., T.B., M.L., W.S.)
| | - Grazyna Kwapiszewska
- Cardio-Pulmonary Institute (X.C., V.K., A.L., P.C., C.V., A.I.V.-A., S. Hadzic, A.K., O.P., S.R., J.W., M.B., A.M., M.H., S.K., L.S., J.K., C.R., C.S., I.A., C.-M.C., S. Herold, W.S., G.K., S.S.P., N.W., E.E.A., S.B.), Universities of Giessen and Marburg Lung Center, German Center for Lung Research (DZL), Justus Liebig University Giessen, Germany
- Institute for Lung Health, Giessen, Germany (P.C., C.V., A.I.V.-A., A.K., J.W., M.B., J.K., C.S., I.A., S. Herold, W.S., G.K., S.S.P., E.E.A., S.B.)
- Ludwig Boltzmann Institute for Lung Vascular Research, Medical University Graz, Austria (S.C., G.K.)
| | - Xiaoying Huang
- Department of Pulmonary and Critical Care Medicine, The First Affiliated Hospital of Wenzhou Medical University, China (X.H., J.-S.Z.)
| | - Jin-San Zhang
- Department of Pulmonary and Critical Care Medicine, The First Affiliated Hospital of Wenzhou Medical University, China (X.H., J.-S.Z.)
| | - Soni Savai Pullamsetti
- Cardio-Pulmonary Institute (X.C., V.K., A.L., P.C., C.V., A.I.V.-A., S. Hadzic, A.K., O.P., S.R., J.W., M.B., A.M., M.H., S.K., L.S., J.K., C.R., C.S., I.A., C.-M.C., S. Herold, W.S., G.K., S.S.P., N.W., E.E.A., S.B.), Universities of Giessen and Marburg Lung Center, German Center for Lung Research (DZL), Justus Liebig University Giessen, Germany
- Institute for Lung Health, Giessen, Germany (P.C., C.V., A.I.V.-A., A.K., J.W., M.B., J.K., C.S., I.A., S. Herold, W.S., G.K., S.S.P., E.E.A., S.B.)
| | - Norbert Weissmann
- Cardio-Pulmonary Institute (X.C., V.K., A.L., P.C., C.V., A.I.V.-A., S. Hadzic, A.K., O.P., S.R., J.W., M.B., A.M., M.H., S.K., L.S., J.K., C.R., C.S., I.A., C.-M.C., S. Herold, W.S., G.K., S.S.P., N.W., E.E.A., S.B.), Universities of Giessen and Marburg Lung Center, German Center for Lung Research (DZL), Justus Liebig University Giessen, Germany
| | - Xiaokun Li
- School of Pharmaceutical Sciences (X.C., X.L.), Wenzhou Medical University, China
| | - Elie El Agha
- Cardio-Pulmonary Institute (X.C., V.K., A.L., P.C., C.V., A.I.V.-A., S. Hadzic, A.K., O.P., S.R., J.W., M.B., A.M., M.H., S.K., L.S., J.K., C.R., C.S., I.A., C.-M.C., S. Herold, W.S., G.K., S.S.P., N.W., E.E.A., S.B.), Universities of Giessen and Marburg Lung Center, German Center for Lung Research (DZL), Justus Liebig University Giessen, Germany
- Department of Medicine V, Internal Medicine, Infectious Diseases and Infection Control (A.L., A.I.V.-A., A.K., M.H., I.A., S. Herold, E.E.A.), Universities of Giessen and Marburg Lung Center, German Center for Lung Research (DZL), Justus Liebig University Giessen, Germany
- Institute for Lung Health, Giessen, Germany (P.C., C.V., A.I.V.-A., A.K., J.W., M.B., J.K., C.S., I.A., S. Herold, W.S., G.K., S.S.P., E.E.A., S.B.)
| | - Saverio Bellusci
- Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision and Brain Health) (X.C., S.B.), Wenzhou Medical University, China
- Cardio-Pulmonary Institute (X.C., V.K., A.L., P.C., C.V., A.I.V.-A., S. Hadzic, A.K., O.P., S.R., J.W., M.B., A.M., M.H., S.K., L.S., J.K., C.R., C.S., I.A., C.-M.C., S. Herold, W.S., G.K., S.S.P., N.W., E.E.A., S.B.), Universities of Giessen and Marburg Lung Center, German Center for Lung Research (DZL), Justus Liebig University Giessen, Germany
- Institute for Lung Health, Giessen, Germany (P.C., C.V., A.I.V.-A., A.K., J.W., M.B., J.K., C.S., I.A., S. Herold, W.S., G.K., S.S.P., E.E.A., S.B.)
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Vosbeck K, Förster S, Mayr T, Sahu A, Haddouti EM, Al-Adilee O, Körber RM, Bisht S, Muders MH, Nesic S, Buness A, Kristiansen G, Schildberg FA, Gütgemann I. Neuropilin2 in Mesenchymal Stromal Cells as a Potential Novel Therapeutic Target in Myelofibrosis. Cancers (Basel) 2024; 16:1924. [PMID: 38792002 PMCID: PMC11119673 DOI: 10.3390/cancers16101924] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2024] [Revised: 05/13/2024] [Accepted: 05/16/2024] [Indexed: 05/26/2024] Open
Abstract
Bone marrow fibrosis in myeloproliferative neoplasm (MPN), myelodysplastic syndromes (MDS), MPN/MDS overlap syndromes and acute myeloid leukemia (AML) is associated with poor prognosis and early treatment failure. Myelofibrosis (MF) is accompanied by reprogramming of multipotent bone marrow mesenchymal stromal cells (MSC) into osteoid and fiber-producing stromal cells. We demonstrate NRP2 and osteolineage marker NCAM1 (neural cell adhesion molecule 1) expression within the endosteal niche in normal bone marrow and aberrantly in MPN, MDS MPN/MDS overlap syndromes and AML (n = 99), as assessed by immunohistochemistry. Increased and diffuse expression in mesenchymal stromal cells and osteoblasts correlates with high MF grade in MPN (p < 0.05 for NRP2 and NCAM1). Single cell RNA sequencing (scRNAseq) re-analysis demonstrated NRP2 expression in endothelial cells and partial co-expression of NRP2 and NCAM1 in normal MSC and osteoblasts. Potential ligands included transforming growth factor β1 (TGFB1) from osteoblasts and megakaryocytes. Murine ThPO and JAK2V617F myelofibrosis models showed co-expression of Nrp2 and Ncam1 in osteolineage cells, while fibrosis-promoting MSC only express Nrp2. In vitro experiments with MC3T3-E1 pre-osteoblasts and analysis of Nrp2-/- mouse femurs suggest that Nrp2 is functionally involved in osteogenesis. In summary, NRP2 represents a potential novel druggable target in patients with myelofibrosis.
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Affiliation(s)
- Karla Vosbeck
- Institute for Pathology, University Hospital Bonn, 53127 Bonn, Germany (T.M.); (O.A.-A.); (M.H.M.); (G.K.)
| | - Sarah Förster
- Institute for Pathology, University Hospital Bonn, 53127 Bonn, Germany (T.M.); (O.A.-A.); (M.H.M.); (G.K.)
| | - Thomas Mayr
- Institute for Pathology, University Hospital Bonn, 53127 Bonn, Germany (T.M.); (O.A.-A.); (M.H.M.); (G.K.)
| | - Anshupa Sahu
- Institute for Medical Biometry, Informatics and Epidemiology, Medical Faculty, University of Bonn, 53127 Bonn, Germany;
| | - El-Mustapha Haddouti
- Department of Orthopedics and Trauma Surgery, University Hospital Bonn, 53127 Bonn, Germany; (E.-M.H.)
| | - Osamah Al-Adilee
- Institute for Pathology, University Hospital Bonn, 53127 Bonn, Germany (T.M.); (O.A.-A.); (M.H.M.); (G.K.)
| | - Ruth-Miriam Körber
- Department of Medicine III, University Hospital Bonn, 53127 Bonn, Germany; (R.-M.K.); (S.B.)
| | - Savita Bisht
- Department of Medicine III, University Hospital Bonn, 53127 Bonn, Germany; (R.-M.K.); (S.B.)
| | - Michael H. Muders
- Institute for Pathology, University Hospital Bonn, 53127 Bonn, Germany (T.M.); (O.A.-A.); (M.H.M.); (G.K.)
| | - Svetozar Nesic
- Core Unit for Bioinformatics Data Analysis, Medical Faculty, University of Bonn, Venusberg-Campus 1, 53127 Bonn, Germany; (S.N.); (A.B.)
| | - Andreas Buness
- Core Unit for Bioinformatics Data Analysis, Medical Faculty, University of Bonn, Venusberg-Campus 1, 53127 Bonn, Germany; (S.N.); (A.B.)
| | - Glen Kristiansen
- Institute for Pathology, University Hospital Bonn, 53127 Bonn, Germany (T.M.); (O.A.-A.); (M.H.M.); (G.K.)
| | - Frank A. Schildberg
- Department of Orthopedics and Trauma Surgery, University Hospital Bonn, 53127 Bonn, Germany; (E.-M.H.)
| | - Ines Gütgemann
- Institute for Pathology, University Hospital Bonn, 53127 Bonn, Germany (T.M.); (O.A.-A.); (M.H.M.); (G.K.)
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Carlander ALF, Gundestrup AK, Jansson PM, Follin B, Hoeeg C, Kousholt BS, Larsen RT, Jakobsen KK, Rimborg S, Fischer-Nielsen A, Grønhøj C, Buchwald CV, Lynggaard CD. Mesenchymal Stromal/Stem Cell Therapy Improves Salivary Flow Rate in Radiation-Induced Salivary Gland Hypofunction in Preclinical in vivo Models: A Systematic Review and Meta-Analysis. Stem Cell Rev Rep 2024; 20:1078-1092. [PMID: 38430363 PMCID: PMC11087340 DOI: 10.1007/s12015-024-10700-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 02/17/2024] [Indexed: 03/03/2024]
Abstract
BACKGROUND Mesenchymal stromal/stem cells (MSCs) have been suggested for salivary gland (SG) restoration following radio-induced salivary gland damage. This study aimed to determine the safety and effectiveness of MSC therapy on radio-induced SG damage and hypofunction in preclinical in vivo studies. METHODS PubMed and EMBASE were systematically searched for preclinical in vivo interventional studies evaluating efficacy and safety of MSC treatment following radio-induced salivary gland damage published before 10th of January 2022. The primary endpoint was salivary flow rate (SFR) evaluated in a meta-analysis. The study protocol was published and registered on PROSPERO ( www.crd.ac.uk/prospero ), registration number CRD42021227336. RESULTS A total of 16 preclinical in vivo studies were included for qualitative analysis (858 experimental animals) and 13 in the meta-analysis (404 experimental animals). MSCs originated from bone marrow (four studies), adipose tissue (10 studies) and salivary gland tissue (two studies) and were administered intravenously (three studies), intra-glandularly (11 studies) or subcutaneously (one study). No serious adverse events were reported. The overall effect on SFR was significantly increased with a standardized mean difference (SMD) of 6.99 (95% CI: 2.55-11.42). Studies reported improvements in acinar tissue, vascular areas and paracrine factors. CONCLUSION In conclusion, this systematic review and meta-analysis showed a significant effect of MSC therapy for restoring SG functioning and regenerating SG tissue following radiotherapy in preclinical in vivo studies without serious adverse events. MSC therapy holds significant therapeutic potential in the treatment of radio-induced xerostomia, but comprehensive, randomized, clinical trials in humans are required to ascertain their efficacy in a clinical setting.
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Affiliation(s)
- Amanda-Louise Fenger Carlander
- Department of Otolaryngology and Audiology, Head and Neck Surgery, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark.
- Department of Otolaryngology, Head and Neck Surgery and Audiology, Rigshospitalet, Copenhagen University hospital, Copenhagen, Denmark.
| | - Anders Kierkegaard Gundestrup
- Department of Otolaryngology and Audiology, Head and Neck Surgery, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark
| | - Per Marcus Jansson
- Department of Otolaryngology and Audiology, Head and Neck Surgery, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark
| | - Bjarke Follin
- Cardiology Stem Cell Centre, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark
| | - Cecilie Hoeeg
- Cardiology Stem Cell Centre, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark
| | - Birgitte Saima Kousholt
- Department of Clinical Medicine, Aarhus University Group for Understanding Systematic Reviews and Meta analyses in Translational Preclinical Science, Aarhus University, Copenhagen, Denmark
| | - Rasmus Tolstrup Larsen
- Department of Occupational Therapy and Physiotherapy, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark
- Section of Social Medicine, Department of Public Health, University of Copenhagen, Copenhagen, Denmark
| | - Kathrine Kronberg Jakobsen
- Department of Otolaryngology and Audiology, Head and Neck Surgery, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark
| | - Susie Rimborg
- The Royal Danish Library, Copenhagen University Library, Copenhagen, Denmark
| | - Anne Fischer-Nielsen
- Department of Immunology, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark
| | - Christian Grønhøj
- Department of Otolaryngology and Audiology, Head and Neck Surgery, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark
| | - Christian von Buchwald
- Department of Otolaryngology and Audiology, Head and Neck Surgery, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark
| | - Charlotte Duch Lynggaard
- Department of Otolaryngology and Audiology, Head and Neck Surgery, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark
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Niu X, Xu X, Xu C, Cheuk YC, Rong R. Recent Advances of MSCs in Renal IRI: From Injury to Renal Fibrosis. Bioengineering (Basel) 2024; 11:432. [PMID: 38790298 PMCID: PMC11117619 DOI: 10.3390/bioengineering11050432] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/29/2024] [Revised: 04/21/2024] [Accepted: 04/23/2024] [Indexed: 05/26/2024] Open
Abstract
Renal fibrosis is a pathological endpoint of maladaptation after ischemia-reperfusion injury (IRI), and despite many attempts, no good treatment has been achieved so far. At the core of renal fibrosis is the differentiation of various types of cells into myofibroblasts. MSCs were once thought to play a protective role after renal IRI. However, growing evidence suggests that MSCs have a two-sided nature. In spite of their protective role, in maladaptive situations, MSCs start to differentiate towards myofibroblasts, increasing the myofibroblast pool and promoting renal fibrosis. Following renal IRI, it has been observed that Bone Marrow-Derived Mesenchymal Stem Cells (BM-MSCs) and Renal Resident Mesenchymal Stem Cells (RR-MSCs) play important roles. This review presents evidence supporting their involvement, discusses their potential mechanisms of action, and suggests several new targets for future research.
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Affiliation(s)
- Xinhao Niu
- Department of Urology, Zhongshan Hospital, Fudan University, Shanghai 200032, China
- Shanghai Key Laboratory of Organ Transplantation, Shanghai 200032, China
| | - Xiaoqing Xu
- Department of Urology, Zhongshan Hospital, Fudan University, Shanghai 200032, China
- Shanghai Key Laboratory of Organ Transplantation, Shanghai 200032, China
| | - Cuidi Xu
- Department of Urology, Zhongshan Hospital, Fudan University, Shanghai 200032, China
- Shanghai Key Laboratory of Organ Transplantation, Shanghai 200032, China
| | - Yin Celeste Cheuk
- Department of Urology, Zhongshan Hospital, Fudan University, Shanghai 200032, China
- Shanghai Key Laboratory of Organ Transplantation, Shanghai 200032, China
| | - Ruiming Rong
- Department of Urology, Zhongshan Hospital, Fudan University, Shanghai 200032, China
- Shanghai Key Laboratory of Organ Transplantation, Shanghai 200032, China
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Yan Z, Shi Y, Yang R, Xue J, Fu C. ELABELA-derived peptide ELA13 attenuates kidney fibrosis by inhibiting the Smad and ERK signaling pathways. J Zhejiang Univ Sci B 2024; 25:341-353. [PMID: 38584095 PMCID: PMC11009446 DOI: 10.1631/jzus.b2300033] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2023] [Accepted: 04/13/2023] [Indexed: 04/09/2024]
Abstract
Kidney fibrosis is an inevitable result of various chronic kidney diseases (CKDs) and significantly contributes to end-stage renal failure. Currently, there is no specific treatment available for renal fibrosis. ELA13 (amino acid sequence: RRCMPLHSRVPFP) is a conserved region of ELABELA in all vertebrates; however, its biological activity has been very little studied. In the present study, we evaluated the therapeutic effect of ELA13 on transforming growth factor-β1 (TGF-β1)-treated NRK-52E cells and unilateral ureteral occlusion (UUO) mice. Our results demonstrated that ELA13 could improve renal function by reducing creatinine and urea nitrogen content in serum, and reduce the expression of fibrosis biomarkers confirmed by Masson staining, immunohistochemistry, real-time polymerase chain reaction (RT-PCR), and western blot. Inflammation biomarkers were increased after UUO and decreased by administration of ELA13. Furthermore, we found that the levels of essential molecules in the mothers against decapentaplegic (Smad) and extracellular signal-regulated kinase (ERK) pathways were reduced by ELA13 treatment in vivo and in vitro. In conclusion, ELA13 protected against kidney fibrosis through inhibiting the Smad and ERK signaling pathways and could thus be a promising candidate for anti-renal fibrosis treatment.
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Affiliation(s)
- Zhibin Yan
- Zhejiang Provincial Key Laboratory of Silkworm Bioreactor and Biomedicine, College of Life Sciences and Medicine, Zhejiang Sci-Tech University, Hangzhou 310018, China
| | - Ying Shi
- State Key Laboratory of Applied Organic Chemistry, College of Chemistry and Chemical Engineering, Lanzhou University, Lanzhou 730000, China
| | - Runling Yang
- Key Laboratory of Preclinical Study for New Drugs of Gansu Province, School of Basic Medical Sciences & Research Unit of Peptide Science, Chinese Academy of Medical Sciences, 2019RU066, Lanzhou University, Lanzhou 730000, China
| | - Jijun Xue
- State Key Laboratory of Applied Organic Chemistry, College of Chemistry and Chemical Engineering, Lanzhou University, Lanzhou 730000, China
| | - Caiyun Fu
- Zhejiang Provincial Key Laboratory of Silkworm Bioreactor and Biomedicine, College of Life Sciences and Medicine, Zhejiang Sci-Tech University, Hangzhou 310018, China.
- Key Laboratory of Preclinical Study for New Drugs of Gansu Province, School of Basic Medical Sciences & Research Unit of Peptide Science, Chinese Academy of Medical Sciences, 2019RU066, Lanzhou University, Lanzhou 730000, China.
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Zhu D, Sun Z, Wei J, Zhang Y, An W, Lin Y, Li X. BMP7-Loaded Human Umbilical Cord Mesenchymal Stem Cell-Derived Small Extracellular Vesicles Ameliorate Liver Fibrosis by Targeting Activated Hepatic Stellate Cells. Int J Nanomedicine 2024; 19:3475-3495. [PMID: 38623080 PMCID: PMC11018131 DOI: 10.2147/ijn.s450284] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2023] [Accepted: 03/23/2024] [Indexed: 04/17/2024] Open
Abstract
Purpose Human umbilical cord mesenchymal stem cell (hucMSC)-derived small extracellular vesicles (sEVs) are natural nanocarriers with promising potential in treating liver fibrosis and have widespread applications in the fields of nanomedicine and regenerative medicine. However, the therapeutic efficacy of natural hucMSC-sEVs is currently limited owing to their non-specific distribution in vivo and partial removal by mononuclear macrophages following systemic delivery. Thus, the therapeutic efficacy can be improved through the development of engineered hucMSC-sEVs capable to overcome these limitations. Patients and Methods To improve the anti-liver fibrosis efficacy of hucMSC-sEVs, we genetically engineered hucMSC-sEVs to overexpress the anti-fibrotic gene bone morphogenic protein 7 (BMP7) in parental cells. This was achieved using lentiviral transfection, following which BMP7-loaded hucMSC-sEVs were isolated through ultracentrifugation. First, the liver fibrosis was induced in C57BL/6J mice by intraperitoneal injection of 50% carbon tetrachloride (CCL4) twice a week for 8 weeks. These mice were subsequently treated with BMP7+sEVs via tail vein injection, and the anti-liver fibrosis effect of BMP7+sEVs was validated using small animal in vivo imaging, immunohistochemistry (IHC), tissue immunofluorescence, and enzyme-linked immunosorbent assay (ELISA). Finally, cell function studies were performed to confirm the in vivo results. Results Liver imaging and liver histopathology confirmed that the engineered hucMSC-sEVs could reach the liver of mice and aggregate around activated hepatic stellate cells (aHSCs) with a significantly stronger anti-liver fibrosis effect of BMP7-loaded hucMSC-sEVs compared to those of blank or negative control-transfected hucMSC-sEVs. In vitro, BMP7-loaded hucMSC-sEVs promoted the phenotypic reversal of aHSCs and inhibited their proliferation to enhance the anti-fibrotic effects. Conclusion These engineered BMP7-loaded hucMSC-sEVs offer a novel and promising strategy for the clinical treatment of liver fibrosis.
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Affiliation(s)
- Dan Zhu
- First Clinical Medical College, Lanzhou University, Lanzhou, People’s Republic of China
| | - Zongbin Sun
- First Clinical Medical College, Lanzhou University, Lanzhou, People’s Republic of China
| | - Jiayun Wei
- Gansu Province Key Laboratory of Biotherapy and Regenerative Medicine, First Hospital of Lanzhou University, Lanzhou University, Lanzhou, People’s Republic of China
| | - Yulin Zhang
- Gansu Province Key Laboratory of Biotherapy and Regenerative Medicine, First Hospital of Lanzhou University, Lanzhou University, Lanzhou, People’s Republic of China
| | - Wenjing An
- Gansu Province Key Laboratory of Biotherapy and Regenerative Medicine, First Hospital of Lanzhou University, Lanzhou University, Lanzhou, People’s Republic of China
| | - Yan Lin
- First Clinical Medical College, Lanzhou University, Lanzhou, People’s Republic of China
| | - Xun Li
- First Clinical Medical College, Lanzhou University, Lanzhou, People’s Republic of China
- Gansu Province Key Laboratory of Biotherapy and Regenerative Medicine, First Hospital of Lanzhou University, Lanzhou University, Lanzhou, People’s Republic of China
- General Surgery Department, First Hospital of Lanzhou University, Lanzhou University, Lanzhou, People’s Republic of China
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Song M, Ma L, Zhu Y, Gao H, Hu R. Umbilical cord mesenchymal stem cell-derived exosomes inhibits fibrosis in human endometrial stromal cells via miR-140-3p/FOXP1/Smad axis. Sci Rep 2024; 14:8321. [PMID: 38594471 PMCID: PMC11004014 DOI: 10.1038/s41598-024-59093-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2024] [Accepted: 04/08/2024] [Indexed: 04/11/2024] Open
Abstract
Endometrial fibrosis is the histologic appearance of intrauterine adhesion (IUA). Emerging evidences demonstrated umbilical cord mesenchymal stem cell-derived exosomes (UCMSC-exo) could alleviate endometrial fibrosis. But the specific mechanism is not clear. In this study, we explored the effect of UCMSC-exo on endometrial fibrosis, and investigated the possible role of miR-140-3p/FOXP1/Smad axis in anti-fibrotic properties of UCMSC-exo. UCMSC-exo were isolated and identified. Transforming growth factor-β (TGF-β) was used to induce human endometrial stromal cell (HESC) fibrosis. Dual luciferase assay was performed to verify the relationship between miR-140-3p and FOXP1. The expressions of fibrotic markers, SIP1, and p-Smad2/p-Smad3 in HESCs stimulated with UCMSC-exo were detected by western blot. In addition, the effects of miR-140-3p mimic, miR-140-3p inhibitor and FOXP1 over-expression on endometrial fibrosis were assessed. The isolated UCMSC-exo had a typical cup-shaped morphology and could be internalized into HESCs. The expressions of fibrotic markers were significantly increased by TGF-β, which was reversed by UCMSC-exo. MiR-140-3p in UCMSC-exo ameliorated TGf-β-induced HESCs fibrosis. FOXP1 was identified as the direct target of miR-140-3p, which could inversely regulate miR-140-3p's function on HESCs fibrosis. Furthermore, we demonstrated that miR-140-3p in UCMSC-exo regulated Smad signal pathway to exert the anti-fibrotic effect in HESCs. The anti-fibrotic effect of UCMSC-derived exosomes against HESC fibrosis was at least partially achieved by miR-140-3p/FOXP1/Smad axis.
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Affiliation(s)
- Mengling Song
- Department of Reproductive Medicine, General Hospital of Ningxia Medical University (The First Clinical Medical College of Ningxia Medical University), 804 Shengli Street, Xingqing Square, Yinchuan, 750004, Ningxia, China.
| | - Lijun Ma
- Department of Human Anatomy, Histology and Embryology, School of Basic Medicine, Ningxia Medical University, Yinchuan, 750004, Ningxia, China
| | - Yongzhao Zhu
- Institute of Medical Sciences, General Hospital of Ningxia Medical University, Yinchuan, 750004, Ningxia, China
| | - Huimin Gao
- General Hospital of Ningxia Medical University (the First Clinical Medical College of Ningxia Medical University), Yinchuan, 750004, Ningxia, China
| | - Rong Hu
- Department of Reproductive Medicine, General Hospital of Ningxia Medical University (The First Clinical Medical College of Ningxia Medical University), 804 Shengli Street, Xingqing Square, Yinchuan, 750004, Ningxia, China.
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Shi Q, Xia Y, Wu M, Pan Y, Wu S, Lin J, Kong Y, Yu Z, Zan X, Liu P, Xia J. Mi-BMSCs alleviate inflammation and fibrosis in CCl 4-and TAA-induced liver cirrhosis by inhibiting TGF-β/Smad signaling. Mater Today Bio 2024; 25:100958. [PMID: 38327975 PMCID: PMC10847164 DOI: 10.1016/j.mtbio.2024.100958] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2023] [Revised: 01/08/2024] [Accepted: 01/15/2024] [Indexed: 02/09/2024] Open
Abstract
Cirrhosis is an aggressive disease, and over 80 % of liver cancer patients are complicated by cirrhosis, which lacks effective therapies. Transplantation of mesenchymal stem cells (MSCs) is a promising option for treating liver cirrhosis. However, this therapeutic approach is often challenged by the low homing ability and short survival time of transplanted MSCs in vivo. Therefore, a novel and efficient cell delivery system for MSCs is urgently required. This new system can effectively extend the persistence and duration of MSCs in vivo. In this study, we present novel porous microspheres with microfluidic electrospray technology for the encapsulation of bone marrow-derived MSCs (BMSCs) in the treatment of liver cirrhosis. Porous microspheres loaded with BMSCs (Mi-BMSCs) exhibit good biocompatibility and demonstrate better anti-inflammatory properties than BMSCs alone. Mi-BMSCs significantly increase the duration of BMSCs and exert potent anti-inflammatory and anti-fibrosis effects against CCl4 and TAA-induced liver cirrhosis by targeting the TGF-β/Smad signaling pathway to ameliorate cirrhosis, which highlight the potential of Mi-BMSCs as a promising therapeutic approach for early liver cirrhosis.
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Affiliation(s)
- Qing Shi
- Key Laboratory of Diagnosis and Treatment of Severe Hepato-Pancreatic Diseases of Zhejiang Province, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, Zhejiang, China
| | - Yuhan Xia
- Key Laboratory of Diagnosis and Treatment of Severe Hepato-Pancreatic Diseases of Zhejiang Province, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, Zhejiang, China
| | - Minmin Wu
- Key Laboratory of Diagnosis and Treatment of Severe Hepato-Pancreatic Diseases of Zhejiang Province, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, Zhejiang, China
| | - Yating Pan
- Key Laboratory of Diagnosis and Treatment of Severe Hepato-Pancreatic Diseases of Zhejiang Province, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, Zhejiang, China
| | - Shiyi Wu
- Key Laboratory of Diagnosis and Treatment of Severe Hepato-Pancreatic Diseases of Zhejiang Province, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, Zhejiang, China
| | - Jiawei Lin
- Key Laboratory of Diagnosis and Treatment of Severe Hepato-Pancreatic Diseases of Zhejiang Province, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, Zhejiang, China
| | - Yifan Kong
- Key Laboratory of Diagnosis and Treatment of Severe Hepato-Pancreatic Diseases of Zhejiang Province, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, Zhejiang, China
| | - Zhijie Yu
- Wenzhou Key Laboratory of Hematology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, Zhejiang, China
| | - Xingjie Zan
- Wenzhou Institute, Wenzhou Key Laboratory of Perioperative Medicine, University of Chinese Academy of Sciences, Wenzhou, 325001, China
| | - Pixu Liu
- Key Laboratory of Diagnosis and Treatment of Severe Hepato-Pancreatic Diseases of Zhejiang Province, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, Zhejiang, China
| | - Jinglin Xia
- Key Laboratory of Diagnosis and Treatment of Severe Hepato-Pancreatic Diseases of Zhejiang Province, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, Zhejiang, China
- Liver Cancer Institute, Zhongshan Hospital of Fudan University, Shanghai, 200032, China
- National Clinical Research Center for Interventional Medicine, Shanghai, 200032, China
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49
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Jussila A, Zhang B, Kirti S, Atit R. Tissue fibrosis associated depletion of lipid-filled cells. Exp Dermatol 2024; 33:e15054. [PMID: 38519432 PMCID: PMC10977660 DOI: 10.1111/exd.15054] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2023] [Revised: 02/06/2024] [Accepted: 02/29/2024] [Indexed: 03/24/2024]
Abstract
Fibrosis is primarily described as the deposition of excessive extracellular matrix, but in many tissues it also involves a loss of lipid or lipid-filled cells. Lipid-filled cells are critical to tissue function and integrity in many tissues including the skin and lungs. Thus, loss or depletion of lipid-filled cells during fibrogenesis, has implications for tissue function. In some contexts, lipid-filled cells can impact ECM composition and stability, highlighting their importance in fibrotic transformation. Recent papers in fibrosis address this newly recognized fibrotic lipodystrophy phenomenon. Even in disparate tissues, common mechanisms are emerging to explain fibrotic lipodystrophy. These findings have implications for fibrosis in tissues composed of fibroblast and lipid-filled cell populations such as skin, lung, and liver. In this review, we will discuss the roles of lipid-containing cells, their reduction/loss during fibrotic transformation, and the mechanisms of that loss in the skin and lungs.
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Affiliation(s)
- Anna Jussila
- Department of Biology, College of Arts and Sciences, Case Western Reserve University, Cleveland, Ohio, USA
| | - Brian Zhang
- Department of Biology, College of Arts and Sciences, Case Western Reserve University, Cleveland, Ohio, USA
| | - Sakin Kirti
- Department of Biology, College of Arts and Sciences, Case Western Reserve University, Cleveland, Ohio, USA
| | - Radhika Atit
- Department of Biology, College of Arts and Sciences, Case Western Reserve University, Cleveland, Ohio, USA
- Department of Genetics and Genome Sciences, School of Medicine, Case Western Reserve University, Cleveland, Ohio, USA
- Department of Dermatology, School of Medicine, Case Western Reserve University, Cleveland, Ohio, USA
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50
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Yuan HL, Chang L, Fan WW, Liu X, Li Q, Tian C, Zhao J, Li ZA, Pan XH, Zhu XQ. Application and challenges of stem cells in cardiovascular aging. Regen Ther 2024; 25:1-9. [PMID: 38108044 PMCID: PMC10724492 DOI: 10.1016/j.reth.2023.11.009] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2023] [Revised: 10/17/2023] [Accepted: 11/16/2023] [Indexed: 12/19/2023] Open
Abstract
With the rapid development of society and the economy, population aging has become a common challenge faced by many countries in the world today. Structural and functional changes in the cardiovascular system can occur with age, increasing the incidence and severity of cardiovascular diseases in older adults. Due to the limited regenerative capacity of myocardial cells, myocardial infarction and its resulting heart failure and congenital heart disease have become the number one killer of human health. At present, the treatment of cardiovascular diseases includes drug therapy and nondrug therapy. Nondrug therapy mainly includes minimally invasive interventional therapy, surgical diagnosis and treatment, and cell therapy. Long-term drug treatment may cause headache due to vasodilation, lower blood pressure, digestive system dysfunction and other side effects. Surgical treatment is traumatic, difficult to treat, and expensive. In recent years, stem cell therapy has exhibited broad application prospects in basic and clinical research on cardiovascular disease because of its plasticity, self-renewal and multidirectional differentiation potential. Therefore, this paper looks at stem cell therapy for diseases, reviews recent advances in the mechanism and clinical transformation of cardiovascular aging and related diseases in China, and briefly discusses the development trend and future prospects of cardiovascular aging research.
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Affiliation(s)
- He-Ling Yuan
- The Basic Medical Laboratory of the 920th Hospital of Joint Logistics Support Force of PLA, The Transfer Medicine Key Laboratory of Cell Therapy Technology of Yunan Province, The Integrated Engineering Laboratory of Cell Biological Medicine of State and Regions, Kunming 650032, Yunnan Province, China
- Kunming Medical University, Kunming, Yunnan 650500, China
| | - Le Chang
- The Basic Medical Laboratory of the 920th Hospital of Joint Logistics Support Force of PLA, The Transfer Medicine Key Laboratory of Cell Therapy Technology of Yunan Province, The Integrated Engineering Laboratory of Cell Biological Medicine of State and Regions, Kunming 650032, Yunnan Province, China
| | - Wei-Wen Fan
- The Basic Medical Laboratory of the 920th Hospital of Joint Logistics Support Force of PLA, The Transfer Medicine Key Laboratory of Cell Therapy Technology of Yunan Province, The Integrated Engineering Laboratory of Cell Biological Medicine of State and Regions, Kunming 650032, Yunnan Province, China
- Kunming Medical University, Kunming, Yunnan 650500, China
| | - Xin Liu
- The Basic Medical Laboratory of the 920th Hospital of Joint Logistics Support Force of PLA, The Transfer Medicine Key Laboratory of Cell Therapy Technology of Yunan Province, The Integrated Engineering Laboratory of Cell Biological Medicine of State and Regions, Kunming 650032, Yunnan Province, China
- Kunming Medical University, Kunming, Yunnan 650500, China
| | - Qiang Li
- The Basic Medical Laboratory of the 920th Hospital of Joint Logistics Support Force of PLA, The Transfer Medicine Key Laboratory of Cell Therapy Technology of Yunan Province, The Integrated Engineering Laboratory of Cell Biological Medicine of State and Regions, Kunming 650032, Yunnan Province, China
- Kunming Medical University, Kunming, Yunnan 650500, China
| | - Chuan Tian
- The Basic Medical Laboratory of the 920th Hospital of Joint Logistics Support Force of PLA, The Transfer Medicine Key Laboratory of Cell Therapy Technology of Yunan Province, The Integrated Engineering Laboratory of Cell Biological Medicine of State and Regions, Kunming 650032, Yunnan Province, China
| | - Jing Zhao
- The Basic Medical Laboratory of the 920th Hospital of Joint Logistics Support Force of PLA, The Transfer Medicine Key Laboratory of Cell Therapy Technology of Yunan Province, The Integrated Engineering Laboratory of Cell Biological Medicine of State and Regions, Kunming 650032, Yunnan Province, China
| | - Zi-An Li
- The Basic Medical Laboratory of the 920th Hospital of Joint Logistics Support Force of PLA, The Transfer Medicine Key Laboratory of Cell Therapy Technology of Yunan Province, The Integrated Engineering Laboratory of Cell Biological Medicine of State and Regions, Kunming 650032, Yunnan Province, China
| | - Xing-Hua Pan
- The Basic Medical Laboratory of the 920th Hospital of Joint Logistics Support Force of PLA, The Transfer Medicine Key Laboratory of Cell Therapy Technology of Yunan Province, The Integrated Engineering Laboratory of Cell Biological Medicine of State and Regions, Kunming 650032, Yunnan Province, China
| | - Xiang-Qing Zhu
- The Basic Medical Laboratory of the 920th Hospital of Joint Logistics Support Force of PLA, The Transfer Medicine Key Laboratory of Cell Therapy Technology of Yunan Province, The Integrated Engineering Laboratory of Cell Biological Medicine of State and Regions, Kunming 650032, Yunnan Province, China
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