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Karam M, Ortega-Gascó A, Tornero D. Emerging Insights into Brain Inflammation: Stem-Cell-Based Approaches for Regenerative Medicine. Int J Mol Sci 2025; 26:3275. [PMID: 40244116 PMCID: PMC11989304 DOI: 10.3390/ijms26073275] [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: 02/28/2025] [Revised: 03/27/2025] [Accepted: 03/28/2025] [Indexed: 04/18/2025] Open
Abstract
Neuroinflammation is a complex immune response triggered by brain injury or pathological stimuli, and is highly exacerbated in neurodegenerative diseases. It plays a dual role in the central nervous system, promoting repair in acute stages while aggravating disease progression by contributing to neuronal loss, synaptic dysfunction, and glial dysregulation in chronic phases. Inflammatory responses are mainly orchestrated by microglia and infiltrated monocytes, which, when dysregulated, not only harm existing neurons, but also impair the survival and differentiation of neural stem and progenitor cells in the affected brain regions. Modulating neuroinflammation is crucial for harnessing its protective functions while minimizing its detrimental effects. Current therapeutic strategies focus on fine-tuning inflammatory responses through pharmacological agents, bioactive molecules, and stem cell-based therapies. These approaches aim to restore immune homeostasis, support neuroprotection, and promote regeneration in various neurological disorders. However, animal models sometimes fail to reproduce human-specific inflammatory responses in the brain. In this context, stem-cell-derived models provide a powerful tool to study neuroinflammatory mechanisms in a patient-specific and physiologically relevant context. These models facilitate high-throughput screening, personalized medicine, and the development of targeted therapies while addressing the limitations of traditional animal models, paving the way for more targeted and effective treatments.
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Affiliation(s)
- Marie Karam
- Laboratory of Neural Stem Cells and Brain Damage, Department of Biomedical Sciences, Institute of Neurosciences, University of Barcelona, 08036 Barcelona, Spain
- Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), 08036 Barcelona, Spain
| | - Alba Ortega-Gascó
- Laboratory of Neural Stem Cells and Brain Damage, Department of Biomedical Sciences, Institute of Neurosciences, University of Barcelona, 08036 Barcelona, Spain
- Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), 08036 Barcelona, Spain
| | - Daniel Tornero
- Laboratory of Neural Stem Cells and Brain Damage, Department of Biomedical Sciences, Institute of Neurosciences, University of Barcelona, 08036 Barcelona, Spain
- Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), 08036 Barcelona, Spain
- Centro de Investigación Biomédica en Red Sobre Enfermedades Neurodegenerativas (CIBERNED), 28029 Madrid, Spain
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Wang L, Zhao R, Xiao K, Zhou Y, Liu Q, Yu K. Long non-coding RNA NRIR inhibits osteogenesis in peri-implantitis by promoting NLRP3 inflammasome-mediated macrophage pyroptosis. Int Immunopharmacol 2025; 148:114180. [PMID: 39874847 DOI: 10.1016/j.intimp.2025.114180] [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: 10/29/2024] [Revised: 01/01/2025] [Accepted: 01/24/2025] [Indexed: 01/30/2025]
Abstract
BACKGROUND Peri-implantitis is an inflammatory bone disease that seriously affects the health of dental implants. Pyroptosis plays an important role in peri-implantitis and inhibition of pyroptosis may point out a new direction for treating the disease. The long non-coding RNA Negative Regulator of Interferon Response (lncRNA NRIR) is closely related to peri-implantitis and may be involved in the process of pyroptosis. The aim of this study was to explore the regulatory mechanism of NRIR in peri-implantitis. METHODS The expression levels of NRIR and its target gene Cytidine Monophosphate Kinase 2 (CMPK2) in the gingiva surrounding infected implants were explored using bioinformatics analysis. Lipopolysaccharide (LPS)-stimulated macrophage pyroptosis model and a rat model of LPS-induced peri-implantitis were constructed. We used small interfering RNA (siRNA) and plasmids to regulate the expression of NRIR and CMPK2 in macrophages. We used various ways to evaluate inflammation, pyroptosis, osteogenic differentiation, including RT-qPCR, Western blotting, ELISA, Immunofluorescence staining, ALP activity, ARS staining, and Immunohistochemical analysis. RESULTS Initially, we used bioinformatics method to identify high expression of NRIR and CMPK2 in the gingiva surrounding infected implants. Both the knockdown of NRIR and CMPK2 could markedly suppress the expression of NLRP3 inflammasome and the release of interleukin-1β (IL-1β) in LPS-stimulated THP-1-derived macrophages. Meanwhile, upregulation of CMPK2 reversed the negative effects of downregulation of NRIR on macrophage pyroptosis. Functionally, NRIR knockdown in macrophages promoted osteogenic differentiation of bone marrow mesenchymal stem cells (BMSCs). Notably, we identified that IL-1β protein could reverse this trend. Mechanistically, NRIR regulated NLRP3 inflammasome-mediated pyroptosis of macrophages through the NF-κB pathway. Furthermore, the in vivo experiments demonstrated that silencing NRIR inhibited the expression of NLRP3 inflammasome and IL-1β, but promoted the expression of osteogenic differentiation related factors in tissue surrounding the implants. CONCLUSION This study demonstrated that NRIR played a crucial role in the crosstalk between macrophage pyroptosis and BMSCs osteogenic differentiation, thus providing a possible therapeutic target against inflammatory bone disease including peri-implantitis.
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Affiliation(s)
- Lan Wang
- The Affiliated Stomatological Hospital, Southwest Medical University, Luzhou 646000 Sichuan, China.
| | - Renshengjie Zhao
- The Affiliated Stomatological Hospital, Southwest Medical University, Luzhou 646000 Sichuan, China.
| | - Keming Xiao
- The Affiliated Stomatological Hospital, Southwest Medical University, Luzhou 646000 Sichuan, China.
| | - Yang Zhou
- The Affiliated Stomatological Hospital, Southwest Medical University, Luzhou 646000 Sichuan, China.
| | - Qiqi Liu
- The Affiliated Stomatological Hospital, Southwest Medical University, Luzhou 646000 Sichuan, China.
| | - Ke Yu
- The Affiliated Stomatological Hospital, Southwest Medical University, Luzhou 646000 Sichuan, China.
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Valencia J, Yáñez RM, Muntión S, Fernández-García M, Martín-Rufino JD, Zapata AG, Bueren JA, Vicente Á, Sánchez-Guijo F. Improving the therapeutic profile of MSCs: Cytokine priming reduces donor-dependent heterogeneity and enhances their immunomodulatory capacity. Front Immunol 2025; 16:1473788. [PMID: 40034706 PMCID: PMC11872697 DOI: 10.3389/fimmu.2025.1473788] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2024] [Accepted: 01/28/2025] [Indexed: 03/05/2025] Open
Abstract
Introduction MSCs exhibit regenerative, anti-inflammatory and immunomodulatory properties due to the large amount of cytokines, chemokines and growth factors they secrete. MSCs have been extensively evaluated in clinical trials, however, in some cases their therapeutic effects are variable. Therefore, strategies to improve their therapeutic potential, such as preconditioning with proinflammatory factors, have been proposed. Several priming approaches have provided non-conclusive results, and the duration of priming effects on MSC properties or their response to a second inflammatory stimulus have not been fully addressed. Methods We have investigated the impact of triple cytokine priming in MSCs on their characterization and viability, their transcriptomic profile, the functionality of innate and acquired immune cells, as well as the maintenance of the response to priming over time, their subsequent responsiveness to a second inflammatory stimulus. Results Priming MSCs with proinflammatory cytokines (CK-MSCs) do not modify the differentiation capacity of MSCs, nor their immunophenotype and viability. Moreover, cytokine priming enhances the anti-inflammatory and immunomodulatory properties of MSCs against NK and dendritic cells, while maintaining the same T cell immunomodulatory capacity as unstimulated MSCs. Thus, they decrease T-lymphocytes and NK cell proliferation, inhibit the differentiation and allostimulatory capacity of dendritic cells and promote the differentiation of monocytes with an immunosuppressive profile. In addition, we have shown for the first time that proinflammatory priming reduces the variability between different donors and MSC origins. Finally, the effect on CK-MSC is maintained over time and even after a secondary inflammatory stimulus. Conclusions Cytokine-priming improves the therapeutic potential of MSCs and reduces inter-donor variability.
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Affiliation(s)
- Jaris Valencia
- Department of Cell Biology, School of Medicine, Complutense University of Madrid, Madrid, Spain
- Heath Research Institute Hospital Clínico San Carlos (IdISSC), Madrid, Spain
- RICORS TERAV, Instituto de Salud Carlos III (ISCIII), Madrid, Spain
| | - Rosa M. Yáñez
- RICORS TERAV, Instituto de Salud Carlos III (ISCIII), Madrid, Spain
- Hematopoietic Innovative Therapies Division, Centro de Investigaciones Energéticas, Medioambientales y Tecnológicas (CIEMAT) and Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Madrid, Spain
- Heath Research Institute-Fundación Jiménez Díaz (IIS-FJD), Madrid, Spain
| | - Sandra Muntión
- RICORS TERAV, Instituto de Salud Carlos III (ISCIII), Madrid, Spain
- Department of Medicine, University of Salamanca and Cell Therapy Area and Hematology Department, IBSAL-University Hospital of Salamanca, Salamanca, Spain
- Regenerative Medicine and Cellular Therapy Network Center of Castilla y León, Salamanca, Spain
| | - María Fernández-García
- RICORS TERAV, Instituto de Salud Carlos III (ISCIII), Madrid, Spain
- Hematopoietic Innovative Therapies Division, Centro de Investigaciones Energéticas, Medioambientales y Tecnológicas (CIEMAT) and Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Madrid, Spain
- Heath Research Institute-Fundación Jiménez Díaz (IIS-FJD), Madrid, Spain
| | - Jorge Diego Martín-Rufino
- Division of Hematology/Oncology, Boston Children’s Hospital and Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, United States
- Broad Institute of MIT and Harvard, Cambridge, MA, United States
| | - Agustín G. Zapata
- RICORS TERAV, Instituto de Salud Carlos III (ISCIII), Madrid, Spain
- Department of Cell Biology, Faculty of Biology, Complutense University of Madrid, Madrid, Spain
- Heath Research Institute Hospital 12 de Octubre (I+12), Madrid, Spain
| | - Juan A. Bueren
- RICORS TERAV, Instituto de Salud Carlos III (ISCIII), Madrid, Spain
- Hematopoietic Innovative Therapies Division, Centro de Investigaciones Energéticas, Medioambientales y Tecnológicas (CIEMAT) and Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Madrid, Spain
- Heath Research Institute-Fundación Jiménez Díaz (IIS-FJD), Madrid, Spain
| | - Ángeles Vicente
- Department of Cell Biology, School of Medicine, Complutense University of Madrid, Madrid, Spain
- RICORS TERAV, Instituto de Salud Carlos III (ISCIII), Madrid, Spain
- Heath Research Institute Hospital 12 de Octubre (I+12), Madrid, Spain
| | - Fermín Sánchez-Guijo
- RICORS TERAV, Instituto de Salud Carlos III (ISCIII), Madrid, Spain
- Department of Medicine, University of Salamanca and Cell Therapy Area and Hematology Department, IBSAL-University Hospital of Salamanca, Salamanca, Spain
- Regenerative Medicine and Cellular Therapy Network Center of Castilla y León, Salamanca, Spain
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López-Romero LC, Broseta JJ, Roca-Marugán M, Máñez Ramírez N, Hernández-Jaras J. Comprehensive Metabolomic Profiling in Adults with X-Linked Hypophosphatemia: A Case-Control Study. Biomedicines 2024; 13:22. [PMID: 39857606 PMCID: PMC11759187 DOI: 10.3390/biomedicines13010022] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2024] [Revised: 12/19/2024] [Accepted: 12/21/2024] [Indexed: 01/27/2025] Open
Abstract
BACKGROUND X-linked hypophosphatemia (XLH) is a rare disorder characterized by elevated levels of fibroblast growth factor 23 (FGF-23), leading to hypophosphatemia and complications in diagnosis due to its clinical heterogeneity. Metabolomic analysis, which examines metabolites as the final products of cellular processes, is a powerful tool for identifying in vivo biochemical changes, serving as biomarkers of pathological abnormalities, and revealing previously uncharted metabolic pathways. METHODS A multicenter cross-sectional case-control study of adult patients diagnosed with XLH was conducted. Serum metabolomic analysis was performed with an Ultra-Performance Liquid Chromatography equipment (UPLC) coupled to a high-resolution mass spectrometer (MS). An analysis of metabolic pathways using MetaboAnalyst version 5.0 and a quantitative enrichment analysis (QEA) was performed. We employed multivariate statistical models, including a principal component analysis (PCA) and an orthogonal partial least squares discriminant analysis (OPLS-DA) regression model. RESULTS A cohort of 20 XLH patients and 19 control subjects were recruited. A total of 104 metabolites were identified. The differential metabolites identified included glycine, taurine, hypotaurine, phosphoethanolamine, pyruvate, guanidoacetic acid, serine, succinate, 2-aminobutyric acid, glutamine, 2-hydroxyvaleric acid, methionine, ornithine, phosphorylcholine, hypoxanthine, lysine, and N-methylnicotinamide. Enrichment analysis identified disturbances in key metabolic pathways, including phosphatidylethanolamine biosynthesis, sphingolipid metabolism, and phosphatidylcholine biosynthesis. Additionally, pathways related to cysteine metabolism, glycolysis, and pyruvate metabolism. CONCLUSIONS This study identified significant differences in the metabolic profiles of individuals with XLH compared to healthy controls. These findings enhance understanding of potential pathogenic mechanisms and offer a metabolic basis for further in-depth investigations into XLH.
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Affiliation(s)
| | - José Jesús Broseta
- Department of Nephrology and Renal Transplantation, Hospital Clínic of Barcelona, 08036 Barcelona, Spain;
| | - Marta Roca-Marugán
- Metabolomics Unit, Health Research Institute Hospital La Fe (IIS La Fe), 46026 Valencia, Spain;
| | - Noemí Máñez Ramírez
- Day Hospital Hematology and Oncology, Nursing Service, Hospital Universitari i Politècnic La Fe, 46026 Valencia, Spain;
| | - Julio Hernández-Jaras
- Department of Nephrology, Hospital Universitari i Politècnic La Fe, 46026 Valencia, Spain;
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Afkhami H, Yarahmadi A, Bostani S, Yarian N, Haddad MS, Lesani SS, Aghaei SS, Zolfaghari MR. Converging frontiers in cancer treatment: the role of nanomaterials, mesenchymal stem cells, and microbial agents-challenges and limitations. Discov Oncol 2024; 15:818. [PMID: 39707033 DOI: 10.1007/s12672-024-01590-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/23/2024] [Accepted: 11/14/2024] [Indexed: 12/23/2024] Open
Abstract
Globally, people widely recognize cancer as one of the most lethal diseases due to its high mortality rates and lack of effective treatment options. Ongoing research into cancer therapies remains a critical area of inquiry, holding significant social relevance. Currently used treatment, such as chemotherapy, radiation, or surgery, often suffers from other problems like damaging side effects, inaccuracy, and the lack of ability to clear tumors. Conventional cancer therapies are usually imprecise and ineffective and usually develop resistance to treatments and cancer recurs. Cancer patients need fresh and innovative treatment that can reduce side effects while maximizing effectiveness. In recent decades several breakthroughs in these, and other areas of medical research, have paved the way for new avenues of fighting cancer including more focused and more effective alternatives. This study reviews exciting possibilities for mesenchymal stem cells (MSCs), nanomaterials, and microbial agents in the modern realm of cancer treatment. Nanoparticles (NPs) have demonstrated surprisingly high potential. They improve drug delivery systems (DDS) significantly, enhance imaging techniques remarkably, and target cancer cells selectively while protecting healthy tissues. MSCs play a double role in tissue repair and are a vehicle for novel cancer treatments such as gene treatments or NPs loaded with therapeutic agents. Additionally, therapies utilizing microbial agents, particularly those involving bacteria, offer an inventive approach to cancer treatment. This review investigates the potential of nanomaterials, MSCs, and microbial agents in addressing the shortcomings of conventional cancer therapies. We will also discuss the challenges and limitations of using these therapeutic approaches.
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Affiliation(s)
- Hamed Afkhami
- Cellular and Molecular Research Center, Qom University of Medical Sciences, Qom, Iran
- Nervous System Stem Cells Research Center, Semnan University of Medical Sciences, Semnan, Iran
- Department of Medical Microbiology, Faculty of Medicine, Shahed University, Tehran, Iran
| | - Aref Yarahmadi
- Department of Biology, Khorramabad Branch, Islamic Azad University, Khorramabad, Iran
| | - Shoroq Bostani
- Department of Microbiology, Qom Branch, Islamic Azad University, Qom, Iran
| | - Nahid Yarian
- Department of Microbiology, Qom Branch, Islamic Azad University, Qom, Iran
| | | | - Shima Sadat Lesani
- Department of Microbiology, Qom Branch, Islamic Azad University, Qom, Iran
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Schmidt K, Lerm D, Schmidt A, Dickel N, Fiedler J, Thum T, Kunz M. Automated High-Throughput Live Cell Monitoring of Scratch Wound Closure. Biomed Eng Comput Biol 2024; 15:11795972241295619. [PMID: 40291412 PMCID: PMC12032466 DOI: 10.1177/11795972241295619] [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: 07/02/2024] [Accepted: 10/09/2024] [Indexed: 04/30/2025] Open
Abstract
Background Angiogenesis and regenerative wound healing rely on the promotion of distinct endothelial cell phenotypes exhibiting increased migratory capacity. Monitoring of these hallmark events in vitro is invaluable for discovering novel therapeutics. However, respective methods often lack a high-throughput character or accurate analysis tools, which are essential for effective screening suitability. Methods and results We stained nuclei of confluent human umbilical vein endothelial cells with Hoechst33342 prior to induction of an artificial scratch wound. Treatments with various growth factors and several concentrations of nintedanib were performed to microscopically evaluate impacts on wound closure. We developed 2 tools for automated analysis of wound closure image sets. Utilizing cell-free area measuring or cellular density evaluation, respectively, migration behavior was assessed well-wise for each time point. We identified pro-migratory effects of interleukin 1β as well as inhibitory actions of nintedanib. Hoechst33342 staining allowed for cell counting which was excluded as a contributing factor to wound closure in our assay. Conclusion We developed a cost-effective, high-throughput pipeline for monitoring cell migration in vitro. We believe that our protocol will accelerate pre-clinical screenings not only for medications targeting endothelial wound closure but also drug discovery research in a broad range of diseases involving cellular migration.
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Affiliation(s)
- Kevin Schmidt
- Institute of Molecular and Translational Therapeutic Strategies, Hannover Medical School, Hannover, Germany
- Fraunhofer Institute for Toxicology and Experimental Medicine ITEM, Hannover, Germany
- Fraunhofer Cluster of Excellence Immune-Mediated Diseases, Hannover, Germany
| | - Dominik Lerm
- Chair of Medical Informatics, Friedrich-Alexander University of Erlangen-Nürnberg, Erlangen, Germany
| | - Arne Schmidt
- Institute of Molecular and Translational Therapeutic Strategies, Hannover Medical School, Hannover, Germany
- Fraunhofer Institute for Toxicology and Experimental Medicine ITEM, Hannover, Germany
- Fraunhofer Cluster of Excellence Immune-Mediated Diseases, Hannover, Germany
| | - Nicholas Dickel
- Chair of Medical Informatics, Friedrich-Alexander University of Erlangen-Nürnberg, Erlangen, Germany
| | - Jan Fiedler
- Institute of Molecular and Translational Therapeutic Strategies, Hannover Medical School, Hannover, Germany
- Fraunhofer Institute for Toxicology and Experimental Medicine ITEM, Hannover, Germany
- Fraunhofer Cluster of Excellence Immune-Mediated Diseases, Hannover, Germany
| | - Thomas Thum
- Institute of Molecular and Translational Therapeutic Strategies, Hannover Medical School, Hannover, Germany
- Fraunhofer Institute for Toxicology and Experimental Medicine ITEM, Hannover, Germany
- Fraunhofer Cluster of Excellence Immune-Mediated Diseases, Hannover, Germany
| | - Meik Kunz
- Fraunhofer Cluster of Excellence Immune-Mediated Diseases, Hannover, Germany
- Chair of Medical Informatics, Friedrich-Alexander University of Erlangen-Nürnberg, Erlangen, Germany
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Shan XQ, Zhao L. Enhancing the functionality of mesenchymal stem cells: An attractive treatment strategy for metabolic dysfunction-associated steatotic liver disease? World J Stem Cells 2024; 16:854-859. [PMID: 39493827 PMCID: PMC11525648 DOI: 10.4252/wjsc.v16.i10.854] [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: 07/21/2024] [Revised: 09/06/2024] [Accepted: 10/08/2024] [Indexed: 10/25/2024] Open
Abstract
The intrinsic heterogeneity of metabolic dysfunction-associated fatty liver disease (MASLD) and the intricate pathogenesis have impeded the advancement and clinical implementation of therapeutic interventions, underscoring the critical demand for novel treatments. A recent publication by Li et al proposes mesenchymal stem cells as promising effectors for the treatment of MASLD. This editorial is a continuum of the article published by Jiang et al which focuses on the significance of strategies to enhance the functionality of mesenchymal stem cells to improve efficacy in curing MASLD, including physical pretreatment, drug or chemical pretreatment, pretreatment with bioactive substances, and genetic engineering.
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Affiliation(s)
- Xiao-Qian Shan
- First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, National Clinical Research Center for Chinese Medicine Acupuncture and Moxibustion, Tianjin 300381, China
| | - Lan Zhao
- First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, National Clinical Research Center for Chinese Medicine Acupuncture and Moxibustion, Tianjin 300381, China.
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Bi J, Mo C, Li S, Zeng J, Chai Y, Yao M, Liu Z, Yuan P, Ni J, Xu S. High concentrations of NaF aggravate periodontitis by promoting M1 polarization in macrophages. Int Immunopharmacol 2024; 140:112830. [PMID: 39096872 DOI: 10.1016/j.intimp.2024.112830] [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: 06/19/2024] [Revised: 07/15/2024] [Accepted: 07/26/2024] [Indexed: 08/05/2024]
Abstract
High-concentration fluoride treatment is commonly used to prevent dental caries in the oral cavity, and fluorine-containing protective paint is used to alleviate common root sensitivity symptoms in patients with periodontitis after periodontal treatment. Recent studies have confirmed its safe use in normal oral environments. However, whether fluoride treatment affects the progression of periodontitis in an inflammatory microenvironment remains unclear. Immunometabolism is crucial for maintaining bone regeneration and repair in periodontitis, and the precise regulation of macrophage polarisation is crucial to this process. Fluoride can influence the immune microenvironment of bone tissue by regulating immune metabolic processes. Herein, we investigated the effects of high concentrations of sodium fluoride (NaF) on periodontal tissues. We examined the expression of osteogenic and M1/M2 macrophage polarisation markers and glucose metabolism in macrophages. RNA sequencing was used to study differentially expressed genes related to M1 polarisation and glucose metabolism in treated macrophages. The results showed that NaF indirectly affects human periodontal ligament cells (hPDLCs), aggravating bone loss, tissue destruction, and submandibular lymph node drainage. Furthermore, NaF promoted glycolysis in macrophages and M1 polarisation while inhibiting osteogenic differentiation. These findings suggest that NaF has a direct effect on hPDLCs. Moreover, we found that high concentrations of NaF stimulated M1 polarisation in macrophages by promoting glycolysis. Overall, these results suggest that M1 macrophages promote the osteoclastic ability of hPDLCs and inhibit their osteogenic ability, eventually aggravating periodontitis. These findings provide important insights into the mechanism of action of NaF in periodontal tissue regeneration and reconstruction, which is critical for providing appropriate recommendations for the use of fluoride in patients with periodontitis.
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Affiliation(s)
- Jiaming Bi
- Department of Endodontics, Stomatological Hospital, School of Stomatology, Southern Medical University, Guangzhou, China
| | - Chuzi Mo
- Department of Endodontics, Stomatological Hospital, School of Stomatology, Southern Medical University, Guangzhou, China
| | - Siwei Li
- Department of Endodontics, Stomatological Hospital, School of Stomatology, Southern Medical University, Guangzhou, China
| | - Jiawei Zeng
- Department of Endodontics, Stomatological Hospital, School of Stomatology, Southern Medical University, Guangzhou, China
| | - Yan Chai
- Department of Endodontics, Stomatological Hospital, School of Stomatology, Southern Medical University, Guangzhou, China
| | - Mingyan Yao
- Department of Endocrinology, The Third Hospital of Hebei Medical University, Shijiazhuang, China; Department of Endocrinology, Baoding No.1 Central Hospital, Baoding, China
| | - Zhongjun Liu
- Department of Endodontics, Stomatological Hospital, School of Stomatology, Southern Medical University, Guangzhou, China
| | - Peiyan Yuan
- Department of Endodontics, Stomatological Hospital, School of Stomatology, Southern Medical University, Guangzhou, China
| | - Jia Ni
- Department of Periodontics, Stomatological Hospital, School of Stomatology, Southern Medical University, Guangzhou, China.
| | - Shuaimei Xu
- Department of Endodontics, Stomatological Hospital, School of Stomatology, Southern Medical University, Guangzhou, China.
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Guo Y, Shi Z, Han L, Qin X, You J, Zhang Q, Chen X, Zhao Y, Sun J, Xia Y. Infection-Sensitive SPION/PLGA Scaffolds Promote Periodontal Regeneration via Antibacterial Activity and Macrophage-Phenotype Modulation. ACS APPLIED MATERIALS & INTERFACES 2024; 16:41855-41868. [PMID: 39093305 DOI: 10.1021/acsami.4c06430] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 08/04/2024]
Abstract
Inflammation caused by a bacterial infection and the subsequent dysregulation of the host immune-inflammatory response are detrimental to periodontal regeneration. Herein, we present an infection-sensitive scaffold prepared by layer-by-layer assembly of Feraheme-like superparamagnetic iron oxide nanoparticles (SPIONs) on the surface of a three-dimensional-printed polylactic-co-glycolic acid (PLGA) scaffold. The SPION/PLGA scaffold is magnetic, hydrophilic, and bacterial-adhesion resistant. As indicated by gene expression profiling and confirmed by quantitative real-time reverse transcription polymerase chain reaction and flow cytometry analysis, the SPION/PLGA scaffold facilitates macrophage polarization toward the regenerative M2 phenotype by upregulating IL-10, which is the molecular target of repair promotion, and inhibits macrophage polarization toward the proinflammatory M1 phenotype by downregulating NLRP3, which is the molecular target of anti-inflammation. As a result, macrophages modulated by the SPS promote osteogenic differentiation of bone marrow mesenchymal stromal cells (BMSCs) in vitro. In a rat periodontal defect model, the SPION/PLGA scaffold increased IL-10 secretion and decreased NLRP3 and IL-1β secretion with Porphyromonas gingivalis infection, achieving superior periodontal regeneration than the PLGA scaffold alone. Therefore, this antibacterial SPION/PLGA scaffold has anti-inflammatory and bacterial antiadhesion properties to fight infection and promote periodontal regeneration by immunomodulation. These findings provide an important strategy for developing engineered scaffolds to treat periodontal defects.
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Affiliation(s)
- Yu Guo
- The Affiliated Stomatological Hospital of Nanjing Medical University, Nanjing, Jiangsu 210029, China
- State Key Laboratory Cultivation Base of Research, Prevention and Treatment for Oral Diseases, Nanjing Medical University, Nanjing, Jiangsu 210029, China
- Jiangsu Province Engineering Research Center of Stomatological Translational Medicine, Nanjing Medical University, Nanjing, Jiangsu 210029, China
| | - Zihan Shi
- The Affiliated Stomatological Hospital of Nanjing Medical University, Nanjing, Jiangsu 210029, China
- State Key Laboratory Cultivation Base of Research, Prevention and Treatment for Oral Diseases, Nanjing Medical University, Nanjing, Jiangsu 210029, China
- Jiangsu Province Engineering Research Center of Stomatological Translational Medicine, Nanjing Medical University, Nanjing, Jiangsu 210029, China
| | - Liping Han
- The Affiliated Stomatological Hospital of Nanjing Medical University, Nanjing, Jiangsu 210029, China
- The First Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, Zhejiang 310006, China
| | - Xuan Qin
- The Affiliated Stomatological Hospital of Nanjing Medical University, Nanjing, Jiangsu 210029, China
- State Key Laboratory Cultivation Base of Research, Prevention and Treatment for Oral Diseases, Nanjing Medical University, Nanjing, Jiangsu 210029, China
- Jiangsu Province Engineering Research Center of Stomatological Translational Medicine, Nanjing Medical University, Nanjing, Jiangsu 210029, China
| | - Jiayi You
- The Affiliated Stomatological Hospital of Nanjing Medical University, Nanjing, Jiangsu 210029, China
- State Key Laboratory Cultivation Base of Research, Prevention and Treatment for Oral Diseases, Nanjing Medical University, Nanjing, Jiangsu 210029, China
- Jiangsu Province Engineering Research Center of Stomatological Translational Medicine, Nanjing Medical University, Nanjing, Jiangsu 210029, China
| | - Qian Zhang
- The Affiliated Stomatological Hospital of Nanjing Medical University, Nanjing, Jiangsu 210029, China
- Suzhou Stomatological Hospital, Suzhou, Jiangsu 215000, China
| | - Xichen Chen
- Analytical and Testing Center, Nanjing Medical University, Nanjing, Jiangsu 211166, China
| | - Yantao Zhao
- Senior Department of Orthopedics, the Fourth Medical Center of PLA General Hospital, Beijing 100048, China
- Beijing Engineering Research Center of Orthopedics Implants, Beijing, 100048, China
- State Key Laboratory of Military Stomatology, Shanxi, Xi'an 710032, China
| | - Jianfei Sun
- Jiangsu Key Laboratory for Biomaterials and Devices, School of Biological Science and Medical Engineering, Southeast University, Nanjing, Jiangsu 210096, China
| | - Yang Xia
- The Affiliated Stomatological Hospital of Nanjing Medical University, Nanjing, Jiangsu 210029, China
- State Key Laboratory Cultivation Base of Research, Prevention and Treatment for Oral Diseases, Nanjing Medical University, Nanjing, Jiangsu 210029, China
- Jiangsu Province Engineering Research Center of Stomatological Translational Medicine, Nanjing Medical University, Nanjing, Jiangsu 210029, China
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10
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Yao H, Sun C, Wang C, Liu J, Li Y, Li L, Zhao B, Liu J. The Double-Edged Sword Property of Mesenchymal Stem Cell-Derived Exosomal microRNAs in Colorectal Cancer. THE TURKISH JOURNAL OF GASTROENTEROLOGY : THE OFFICIAL JOURNAL OF TURKISH SOCIETY OF GASTROENTEROLOGY 2024; 35:755-762. [PMID: 39412096 PMCID: PMC11465186 DOI: 10.5152/tjg.2024.23541] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 10/25/2023] [Accepted: 05/19/2024] [Indexed: 10/20/2024]
Abstract
Mesenchymal stem cells (MSCs)-based therapies are promising therapeutic strategies for cancer treatment, because of their strong immunomodulatory and tissue regeneration abilities. In case of colorectal cancer (CRC), MSCs indicate a double-edged sword activity. Some reports declared the inhibitory effects of MSCs on the proliferation, migration, and infiltration of cancer cells to suppress the CRC initiation and development, whereas others showed the tumor-promoter impacts of MSCs on the progression of CRC. Recent investigations have revealed that exosomal microRNAs (Exo-miRs) derived from MSCs (MSCs-Exo-miRs) are attributed to such paradoxical effect. Thus, the current review aimed to seek the role of MSCs-Exo-miRs in CRC progression and their therapeutic potential for the CRC treatment.
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Affiliation(s)
- Hongliang Yao
- The Second Department of General Surgery, Hengshui People’s Hospital, Hengshui, Hebei Province, China
| | - Caihua Sun
- The Second Department of General Surgery, Hengshui People’s Hospital, Hengshui, Hebei Province, China
| | - Chengjun Wang
- The Second Department of General Surgery, Hengshui People’s Hospital, Hengshui, Hebei Province, China
| | - Jipan Liu
- The Second Department of General Surgery, Hengshui People’s Hospital, Hengshui, Hebei Province, China
| | - Yun Li
- The Second Department of General Surgery, Hengshui People’s Hospital, Hengshui, Hebei Province, China
| | - Li Li
- The Second Department of General Surgery, Hengshui People’s Hospital, Hengshui, Hebei Province, China
| | - Bin Zhao
- The Second Department of General Surgery, Hengshui People’s Hospital, Hengshui, Hebei Province, China
| | - Jia Liu
- The Second Department of General Surgery, Hengshui People’s Hospital, Hengshui, Hebei Province, China
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11
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Ali M, He Y, Chang ASN, Wu A, Liu J, Cao Y, Mohammad Y, Popat A, Walsh L, Ye Q, Xu C, Kumeria T. Osteoimmune-modulating and BMP-2-eluting anodised 3D printed titanium for accelerated bone regeneration. J Mater Chem B 2023; 12:97-111. [PMID: 37842835 DOI: 10.1039/d3tb01029e] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/17/2023]
Abstract
3D printing of titanium (Ti) metal has potential to transform the field of personalised orthopaedics and dental implants. However, the impacts of controlled surface topographical features of 3D printed Ti implants on their interactions with the cellular microenvironment and incorporation of biological growth factors, which are critical in guiding the integration of implants with bone, are not well studied. In the present study, we explore the role of surface topological features of 3D printed Ti implants using an anodised titania nanotube (TiNT) surface layer in guiding their immune cell interaction and ability to deliver bioactive form of growth factors. TiNT layers with precisely controlled pore diameter (between 21and 130 nm) were anodically grown on 3D printed Ti surfaces to impart a nano-micro rough topology. Immune biomarker profiles at gene and protein levels show that anodised 3D Ti surfaces with smaller pores resulted in classical activation of macrophages (M1-like), while larger pores (i.e., >100 nm) promoted alternate activation of macrophages (M2-like). The in vitro bone mineralisation studies using the conditioned media from the immunomodulatory studies elucidate a clear impact of pore diameter on bone mineralisation. The tubular structure of TiNTs was utilised as a container to incorporate recombinant human bone morphogenetic protein-2 (BMP-2) in the presence of various sugar and polymeric cryoprotectants. Sucrose offered the most sustainable release of preserved BMP-2 from TiNTs. Downstream effects of released BMP-2 on macrophages as well as bone mineralisation were assessed showing bioactivity retention of the released rhBMP-2. Overall, the TiNT surface topography in combination with controlled, sustained, and local release of bioactive growth factors can potentially enhance the osseointegration outcomes of custom 3D printed Ti implants in the clinic.
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Affiliation(s)
- Masood Ali
- Therapeutics Research Group, Frazer Institute, Faculty of Medicine, University of Queensland, Brisbane, QLD 4102, Australia
| | - Yan He
- Institute of Regenerative and Translational Medicine, Wuhan University of Science and Technology, Wuhan 430040, China
| | - Anna Sze Ni Chang
- School of Pharmacy, The University of Queensland, Brisbane, Queensland 4102, Australia.
| | - Alice Wu
- School of Pharmacy, The University of Queensland, Brisbane, Queensland 4102, Australia.
| | - Jingyu Liu
- School of Mechanical, Medical and process Engineering, Queensland University of Technology, Brisbane, Queensland 4000, Australia
| | - Yuxue Cao
- School of Pharmacy, The University of Queensland, Brisbane, Queensland 4102, Australia.
| | - Yousuf Mohammad
- Therapeutics Research Group, Frazer Institute, Faculty of Medicine, University of Queensland, Brisbane, QLD 4102, Australia
- School of Pharmacy, The University of Queensland, Brisbane, Queensland 4102, Australia.
| | - Amirali Popat
- School of Pharmacy, The University of Queensland, Brisbane, Queensland 4102, Australia.
| | - Laurie Walsh
- School of Dentistry, The University of Queensland, Herston, Queensland 4006, Australia.
| | - Qingsong Ye
- Centre of Regenerative Medicine, Department of Stomatology, Renmin Hospital of Wuhan University, Wuhan 430060, China.
| | - Chun Xu
- School of Dentistry, The University of Queensland, Herston, Queensland 4006, Australia.
| | - Tushar Kumeria
- School of Pharmacy, The University of Queensland, Brisbane, Queensland 4102, Australia.
- School of Materials Science and Engineering, University of New South Wales, Kensington, Sydney, New South Wales 2052, Australia
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12
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Kaur R, Bhardwaj A, Gupta S. Cancer treatment therapies: traditional to modern approaches to combat cancers. Mol Biol Rep 2023; 50:9663-9676. [PMID: 37828275 DOI: 10.1007/s11033-023-08809-3] [Citation(s) in RCA: 88] [Impact Index Per Article: 44.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2023] [Accepted: 09/08/2023] [Indexed: 10/14/2023]
Abstract
As far as health issues are concerned, cancer causes one out of every six deaths around the globe. As potent therapeutics are still awaited for the successful treatment of cancer, some unconventional treatments like radiotherapy, surgery, and chemotherapy and some advanced technologies like gene therapy, stem cell therapy, natural antioxidants, targeted therapy, photodynamic therapy, nanoparticles, and precision medicine are available to diagnose and treat cancer. In the present scenario, the prime focus is on developing efficient nanomedicines to treat cancer. Although stem cell therapy has the capability to target primary as well as metastatic cancer foci, it also has the ability to repair and regenerate injured tissues. However, nanoparticles are designed to have such novel therapeutic capabilities. Targeted therapy is also now available to arrest the growth and development of cancer cells without damaging healthy tissues. Another alternative approach in this direction is photodynamic therapy (PDT), which has more potential to treat cancer as it does minimal damage and does not limit other technologies, as in the case of chemotherapy and radiotherapy. The best possible way to treat cancer is by developing novel therapeutics through translational research. In the present scenario, an important event in modern oncology therapy is the shift from an organ-centric paradigm guiding therapy to complete molecular investigations. The lacunae in anticancer therapy may be addressed through the creation of contemporary and pertinent cancer therapeutic techniques. In the meantime, the growth of nanotechnology, material sciences, and biomedical sciences has revealed a wide range of contemporary therapies with intelligent features, adaptable functions, and modification potential. The development of numerous therapeutic techniques for the treatment of cancer is summarized in this article. Additionally, it can serve as a resource for oncology and immunology researchers.
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Affiliation(s)
- Rasanpreet Kaur
- Department of Biotechnology, GLA University, Mathura, 281406, Uttar Pradesh, India
| | - Alok Bhardwaj
- Department of Biotechnology, GLA University, Mathura, 281406, Uttar Pradesh, India.
| | - Saurabh Gupta
- Department of Biotechnology, GLA University, Mathura, 281406, Uttar Pradesh, India.
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13
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Hsu YH, Chen CN, Chang HI, Tsai HL, Chang YH, Cheng IS, Yang YS, Huang KY. Manipulation of osteogenic and adipogenic differentiation of human degenerative disc and ligamentum flavum derived progenitor cells using IL-1β, IL-19, and IL-20. EUROPEAN SPINE JOURNAL : OFFICIAL PUBLICATION OF THE EUROPEAN SPINE SOCIETY, THE EUROPEAN SPINAL DEFORMITY SOCIETY, AND THE EUROPEAN SECTION OF THE CERVICAL SPINE RESEARCH SOCIETY 2023; 32:3413-3424. [PMID: 37563485 DOI: 10.1007/s00586-023-07878-z] [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: 02/23/2023] [Revised: 06/22/2023] [Accepted: 07/28/2023] [Indexed: 08/12/2023]
Abstract
PURPOSE To elucidate whether pro-inflammatory cytokines might influence the commitment of intervertebral disc (IVD)- and ligamentum flavum (LF)-derived progenitor cells toward either osteogenesis or adipogenesis, specifically Interleukin-1β (IL-1β), IL-19, and IL-20. METHODS Sixty patients with degenerative spondylolisthesis and lumbar or lumbosacral spinal stenosis were included in the study. Injuries to the spine, infections, and benign or malignant tumors were excluded. From nine patient samples, IVD- and LF-derived cells were isolated after primary culture, and two clinical samples were excluded due to mycoplasma infection. The effects of IL-1β, IL-19, as well as IL-20 in regulating osteogenic and adipogenic differentiation in vitro were investigated. RESULTS Primary IVD- and LF-derived cells were found to have a similar cell morphology and profile of surface markers (CD44, CD90, and CD105) as placenta-derived mesenchymal stem cells (MSCs). Primary IVD/LF cells have a high capacity to differentiate into osteocytes and adipocytes. IL-19 had a tendency to promote adipogenesis. IL-20 inhibited osteogenesis and promoted adipogenesis; IL-1β promoted osteogenesis but inhibited adipogenesis. CONCLUSION IL-1β, IL-19, and IL-20 impact the adipogenic and osteogenic differentiation of IVD-derived and LF-derived cells. Modulating the expression of IL-1β, IL-19, and IL-20 provides a potential avenue for controlling cell differentiation of IVD- and LF-derived cells, which might have beneficial effect for degenerative spondylolisthesis and spinal stenosis.
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Affiliation(s)
- Yu-Hsiang Hsu
- Institute of Clinical Medicine, College of Medicine, National Cheng Kung University, Tainan, Taiwan
- Research Center of Clinical Medicine, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan
| | - Cheng-Nan Chen
- Department of Biochemical Science and Technology, National Chiayi University, Chiayi City, Taiwan
| | - Hsin-I Chang
- Department of Biochemical Science and Technology, National Chiayi University, Chiayi City, Taiwan
| | - Hui-Ling Tsai
- Department of Orthopedics, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, No. 138, Sheng-Li Road, Tainan, 704, Taiwan
| | - Yu-Hsien Chang
- Institute of Clinical Medicine, College of Medicine, National Cheng Kung University, Tainan, Taiwan
| | - I-Szu Cheng
- College of Medicine, National Cheng Kung University, Tainan, Taiwan
| | - Yu-Shiuan Yang
- Education Center, College of Medicine, National Cheng Kung University Hospital, National Cheng Kung University, Tainan, Taiwan
| | - Kuo-Yuan Huang
- Department of Orthopedics, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, No. 138, Sheng-Li Road, Tainan, 704, Taiwan.
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14
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Zou X, Liu C, Wu X, Yuan Z, Yan F. Changes in N6-methyladenosine RNA methylomes of human periodontal ligament cells in response to inflammatory conditions. J Periodontal Res 2023; 58:444-455. [PMID: 36733232 DOI: 10.1111/jre.13105] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2022] [Revised: 12/26/2022] [Accepted: 01/17/2023] [Indexed: 02/04/2023]
Abstract
OBJECTIVE To investigate the changes in the m6A methylation modification profile of human periodontal ligament cells (hPDLCs) in response to inflammatory conditions. BACKGROUND Periodontitis is an infectious disease of the periodontal support tissue that leads to the loss of alveolar bone. HPDLCs are primary cells that can repair periodontal tissue defects caused by periodontitis. However, the inflammatory conditions induce inflammatory damage and decrease ossification of hPDLCs. This inflammatory response depends on genetic and epigenetic mechanisms, including m6A methylation. METHODS HPDLCs were cultured with osteogenic induction medium (NC group), while TNF-α (10 ng/mL) and IL-1β (5 ng/mL) were added to simulate inflammatory conditions (Inflam group). Then RNA-seq and MeRIP-seq analyses were performed to identify m6A methylation modification in the transcriptome range of hPDLCs. RESULTS The results showed that the osteogenic differentiation of hPDLCs was inhibited under inflammatory conditions. RNA-seq analysis also revealed that the decreased genes in response to inflammatory conditions were primarily annotated in processes associated with ossification. Compared with the NC group, differentially m6A-methylated genes were primarily enriched in histone modification processes. Among 145 histone modification genes, 25 genes have been reported to be involved in the regulation of osteogenic differentiation, and they include KAT6B, EP300, BMI1, and KDMs (KDM1A, KDM2A, KDM3A, KDM4B, and KDM5A). CONCLUSION This study demonstrated that the m6A landscape of hPDLCs was changed in response to inflammation. M6A methylation differences among histone modification genes may act on the osteogenic differentiation of hPDLCs.
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Affiliation(s)
- Xihong Zou
- Department of Periodontology, Nanjing Stomatological Hospital, Medical School of Nanjing University, Nanjing, China
| | - Chaoyi Liu
- Hangzhou Stomatological Hospital, Hangzhou, China
| | - Xudong Wu
- State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing, China
| | - Zhiyao Yuan
- Department of Periodontology, Nanjing Stomatological Hospital, Medical School of Nanjing University, Nanjing, China
| | - Fuhua Yan
- Department of Periodontology, Nanjing Stomatological Hospital, Medical School of Nanjing University, Nanjing, China
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15
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Löffler J, Noom A, Ellinghaus A, Dienelt A, Kempa S, Duda GN. A comprehensive molecular profiling approach reveals metabolic alterations that steer bone tissue regeneration. Commun Biol 2023; 6:327. [PMID: 36973478 PMCID: PMC10042875 DOI: 10.1038/s42003-023-04652-1] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2022] [Accepted: 03/01/2023] [Indexed: 03/29/2023] Open
Abstract
Bone regeneration after fracture is a complex process with high and dynamic energy demands. The impact of metabolism on bone healing progression and outcome, however, is so far understudied. Our comprehensive molecular profiling reveals that central metabolic pathways, such as glycolysis and the citric acid cycle, are differentially activated between rats with successful or compromised bone regeneration (young versus aged female Sprague-Dawley rats) early in the inflammatory phase of bone healing. We also found that the citric acid cycle intermediate succinate mediates individual cellular responses and plays a central role in successful bone healing. Succinate induces IL-1β in macrophages, enhances vessel formation, increases mesenchymal stromal cell migration, and potentiates osteogenic differentiation and matrix formation in vitro. Taken together, metabolites-here particularly succinate-are shown to play central roles as signaling molecules during the onset of healing and in steering bone tissue regeneration.
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Affiliation(s)
- Julia Löffler
- Julius Wolff Institute (JWI), Berlin Institute of Health at Charité-Universitätsmedizin Berlin, 13353, Berlin, Germany
- BIH Center for Regenerative Therapies (BCRT), Berlin Institute of Health at Charité-Universitätsmedizin Berlin, 13353, Berlin, Germany
- Berlin Institute for Medical Systems Biology, Max-Delbrück-Center for Molecular Medicine, 10115, Berlin, Germany
| | - Anne Noom
- Julius Wolff Institute (JWI), Berlin Institute of Health at Charité-Universitätsmedizin Berlin, 13353, Berlin, Germany
- BIH Center for Regenerative Therapies (BCRT), Berlin Institute of Health at Charité-Universitätsmedizin Berlin, 13353, Berlin, Germany
| | - Agnes Ellinghaus
- Julius Wolff Institute (JWI), Berlin Institute of Health at Charité-Universitätsmedizin Berlin, 13353, Berlin, Germany
- BIH Center for Regenerative Therapies (BCRT), Berlin Institute of Health at Charité-Universitätsmedizin Berlin, 13353, Berlin, Germany
| | - Anke Dienelt
- Julius Wolff Institute (JWI), Berlin Institute of Health at Charité-Universitätsmedizin Berlin, 13353, Berlin, Germany
- BIH Center for Regenerative Therapies (BCRT), Berlin Institute of Health at Charité-Universitätsmedizin Berlin, 13353, Berlin, Germany
| | - Stefan Kempa
- Berlin Institute for Medical Systems Biology, Max-Delbrück-Center for Molecular Medicine, 10115, Berlin, Germany.
| | - Georg N Duda
- Julius Wolff Institute (JWI), Berlin Institute of Health at Charité-Universitätsmedizin Berlin, 13353, Berlin, Germany.
- BIH Center for Regenerative Therapies (BCRT), Berlin Institute of Health at Charité-Universitätsmedizin Berlin, 13353, Berlin, Germany.
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16
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Gan J, Guo L, Zhang X, Yu Q, Yang Q, Zhang Y, Zeng W, Jiang X, Guo M. Anti-inflammatory therapy of atherosclerosis: focusing on IKKβ. J Inflamm (Lond) 2023; 20:8. [PMID: 36823573 PMCID: PMC9951513 DOI: 10.1186/s12950-023-00330-5] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2022] [Accepted: 01/24/2023] [Indexed: 02/25/2023] Open
Abstract
Chronic low-grade inflammation has been identified as a major contributor in the development of atherosclerosis. Nuclear Factor-κappa B (NF-κB) is a critical transcription factors family of the inflammatory pathway. As a major catalytic subunit of the IKK complex, IκB kinase β (IKKβ) drives canonical activation of NF-κB and is implicated in the link between inflammation and atherosclerosis, making it a promising therapeutic target. Various natural product derivatives, extracts, and synthetic, show anti-atherogenic potential by inhibiting IKKβ-mediated inflammation. This review focuses on the latest knowledge and current research landscape surrounding anti-atherosclerotic drugs that inhibit IKKβ. There will be more opportunities to fully understand the complex functions of IKKβ in atherogenesis and develop new effective therapies in the future.
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Affiliation(s)
- Jiali Gan
- grid.410648.f0000 0001 1816 6218School of Integrative Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Lin Guo
- grid.410648.f0000 0001 1816 6218School of Integrative Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Xiaolu Zhang
- grid.410648.f0000 0001 1816 6218School of Integrative Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Qun Yu
- grid.410648.f0000 0001 1816 6218School of Integrative Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Qiuyue Yang
- grid.410648.f0000 0001 1816 6218School of Integrative Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Yilin Zhang
- grid.410648.f0000 0001 1816 6218School of Integrative Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Wenyun Zeng
- grid.459559.10000 0004 9344 2915Oncology department, Ganzhou People’s Hospital, Ganzhou, Jiangxi China
| | - Xijuan Jiang
- School of Integrative Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, China.
| | - Maojuan Guo
- School of Integrative Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, China.
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17
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Zhang Y, Lv P, Li Y, Zhang Y, Cheng C, Hao H, Yue H. Inflammatory Cytokine Interleukin-6 (IL-6) Promotes the Proangiogenic Ability of Adipose Stem Cells from Obese Subjects via the IL-6 Signaling Pathway. Curr Stem Cell Res Ther 2023; 18:93-104. [PMID: 36883256 DOI: 10.2174/1574888x17666220429103935] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2021] [Revised: 01/05/2022] [Accepted: 03/01/2022] [Indexed: 11/22/2022]
Abstract
BACKGROUND The prevalence of obesity, as well as obesity-induced chronic inflammatory diseases, is increasing worldwide. Chronic inflammation is related to the complex process of angiogenesis, and we found that adipose-derived stem cells from obese subjects (obADSCs) had proangiogenic features, including higher expression levels of interleukin-6 (IL-6), Notch ligands and receptors, and proangiogenic cytokines, than those from control subjects. We hypothesized that IL-6 and Notch signaling pathways are essential for regulating the proangiogenic characteristics of obADSCs. OBJECTIVE This study aimed to investigate whether the inflammatory cytokine interleukin 6 (IL-6) promotes the proangiogenic capacity of adipose stem cells in obese subjects via the IL-6 signaling pathway. METHODS We compared the phenotype analysis as well as cell doubling time, proliferation, migration, differentiation, and proangiogenic properties of ADSCs in vitro. Moreover, we used small interfering RNAs to inhibit the gene and protein expression of IL-6. RESULTS We found that ADSCs isolated from control individuals (chADSCs) and obADSCs had similar phenotypes and growth characteristics, and chADSCs had a stronger differentiation ability than obADSCs. However, obADSCs were more potent in promoting EA.hy926 cell migration and tube formation than chADSCs in vitro. We confirmed that IL-6 siRNA significantly reduced the transcriptional level of IL-6 in obADSCs, thereby reducing the expression of vascular endothelial growth factor (VEGF)- A, VEGF receptor 2, transforming growth factor β, and Notch ligands and receptors in obADSCs. CONCLUSION The finding suggests that inflammatory cytokine interleukin-6 (IL-6) promotes the proangiogenic ability of obADSCs via the IL-6 signaling pathway.
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Affiliation(s)
- Yuanyuan Zhang
- Translational Medicine Center, Zhengzhou Central Hospital Affiliated to Zhengzhou University, Zhengzhou, Henan, 450007, China
| | - Pengju Lv
- Translational Medicine Center, Zhengzhou Central Hospital Affiliated to Zhengzhou University, Zhengzhou, Henan, 450007, China
| | - Yalong Li
- Stem Cell Research Center, Henan Key Laboratory of Stem Cell Differentiation and Modification Henan Provincial People's Hospital, People's Hospital of Zhengzhou University, Zhengzhou, Henan, 450003, China.,People's Hospital of Henan University, Zhengzhou, Henan, 450003, China
| | - Yonghui Zhang
- Stem Cell Research Center, Henan Key Laboratory of Stem Cell Differentiation and Modification Henan Provincial People's Hospital, People's Hospital of Zhengzhou University, Zhengzhou, Henan, 450003, China.,People's Hospital of Henan University, Zhengzhou, Henan, 450003, China
| | - Chaofei Cheng
- Stem Cell Research Center, Henan Key Laboratory of Stem Cell Differentiation and Modification Henan Provincial People's Hospital, People's Hospital of Zhengzhou University, Zhengzhou, Henan, 450003, China.,People's Hospital of Henan University, Zhengzhou, Henan, 450003, China
| | - Hongbo Hao
- Neuroscience Initiative, Advanced Science Research Center at the Graduate Center, City University of New York, New York, 10031, USA
| | - Han Yue
- Stem Cell Research Center, Henan Key Laboratory of Stem Cell Differentiation and Modification Henan Provincial People's Hospital, People's Hospital of Zhengzhou University, Zhengzhou, Henan, 450003, China.,People's Hospital of Henan University, Zhengzhou, Henan, 450003, China
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18
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Smith EJ, Beaumont RE, McClellan A, Sze C, Palomino Lago E, Hazelgrove L, Dudhia J, Smith RKW, Guest DJ. Tumour necrosis factor alpha, interleukin 1 beta and interferon gamma have detrimental effects on equine tenocytes that cannot be rescued by IL-1RA or mesenchymal stromal cell-derived factors. Cell Tissue Res 2023; 391:523-544. [PMID: 36543895 PMCID: PMC9974687 DOI: 10.1007/s00441-022-03726-6] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2022] [Accepted: 12/10/2022] [Indexed: 12/24/2022]
Abstract
Tendon injuries occur commonly in both human and equine athletes, and poor tendon regeneration leads to functionally deficient scar tissue and an increased frequency of re-injury. Despite evidence suggesting inadequate resolution of inflammation leads to fibrotic healing, our understanding of the inflammatory pathways implicated in tendinopathy remains poorly understood, meaning successful targeted treatments are lacking. Here, we demonstrate IL-1β, TNFα and IFN-γ work synergistically to induce greater detrimental consequences for equine tenocytes than when used individually. This includes altering tendon associated and matrix metalloproteinase gene expression and impairing the cells' ability to contract a 3-D collagen gel, a culture technique which more closely resembles the in vivo environment. Moreover, these adverse effects cannot be rescued by direct suppression of IL-1β using IL-1RA or factors produced by BM-MSCs. Furthermore, we provide evidence that NF-κB, but not JNK, P38 MAPK or STAT 1, is translocated to the nucleus and able to bind to DNA in tenocytes following TNFα and IL-1β stimulation, suggesting this signalling cascade may be responsible for the adverse downstream consequences of these inflammatory cytokines. We suggest a superior approach for treatment of tendinopathy may therefore be to target specific signalling pathways such as NF-κB.
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Affiliation(s)
- Emily J Smith
- Department of Clinical Sciences and Services, The Royal Veterinary College, Hawkshead Lane, North Mymms, Hatfield, Herts, AL9 7TA, UK.
| | - Ross E Beaumont
- Department of Clinical Sciences and Services, The Royal Veterinary College, Hawkshead Lane, North Mymms, Hatfield, Herts, AL9 7TA, UK
| | - Alyce McClellan
- Centre for Preventative Medicine, Animal Health Trust, Newmarket, Suffolk, CB8 7UU, UK
| | - Cheryl Sze
- Centre for Preventative Medicine, Animal Health Trust, Newmarket, Suffolk, CB8 7UU, UK
| | - Esther Palomino Lago
- Department of Clinical Sciences and Services, The Royal Veterinary College, Hawkshead Lane, North Mymms, Hatfield, Herts, AL9 7TA, UK
| | - Liberty Hazelgrove
- Department of Clinical Sciences and Services, The Royal Veterinary College, Hawkshead Lane, North Mymms, Hatfield, Herts, AL9 7TA, UK
- Kingston University, River House, 53-57 High Street, Kingston upon Thames, Surrey, KT1 1LQ, UK
| | - Jayesh Dudhia
- Department of Clinical Sciences and Services, The Royal Veterinary College, Hawkshead Lane, North Mymms, Hatfield, Herts, AL9 7TA, UK
| | - Roger K W Smith
- Department of Clinical Sciences and Services, The Royal Veterinary College, Hawkshead Lane, North Mymms, Hatfield, Herts, AL9 7TA, UK
| | - Deborah J Guest
- Department of Clinical Sciences and Services, The Royal Veterinary College, Hawkshead Lane, North Mymms, Hatfield, Herts, AL9 7TA, UK.
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19
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Xu X, Wang M, Wang Z, Chen Q, Chen X, Xu Y, Dai M, Wu B, Li Y. The bridge of the gut-joint axis: Gut microbial metabolites in rheumatoid arthritis. Front Immunol 2022; 13:1007610. [PMID: 36275747 PMCID: PMC9583880 DOI: 10.3389/fimmu.2022.1007610] [Citation(s) in RCA: 23] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2022] [Accepted: 09/22/2022] [Indexed: 11/13/2022] Open
Abstract
Rheumatoid arthritis (RA) is an autoimmune disease characterized by joint destruction, synovitis, and pannus formation. Gut microbiota dysbiosis may exert direct pathogenic effects on gut homeostasis. It may trigger the host's innate immune system and activate the "gut-joint axis", which exacerbates the RA. However, although the importance of the gut microbiota in the development and progression of RA is widely recognized, the mechanisms regulating the interactions between the gut microbiota and the host immune system remain incompletely defined. In this review, we discuss the role of gut microbiota-derived biological mediators, such as short-chain fatty acids, bile acids, and tryptophan metabolites, in maintaining intestinal barrier integrity, immune balance and bone destruction in RA patients as the bridge of the gut-joint axis.
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Affiliation(s)
- Xiaoyu Xu
- College of Traditional Chinese Medicine, Chongqing Medical University, Chongqing, China
- Department of Rheumatology, Chongqing Hospital of Traditional Chinese Medicine, Chongqing, China
| | - Miao Wang
- Department of Rheumatology, Chongqing Hospital of Traditional Chinese Medicine, Chongqing, China
| | - Zikang Wang
- College of Traditional Chinese Medicine, Chongqing Medical University, Chongqing, China
| | - Qian Chen
- College of Traditional Chinese Medicine, Chongqing Medical University, Chongqing, China
| | - Xixuan Chen
- College of Traditional Chinese Medicine, Chongqing Medical University, Chongqing, China
| | - Yingyue Xu
- Department of Rheumatology, Chongqing Hospital of Traditional Chinese Medicine, Chongqing, China
| | - Min Dai
- Department of Rheumatology, Chongqing Hospital of Traditional Chinese Medicine, Chongqing, China
| | - Bin Wu
- College of Traditional Chinese Medicine, Chongqing Medical University, Chongqing, China
- Department of Rheumatology, Chongqing Hospital of Traditional Chinese Medicine, Chongqing, China
| | - Yanping Li
- College of Traditional Chinese Medicine, Chongqing Medical University, Chongqing, China
- Department of Rheumatology, Chongqing Hospital of Traditional Chinese Medicine, Chongqing, China
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20
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Abstract
Lifestyle factors are modifiable behavioral factors that have a significant impact on health and longevity. Diet-induced obesity and physical activity/exercise are two prevalent lifestyle factors that have strong relationships to overall health. The mechanisms linking obesity to negative health outcomes and the mechanisms linking increased participation in physical activity/exercise to positive health outcomes are beginning to be elucidated. Chronic inflammation, due in part to overproduction of myeloid cells from hematopoietic stem cells (HSCs) in the bone marrow, is an established mechanism responsible for the negative health effects of obesity. Recent work has shown that exercise training can reverse the aberrant myelopoiesis present in obesity in part by restoring the bone marrow microenvironment. Specifically, exercise training reduces marrow adipose tissue, increases HSC retention factor expression, and reduces pro-inflammatory cytokine levels in the bone marrow. Other, novel mechanistic factors responsible for these exercise-induced effects, including intercellular communication using extracellular vesicles (EVs), is beginning to be explored. This review will summarize the recent literature describing the effects of exercise on hematopoiesis in individuals with obesity and introduce the potential contribution of EVs to this process.
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21
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Mo Q, Zhang W, Zhu A, Backman LJ, Chen J. Regulation of osteogenic differentiation by the pro-inflammatory cytokines IL-1β and TNF-α: current conclusions and controversies. Hum Cell 2022; 35:957-971. [PMID: 35522425 DOI: 10.1007/s13577-022-00711-7] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2022] [Accepted: 04/23/2022] [Indexed: 12/09/2022]
Abstract
Treatment of complex bone fracture diseases is still a complicated problem that is urged to be solved in orthopedics. In bone tissue engineering, the use of mesenchymal stromal/stem cells (MSCs) for tissue repair brings hope to the medical field of bone diseases. MSCs can differentiate into osteoblasts and promote bone regeneration. An increasing number of studies show that the inflammatory microenvironment affects the osteogenic differentiation of MSCs. It is shown that TNF-α and IL-1β play different roles in the osteogenic differentiation of MSCs via different signal pathways. The main factors that affect the role of TNF-α and IL-1β in osteogenic differentiation of MSCs include concentration and the source of stem cells (different species and different tissues). This review in-depth analyzes the roles of pro-inflammatory cytokines in the osteogenic differentiation of MSCs and reveals some current controversies to provide a reference of comprehensively understanding.
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Affiliation(s)
- Qingyun Mo
- School of Medicine, Southeast University, Nanjing, 210009, China
| | - Wei Zhang
- School of Medicine, Southeast University, Nanjing, 210009, China
- Jiangsu Key Laboratory for Biomaterials and Devices, Southeast University, Nanjing, 210096, China
- China Orthopedic Regenerative Medicine Group (CORMed), Hangzhou, China
| | - Aijing Zhu
- School of Medicine, Southeast University, Nanjing, 210009, China
| | - Ludvig J Backman
- Department of Integrative Medical Biology, Anatomy, Umeå University, SE-901 87, Umeå, Sweden
- Department of Community Medicine and Rehabilitation, Physiotherapy, Umeå University, SE-901 87, Umeå, Sweden
| | - Jialin Chen
- School of Medicine, Southeast University, Nanjing, 210009, China.
- Jiangsu Key Laboratory for Biomaterials and Devices, Southeast University, Nanjing, 210096, China.
- China Orthopedic Regenerative Medicine Group (CORMed), Hangzhou, China.
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22
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New Perspectives to Improve Mesenchymal Stem Cell Therapies for Drug-Induced Liver Injury. Int J Mol Sci 2022; 23:ijms23052669. [PMID: 35269830 PMCID: PMC8910533 DOI: 10.3390/ijms23052669] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2021] [Revised: 02/23/2022] [Accepted: 02/24/2022] [Indexed: 02/06/2023] Open
Abstract
Drug-induced liver injury (DILI) is one of the leading causes of acute liver injury. Many factors may contribute to the susceptibility of patients to this condition, making DILI a global medical problem that has an impact on public health and the pharmaceutical industry. The use of mesenchymal stem cells (MSCs) has been at the forefront of regenerative medicine therapies for many years, including MSCs for the treatment of liver diseases. However, there is currently a huge gap between these experimental approaches and their application in clinical practice. In this concise review, we focus on the pathophysiology of DILI and highlight new experimental approaches conceived to improve cell-based therapy by the in vitro preconditioning of MSCs and/or the use of cell-free products as treatment for this liver condition. Finally, we discuss the advantages of new approaches, but also the current challenges that must be addressed in order to develop safer and more effective procedures that will allow cell-based therapies to reach clinical practice, enhancing the quality of life and prolonging the survival time of patients with DILI.
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23
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A senescence stress secretome is a hallmark of therapy-related myeloid neoplasm stromal tissue occurring soon after cytotoxic exposure. Leukemia 2022; 36:2678-2689. [PMID: 36038666 PMCID: PMC9613466 DOI: 10.1038/s41375-022-01686-y] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2021] [Revised: 08/10/2022] [Accepted: 08/12/2022] [Indexed: 11/18/2022]
Abstract
Therapy-related myeloid neoplasm (tMN) is considered a direct consequence of DNA damage in hematopoietic stem cells. Despite increasing recognition that altered stroma can also drive leukemogenesis, the functional biology of the tMN microenvironment remains unknown. We performed multiomic (transcriptome, DNA damage response, cytokine secretome and functional profiling) characterization of bone marrow stromal cells from tMN patients. Critically, we also compared (i) patients with myeloid neoplasm and another cancer but without cytotoxic exposure, (ii) typical primary myeloid neoplasm, and (iii) age-matched controls to decipher the microenvironmental changes induced by cytotoxics vs. neoplasia. Strikingly, tMN exhibited a profoundly senescent phenotype with induction of CDKN1A and β-Galactosidase, defective phenotype, and proliferation. Moreover, tMN stroma showed delayed DNA repair and defective adipogenesis. Despite their dormant state, tMN stromal cells were metabolically highly active with a switch toward glycolysis and secreted multiple pro-inflammatory cytokines indicative of a senescent-secretory phenotype that inhibited adipogenesis. Critically, senolytics not only eliminated dormant cells, but also restored adipogenesis. Finally, sequential patient sampling showed senescence phenotypes are induced within months of cytotoxic exposure, well prior to the onset of secondary cancer. Our data underscores a role of senescence in the pathogenesis of tMN and provide a valuable resource for future therapeutics.
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24
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A Molecular Analysis of Cytokine Content across Extracellular Vesicles, Secretions, and Intracellular Space from Different Site-Specific Adipose-Derived Stem Cells. Int J Mol Sci 2021; 23:ijms23010397. [PMID: 35008824 PMCID: PMC8745205 DOI: 10.3390/ijms23010397] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2021] [Revised: 12/23/2021] [Accepted: 12/27/2021] [Indexed: 11/16/2022] Open
Abstract
Cytokines are multifunctional small proteins that have a vital influence on inflammatory states of tissues and play a role in signalling and cellular control mechanisms. Cytokine expression has primarily been viewed as a form of direct secretion of molecules through an active transportation; however, other forms of active transport such as extracellular vesicles are at play. This is particularly important in stem cells where signalling molecules are key to communication managing the levels of proliferation, migration, and differentiation into mature cells. This study investigated cytokines from intracellular content, direct cellular secretions, and extracellular vesicles from adult adipose-derived stem cells isolated from three distinct anatomical locations: abdomen, thigh, and chin. The cells were cultured investigated using live cell microscopy, cytokine assays, and bioinformatics analysis. The cytokines quantified and examined from each sample type showed a distinct difference between niche areas and sample types. The varying levels of TNF-alpha, IL-6 and IL-8 cytokines were shown to play a crucial role in signalling pathways such as MAPK, ERK1/2 and JAK-STAT in cells. On the other hand, the chemotactic cytokines IL-1rn, Eotaxin, IP-10 and MCP-1 showed the most prominent changes across extracellular vesicles with roles in noncanonical signalling. By examining the local and tangential roles of cytokines in stem cells, their roles in signalling and in regenerative mechanisms may be further understood.
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25
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Choudhery MS. Strategies to improve regenerative potential of mesenchymal stem cells. World J Stem Cells 2021; 13:1845-1862. [PMID: 35069986 PMCID: PMC8727227 DOI: 10.4252/wjsc.v13.i12.1845] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/18/2021] [Revised: 07/31/2021] [Accepted: 12/10/2021] [Indexed: 02/06/2023] Open
Abstract
In the last few decades, stem cell-based therapies have gained attention worldwide for various diseases and disorders. Adult stem cells, particularly mesenchymal stem cells (MSCs), are preferred due to their significant regenerative potential in cellular therapies and are currently involved in hundreds of clinical trials. Although MSCs have high self-renewal as well as differentiation potential, such abilities are compromised with "advanced age" and "disease status" of the donor. Similarly, cell-based therapies require high cell number for clinical applications that often require in vitro expansion of cells. It is pertinent to note that aged individuals are the main segment of population for stem cell-based therapies, however; autologous use of stem cells for such patients (aged and diseased) does not seem to give optimal results due to their compromised potential. In vitro expansion to obtain large numbers of cells also negatively affects the regenerative potential of MSCs. It is therefore essential to improve the regenerative potential of stem cells compromised due to "in vitro expansion", "donor age" and "donor disease status" for their successful autologous use. The current review has been organized to address the age and disease depleted function of resident adult stem cells, and the strategies to improve their potential. To combat the problem of decline in the regenerative potential of cells, this review focuses on the strategies that manipulate the cell environment such as hypoxia, heat shock, caloric restriction and preconditioning with different factors.
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Affiliation(s)
- Mahmood S Choudhery
- Department of Biomedical Sciences, King Edward Medical University, Lahore 54000, Punjab, Pakistan
- Department of Genetics and Molecular Biology, University of Health Sciences, Lahore 54600, Punjab, Pakistan.
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26
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Li N, Fu L, Li Z, Ke Y, Wang Y, Wu J, Yu J. The Role of Immune Microenvironment in Maxillofacial Bone Homeostasis. FRONTIERS IN DENTAL MEDICINE 2021. [DOI: 10.3389/fdmed.2021.780973] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
Abstract
Maxillofacial bone defects are common medical problems caused by congenital defects, necrosis, trauma, tumor, inflammation, and fractures non-union. Maxillofacial bone defects often need bone graft, which has many difficulties, such as limited autogenous bone supply and donor site morbidity. Bone tissue engineering is a promising strategy to overcome the above-mentioned problems. Osteoimmunology is the inter-discipline that focuses on the relationship between the skeletal and immune systems. The immune microenvironment plays a crucial role in bone healing, tissue repair and regeneration in maxillofacial region. Recent studies have revealed the vital role of immune microenvironment and bone homeostasis. In this study, we analyzed the complex interaction between immune microenvironment and bone regeneration process in oral and maxillofacial region, which will be important to improve the clinical outcome of the bone injury treatment.
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27
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Cinat D, Coppes RP, Barazzuol L. DNA Damage-Induced Inflammatory Microenvironment and Adult Stem Cell Response. Front Cell Dev Biol 2021; 9:729136. [PMID: 34692684 PMCID: PMC8531638 DOI: 10.3389/fcell.2021.729136] [Citation(s) in RCA: 35] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2021] [Accepted: 08/18/2021] [Indexed: 12/14/2022] Open
Abstract
Adult stem cells ensure tissue homeostasis and regeneration after injury. Due to their longevity and functional requirements, throughout their life stem cells are subject to a significant amount of DNA damage. Genotoxic stress has recently been shown to trigger a cascade of cell- and non-cell autonomous inflammatory signaling pathways, leading to the release of pro-inflammatory factors and an increase in the amount of infiltrating immune cells. In this review, we discuss recent evidence of how DNA damage by affecting the microenvironment of stem cells present in adult tissues and neoplasms can affect their maintenance and long-term function. We first focus on the importance of self-DNA sensing in immunity activation, inflammation and secretion of pro-inflammatory factors mediated by activation of the cGAS-STING pathway, the ZBP1 pathogen sensor, the AIM2 and NLRP3 inflammasomes. Alongside cytosolic DNA, the emerging roles of cytosolic double-stranded RNA and mitochondrial DNA are discussed. The DNA damage response can also initiate mechanisms to limit division of damaged stem/progenitor cells by inducing a permanent state of cell cycle arrest, known as senescence. Persistent DNA damage triggers senescent cells to secrete senescence-associated secretory phenotype (SASP) factors, which can act as strong immune modulators. Altogether these DNA damage-mediated immunomodulatory responses have been shown to affect the homeostasis of tissue-specific stem cells leading to degenerative conditions. Conversely, the release of specific cytokines can also positively impact tissue-specific stem cell plasticity and regeneration in addition to enhancing the activity of cancer stem cells thereby driving tumor progression. Further mechanistic understanding of the DNA damage-induced immunomodulatory response on the stem cell microenvironment might shed light on age-related diseases and cancer, and potentially inform novel treatment strategies.
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Affiliation(s)
- Davide Cinat
- Department of Biomedical Sciences of Cells and Systems, University Medical Center Groningen, University of Groningen, Groningen, Netherlands.,Department of Radiation Oncology, University Medical Center Groningen, University of Groningen, Groningen, Netherlands
| | - Robert P Coppes
- Department of Biomedical Sciences of Cells and Systems, University Medical Center Groningen, University of Groningen, Groningen, Netherlands.,Department of Radiation Oncology, University Medical Center Groningen, University of Groningen, Groningen, Netherlands
| | - Lara Barazzuol
- Department of Biomedical Sciences of Cells and Systems, University Medical Center Groningen, University of Groningen, Groningen, Netherlands.,Department of Radiation Oncology, University Medical Center Groningen, University of Groningen, Groningen, Netherlands
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28
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Wang Q, Xu L, Willumeit-Römer R, Luthringer-Feyerabend BJC. Macrophage-derived oncostatin M/bone morphogenetic protein 6 in response to Mg-based materials influences pro-osteogenic activity of human umbilical cord perivascular cells. Acta Biomater 2021; 133:268-279. [PMID: 33321219 DOI: 10.1016/j.actbio.2020.12.016] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2020] [Revised: 11/26/2020] [Accepted: 12/08/2020] [Indexed: 01/08/2023]
Abstract
Macrophages are the central immune cell involved in the foreign body reaction to the implants. Furthermore, the magnesium-based materials could modulate macrophage functions, and subsequently influence bone formation via not clearly understood mechanisms. To analysis the roles of materials (magnesium and its gadolinium-based alloy; Mg and Mg-10Gd) on secretion of macrophages and their effects on pro-osteogenic activity, human mesenchymal stem cells (MSC) and macrophages were cocultured directly on the materials surface. Here, oncostatin M (OSM) - glycoprotein 130 (gp130) signaling complex as well as BMP6/SMAD were found to be involved in the Mg and Mg-10Gd multifactorial modulating osteogenic differentiation. Furthermore, materials upregulated the gene expression of bone morphogenetic protein 6 (BMP6) in macrophages, as well as its protein receptors and mothers against decapentaplegic homolog (SMAD) 1/4/5 in cocultured MSC. Besides, both materials could reduce the secretion of tumour necrosis factor alpha (TNFα) and interleukin 1 beta (IL1β) in macrophages and cocultures. These results collectively imply that Mg and Mg-10Gd could create a beneficial microenvironment for osteogenic differentiation and further support Mg-based biomaterial immunomodulatory properties by modulating the interactions of macrophages and MSC for bone regeneration. STATEMENT OF SIGNIFICANCE: Mg-activated macrophages could regulate the pro-osteogenic activity via OSM/gp130 and Smad-related signalling. The neutralisation assay was utilised to confirm the hypothesis of inductive osteoblastic differentiation of human MSC via OSM/gp130 signalling. Current study are essential to evidence that the coordinated communication between macrophages and MSC (OSM/gp130/BMP6/TNFα/IL1β), which could be utilised for improving magnesium-based bone biomaterials and therapeutic applications.
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Affiliation(s)
- Qian Wang
- Institute of Materials Research, Division for Metallic Biomaterials, Helmholtz-Zentrum Geesthacht (HZG), Geesthacht, Germany
| | - Lei Xu
- Institute of Materials Research, Division for Metallic Biomaterials, Helmholtz-Zentrum Geesthacht (HZG), Geesthacht, Germany
| | - Regine Willumeit-Römer
- Institute of Materials Research, Division for Metallic Biomaterials, Helmholtz-Zentrum Geesthacht (HZG), Geesthacht, Germany
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29
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Debela DT, Muzazu SGY, Heraro KD, Ndalama MT, Mesele BW, Haile DC, Kitui SK, Manyazewal T. New approaches and procedures for cancer treatment: Current perspectives. SAGE Open Med 2021; 9:20503121211034366. [PMID: 34408877 PMCID: PMC8366192 DOI: 10.1177/20503121211034366] [Citation(s) in RCA: 621] [Impact Index Per Article: 155.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2021] [Accepted: 07/05/2021] [Indexed: 01/11/2023] Open
Abstract
Cancer is a global health problem responsible for one in six deaths worldwide. Treating cancer has been a highly complex process. Conventional treatment approaches, such as surgery, chemotherapy, and radiotherapy, have been in use, while significant advances are being made in recent times, including stem cell therapy, targeted therapy, ablation therapy, nanoparticles, natural antioxidants, radionics, chemodynamic therapy, sonodynamic therapy, and ferroptosis-based therapy. Current methods in oncology focus on the development of safe and efficient cancer nanomedicines. Stem cell therapy has brought promising efficacy in regenerating and repairing diseased or damaged tissues by targeting both primary and metastatic cancer foci, and nanoparticles brought new diagnostic and therapeutic options. Targeted therapy possessed breakthrough potential inhibiting the growth and spread of specific cancer cells, causing less damage to healthy cells. Ablation therapy has emerged as a minimally invasive procedure that burns or freezes cancers without the need for open surgery. Natural antioxidants demonstrated potential tracking down free radicals and neutralizing their harmful effects thereby treating or preventing cancer. Several new technologies are currently under research in clinical trials, and some of them have already been approved. This review presented an update on recent advances and breakthroughs in cancer therapies.
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Affiliation(s)
- Dejene Tolossa Debela
- Center for Innovative Drug Development and Therapeutic Trials for Africa (CDT-Africa), College of Health Sciences, Addis Ababa University, Addis Ababa, Ethiopia
| | - Seke GY Muzazu
- Center for Innovative Drug Development and Therapeutic Trials for Africa (CDT-Africa), College of Health Sciences, Addis Ababa University, Addis Ababa, Ethiopia
- Enteric Diseases and Vaccines Research Unit, Centre for Infectious Disease Research in Zambia (CIDRZ), Lusaka, Zambia
| | - Kidist Digamo Heraro
- Center for Innovative Drug Development and Therapeutic Trials for Africa (CDT-Africa), College of Health Sciences, Addis Ababa University, Addis Ababa, Ethiopia
- Wachemo University, Hossana, Ethiopia
| | - Maureen Tayamika Ndalama
- Center for Innovative Drug Development and Therapeutic Trials for Africa (CDT-Africa), College of Health Sciences, Addis Ababa University, Addis Ababa, Ethiopia
| | - Betelhiem Woldemedhin Mesele
- Center for Innovative Drug Development and Therapeutic Trials for Africa (CDT-Africa), College of Health Sciences, Addis Ababa University, Addis Ababa, Ethiopia
- Kotebe Metropolitan University, Addis Ababa, Ethiopia
| | - Dagimawi Chilot Haile
- Center for Innovative Drug Development and Therapeutic Trials for Africa (CDT-Africa), College of Health Sciences, Addis Ababa University, Addis Ababa, Ethiopia
- University of Gondar, Gondar, Ethiopia
| | - Sophia Khalayi Kitui
- Center for Innovative Drug Development and Therapeutic Trials for Africa (CDT-Africa), College of Health Sciences, Addis Ababa University, Addis Ababa, Ethiopia
| | - Tsegahun Manyazewal
- Center for Innovative Drug Development and Therapeutic Trials for Africa (CDT-Africa), College of Health Sciences, Addis Ababa University, Addis Ababa, Ethiopia
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30
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You K, Gu H, Yuan Z, Xu X. Tumor Necrosis Factor Alpha Signaling and Organogenesis. Front Cell Dev Biol 2021; 9:727075. [PMID: 34395451 PMCID: PMC8361451 DOI: 10.3389/fcell.2021.727075] [Citation(s) in RCA: 33] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2021] [Accepted: 07/08/2021] [Indexed: 01/04/2023] Open
Abstract
Tumor necrosis factor alpha (TNF-α) plays important roles in processes such as immunomodulation, fever, inflammatory response, inhibition of tumor formation, and inhibition of viral replication. TNF-α and its receptors are ubiquitously expressed in developing organs and they regulate the survival, proliferation, and apoptosis of embryonic stem cells (ESCs) and progenitor cells. TNF-α is an important inflammatory factor that also regulates the inflammatory response during organogenesis, and its cytotoxic effects can interfere with normal developmental processes, even leading to the onset of diseases. This review summarizes the various roles of TNF-α in organogenesis in terms of its secreting pattern, concentration-dependent activities, and interactions with other signaling pathways. We also explored new potential functions of TNF-α.
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Affiliation(s)
- Kai You
- Department of Pediatrics, Shengjing Hospital of China Medical University, Shenyang, China
| | - Hui Gu
- Key Laboratory of Health Ministry for Congenital Malformation, Shengjing Hospital of China Medical University, Shenyang, China
| | - Zhengwei Yuan
- Key Laboratory of Health Ministry for Congenital Malformation, Shengjing Hospital of China Medical University, Shenyang, China
| | - Xuewen Xu
- Key Laboratory of Health Ministry for Congenital Malformation, Shengjing Hospital of China Medical University, Shenyang, China.,Department of Urology, Shengjing Hospital of China Medical University, Shenyang, China
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31
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Guo X, Wu Z. GABARAP ameliorates IL-1β-induced inflammatory responses and osteogenic differentiation in bone marrow-derived stromal cells by activating autophagy. Sci Rep 2021; 11:11561. [PMID: 34078931 PMCID: PMC8172545 DOI: 10.1038/s41598-021-90586-9] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2021] [Accepted: 05/13/2021] [Indexed: 12/13/2022] Open
Abstract
Bone mesenchymal stem cells (BMSCs) are the most commonly investigated progenitor cells in bone defect repair and osteoarthritis subchondral bone regeneration; however, these studies are limited by complex inflammatory conditions. In this study, we investigated whether pro-autophagic γ-aminobutyric acid receptor-associated protein (GABARAP) promotes BMSCs proliferation and osteogenic differentiation by modulating autophagy in the presence or absence of interleukin-1 beta (IL-1β) in vitro. The expression levels of all relevant factors were evaluated by qRT-PCR or western blotting where appropriate. BMSCs differentiation were assessed by Alizarin Red, alkaline phosphatase, safranin O, and Oil Red O staining. Furthermore, the interactions between autophagy and osteogenic differentiation were investigated by co-treatment with the autophagy inhibitor 3-methyladenine (3-MA). As the results, we found that treatment with recombinant human His6-GABARAP protein promoted cell proliferation, inhibited apoptosis, and reduced ROS generation by increasing autophagic activity, particularly when co-cultured with IL-1β. Moreover, His6-GABARAP could effectively increase the osteogenic differentiation of BMSCs. The expression levels of inflammatory factors were significantly decreased by His6-GABARAP treatment, whereas its protective effects were attenuated by 3-MA. This study demonstrates that GABARAP maintains BMSCs survival and strengthens their osteogenic differentiation in an inflammatory environment by upregulating mediators of the autophagy pathway.
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Affiliation(s)
- Xiaobo Guo
- Department of Orthopedics, Jincheng General Hospital, Jincheng, 048000, China.
| | - Zhenyuan Wu
- Department of Orthopedics, Jincheng General Hospital, Jincheng, 048000, China
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32
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Li M, Guo X, Qi W, Wu Z, de Bruijn JD, Xiao Y, Bao C, Yuan H. Macrophage polarization plays roles in bone formation instructed by calcium phosphate ceramics. J Mater Chem B 2021; 8:1863-1877. [PMID: 32067012 DOI: 10.1039/c9tb02932j] [Citation(s) in RCA: 27] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Abstract
To investigate the roles of macrophages in material-instructed bone formation, two calcium phosphate (TCP) ceramics with the same chemistry but various scales of surface topography were employed in this study. After being implanted subcutaneously in FVB mice for 8 weeks, TCPs (TCP ceramics with submicron surface topography) gave rise to bone formation, while TCPb (TCP ceramics with micron surface topography) did not, showing the crucial role of surface topography scale in material-instructed bone formation. Depletion of macrophages with liposomal clodronate (LipClod) blocked such bone formation instructed by TCPs, confirming the role of macrophages in material-instructed bone formation. Macrophage cells (i.e. RAW 264.7 cells) cultured on TCPs in vitro polarized to tissue repair macrophages as evidenced by gene expression and cytokine production, while polarizing to pro-inflammatory macrophages on TCPb. Submicron surface topography of TCP ceramics directed macrophage polarization via PI3K/AKT pathways with the synergistic regulation of integrin β1. Finally, the tissue repair macrophage polarization on TCPs resulted in osteogenic differentiation of mesenchymal stem cells in vitro. At early implantation in FVB mice, TCPs recruited more macrophages which polarized towards tissue repair macrophages with time. The present data demonstrate the important roles of macrophage polarization in bone formation instructed by calcium phosphate ceramics.
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Affiliation(s)
- Mingzheng Li
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, No. 14, Section 3, Ren Min Nan Rd, Chengdu, 610041, Sichuan, China.
| | - Xiaodong Guo
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, No. 14, Section 3, Ren Min Nan Rd, Chengdu, 610041, Sichuan, China.
| | - Wenting Qi
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, No. 14, Section 3, Ren Min Nan Rd, Chengdu, 610041, Sichuan, China.
| | - Zhenzhen Wu
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, No. 14, Section 3, Ren Min Nan Rd, Chengdu, 610041, Sichuan, China.
| | - Joost D de Bruijn
- School of Engineering and Materials Science, Queen Mary University of London, UK
| | - Yu Xiao
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, No. 14, Section 3, Ren Min Nan Rd, Chengdu, 610041, Sichuan, China.
| | - Chongyun Bao
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, No. 14, Section 3, Ren Min Nan Rd, Chengdu, 610041, Sichuan, China.
| | - Huipin Yuan
- Kuros Biosciences BV, Prof. Bronkhorstlaan 10, 3723 MB Bilthoven, The Netherlands and MERLN Institute, Maastricht University, The Netherlands
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Maynard SA, Pchelintseva E, Zwi-Dantsis L, Nagelkerke A, Gopal S, Korchev YE, Shevchuk A, Stevens MM. IL-1β mediated nanoscale surface clustering of integrin α5β1 regulates the adhesion of mesenchymal stem cells. Sci Rep 2021; 11:6890. [PMID: 33767269 PMCID: PMC7994456 DOI: 10.1038/s41598-021-86315-x] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2020] [Accepted: 03/10/2021] [Indexed: 12/18/2022] Open
Abstract
Clinical use of human mesenchymal stem cells (hMSCs) is limited due to their rapid clearance, reducing their therapeutic efficacy. The inflammatory cytokine IL-1β activates hMSCs and is known to enhance their engraftment. Consequently, understanding the molecular mechanism of this inflammation-triggered adhesion is of great clinical interest to improving hMSC retention at sites of tissue damage. Integrins are cell-matrix adhesion receptors, and clustering of integrins at the nanoscale underlies cell adhesion. Here, we found that IL-1β enhances adhesion of hMSCs via increased focal adhesion contacts in an α5β1 integrin-specific manner. Further, through quantitative super-resolution imaging we elucidated that IL-1β specifically increases nanoscale integrin α5β1 availability and clustering at the plasma membrane, whilst conserving cluster area. Taken together, these results demonstrate that hMSC adhesion via IL-1β stimulation is partly regulated through integrin α5β1 spatial organization at the cell surface. These results provide new insight into integrin clustering in inflammation and provide a rational basis for design of therapies directed at improving hMSC engraftment.
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Affiliation(s)
- Stephanie A. Maynard
- grid.7445.20000 0001 2113 8111Department of Materials, Department of Bioengineering and Institute of Biomedical Engineering, Imperial College London, London, SW7 2AZ UK
| | - Ekaterina Pchelintseva
- grid.7445.20000 0001 2113 8111Department of Materials, Department of Bioengineering and Institute of Biomedical Engineering, Imperial College London, London, SW7 2AZ UK
| | - Limor Zwi-Dantsis
- grid.7445.20000 0001 2113 8111Department of Materials, Department of Bioengineering and Institute of Biomedical Engineering, Imperial College London, London, SW7 2AZ UK
| | - Anika Nagelkerke
- grid.7445.20000 0001 2113 8111Department of Materials, Department of Bioengineering and Institute of Biomedical Engineering, Imperial College London, London, SW7 2AZ UK
| | - Sahana Gopal
- grid.7445.20000 0001 2113 8111Department of Materials, Department of Bioengineering and Institute of Biomedical Engineering, Imperial College London, London, SW7 2AZ UK ,grid.7445.20000 0001 2113 8111Department of Medicine, Imperial College London, London, W12 0NN UK
| | - Yuri E. Korchev
- grid.7445.20000 0001 2113 8111Department of Medicine, Imperial College London, London, W12 0NN UK
| | - Andrew Shevchuk
- grid.7445.20000 0001 2113 8111Department of Medicine, Imperial College London, London, W12 0NN UK
| | - Molly M. Stevens
- grid.7445.20000 0001 2113 8111Department of Materials, Department of Bioengineering and Institute of Biomedical Engineering, Imperial College London, London, SW7 2AZ UK
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Zou Z, Liu R, Wang Y, Xing Y, Shi Z, Wang K, Dong D. IL1RN promotes osteoblastic differentiation via interacting with ITGB3 in osteoporosis. Acta Biochim Biophys Sin (Shanghai) 2021; 53:294-303. [PMID: 33493267 DOI: 10.1093/abbs/gmaa174] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2020] [Indexed: 12/14/2022] Open
Abstract
The occurrence and progress of osteoporosis (OP) are partially caused by impaired osteoblast differentiation. Interleukin-I receptor antagonist (IL1RN) is an immune modulatory molecule that commonly functions by means of competing the binding site of IL-1R with IL-1. Although it was recently reported that IL1RN is involved in osteoblast differentiation, the role of IL1RN in osteogenesis remains unclear. In this work, we first investigated the expression pattern of IL1RN in ovariectomy mice and in vitro osteogenic induction of MC3T3-E1 and C3H10T1/2 cells. To verify the exact role of IL1RN in osteoblast differentiation, we established IL1RN-downregulated/upregulated cell lines. The results indicated that IL1RN was constantly expressed in MC3T3-E1 and C3H10T1/2 cells. Interestingly, an increase of IL1RN expression in osteoblasts occurred when osteoblasts were cultured in osteogenic medium (OM). As expected, silencing of IL1RN attenuated the osteogenic effect of OM, while IL1RN overexpression increased the osteogenic staining and promoted the expression of osteogenic markers, including alkaline phosphatase, osterix, and osteocalcin. In addition to evaluating the function of IL1RN in osteoblasts, we also investigated the molecular mechanism of the role of IL1RN in osteoblasts. We found that IL1RN interacts with integrin β3 to activate β-catenin signaling, which finally regulates osteoblast differentiation. Taken together, this study provides the framework that IL1RN, as a novel regulator of osteogenesis, may be a potential therapeutic target for the treatment of OP.
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Affiliation(s)
- Zehua Zou
- Department of Orthopedic, The First Affiliated Hospital of Harbin Medical University, Harbin 150000, China
| | - Ruixuan Liu
- Department of Orthopedic, The First Affiliated Hospital of Harbin Medical University, Harbin 150000, China
| | - Yiwen Wang
- Department of Orthopedic, The First Affiliated Hospital of Harbin Medical University, Harbin 150000, China
| | - Yufei Xing
- Department of Orthopedic, The First Affiliated Hospital of Harbin Medical University, Harbin 150000, China
| | - Zuowei Shi
- Department of Orthopedic, The First Affiliated Hospital of Harbin Medical University, Harbin 150000, China
| | - Kaifu Wang
- Department of Orthopedic, The First Affiliated Hospital of Harbin Medical University, Harbin 150000, China
| | - Daming Dong
- Department of Orthopedic, The First Affiliated Hospital of Harbin Medical University, Harbin 150000, China
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35
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Chen S, Liang H, Ji Y, Kou H, Zhang C, Shang G, Shang C, Song Z, Yang L, Liu L, Wang Y, Liu H. Curcumin Modulates the Crosstalk Between Macrophages and Bone Mesenchymal Stem Cells to Ameliorate Osteogenesis. Front Cell Dev Biol 2021; 9:634650. [PMID: 33634135 PMCID: PMC7900185 DOI: 10.3389/fcell.2021.634650] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2020] [Accepted: 01/04/2021] [Indexed: 01/08/2023] Open
Abstract
Bone healing is thought to be influenced by the cross-talk between bone forming and immune cells. In particular, macrophages play a crucial role in the regulation of osteogenesis. Curcumin, the major bioactive polyphenolic ingredient of turmeric, has been shown to regulate inflammatory response and osteogenic activities. However, whether curcumin could regulate macrophage polarization and subsequently influence osteogenesis remain to be elucidated. In this study, the potential immunomodulatory capability of curcumin on inflammatory response and phenotype switch of macrophages and the subsequent impact on osteogenic differentiation of MSCs are investigated. We demonstrated that curcumin exhibited significant anti-inflammatory effect by polarizing the macrophages toward anti-inflammatory phenotype, with increased expression of IL-4, IL-10, and CD206, and decreased expression of IL-1β, TNF-α, CCR7, and iNOS. In addition, curcumin could improve the osteo-immune microenvironment via promoting osteogenesis-related regenerative cytokine BMP-2 and TGF-β production. Moreover, the co-cultured test of macrophages and BMSCs showed that curcumin-modulated macrophages conditioned medium could promote osteogenic differentiation of BMSCs with increased gene (ALP, Runx-2, OCN, and OPN) and protein (Runx-2 and OCN) expression levels, enhanced ALP activity, and obvious formation of mineralized nodules. Taken together, with the interaction between curcumin-conditioned macrophage and curcumin-stimulated BMSCs, curcumin could remarkably enhance the osteogenic differentiation of BMSCs in LPS-activated inflammatory macrophage-BMSCs coculture system.
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Affiliation(s)
- Songfeng Chen
- Department of Orthopaedics, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Hang Liang
- Department of Orthopaedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Yanhui Ji
- Department of Orthopaedics, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Hongwei Kou
- Department of Orthopaedics, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Chi Zhang
- Department of Orthopaedics, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Guowei Shang
- Department of Orthopaedics, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Chunfeng Shang
- Department of Orthopaedics, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Zongmian Song
- Department of Orthopaedics, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Lin Yang
- Department of Paediatrics, The Zhengzhou Central Hospital Affiliated to Zhengzhou University, Zhengzhou, China
| | - Lei Liu
- Department of Paediatrics, The Zhengzhou Central Hospital Affiliated to Zhengzhou University, Zhengzhou, China
| | - Yongkui Wang
- Department of Orthopaedics, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Hongjian Liu
- Department of Orthopaedics, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
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Das MK, Lunavat TR, Miletic H, Hossain JA. The Potentials and Pitfalls of Using Adult Stem Cells in Cancer Treatment. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2021; 1326:139-157. [PMID: 33615422 DOI: 10.1007/5584_2021_619] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/30/2023]
Abstract
Stem cells play a pivotal role in the developmental stages of an organism and in adulthood as well. Therefore, it is not surprising that stem cells constitute a focus of extensive research. Indeed, several decades of stem cell research have tremendously increased our knowledge on the mechanistic understandings of stem cell biology. Interestingly, revealing the fundamental principles of stem cell biology has also fostered its application for therapeutic purposes. Many of the attributes that the stem cells possess, some of which are unique, allow multifaceted exploitation of stem cells in the treatment of various diseases. Cancer, the leading cause of mortality worldwide, is one of the disease groups that has been benefited by the potentials of therapeutic applications of the stem cells. While the modi operandi of how stem cells contribute to cancer treatment are many-sided, two major principles can be conceived. One mode involves harnessing the regenerative power of the stem cells to promote the generation of blood-forming cells in cancer patients after cytotoxic regimens. A totally different kind of utility of stem cells has been exercised in another mode where the stem cells can potentially deliver a plethora of anti-cancer therapeutics in a tumor-specific manner. While both these approaches can improve the treatment of cancer patients, there exist several issues that warrant further research. This review summarizes the basic principles of the utility of the stem cells in cancer treatment along with the current trends and pinpoints the major obstacles to focus on in the future for further improvement.
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Affiliation(s)
- Mrinal K Das
- Department of Molecular Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway.
| | - Taral R Lunavat
- Department of Biomedicine, University of Bergen, Bergen, Norway
| | - Hrvoje Miletic
- Department of Biomedicine, University of Bergen, Bergen, Norway.,Department of Pathology, Haukeland University Hospital, Bergen, Norway
| | - Jubayer A Hossain
- Department of Biomedicine, University of Bergen, Bergen, Norway. .,Department of Pathology, Haukeland University Hospital, Bergen, Norway.
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37
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Arai Y, Park H, Park S, Kim D, Baek I, Jeong L, Kim BJ, Park K, Lee D, Lee SH. Bile acid-based dual-functional prodrug nanoparticles for bone regeneration through hydrogen peroxide scavenging and osteogenic differentiation of mesenchymal stem cells. J Control Release 2020; 328:596-607. [PMID: 32946872 DOI: 10.1016/j.jconrel.2020.09.023] [Citation(s) in RCA: 28] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2020] [Revised: 08/20/2020] [Accepted: 09/11/2020] [Indexed: 12/11/2022]
Abstract
A high level of reactive oxygen species (ROS) such as hydrogen peroxide (H2O2) upregulates pro-inflammatory cytokines and inhibits the osteogenic differentiation of mesenchymal stem cells (MSCs), which are key factors in bone regeneration. Ursodeoxycholic acid (UDCA), a hydrophilic bile acid, has antioxidant and anti-inflammatory activities and also plays beneficial roles in bone regeneration by stimulating the osteogenic differentiation of MSCs while suppressing their adipogenic differentiation. Despite its remarkable capacity for bone regeneration, multiple injections of UDCA induce adverse side effects such as mechanical stress and contamination in bone defects. To fully exploit the beneficial roles of UDCA, a concept polymeric prodrug was developed based on the hypothesis that removal of overproduced H2O2 will potentiate the osteogenic functions of UDCA. In this work, we report bone regenerative nanoparticles (NPs) formulated from a polymeric prodrug of UDCA (PUDCA) with UDCA incorporated in its backbone through H2O2-responsive peroxalate linkages. The PUDCA NPs displayed potent antioxidant and anti-inflammatory activities in MSCs and induced osteogenic rather than adipogenic differentiation of the MSCs. In rat models of bone defect, the PUDCA NPs exhibited significantly better bone regeneration capacity and anti-inflammatory effects than equivalent amounts of UDCA. We anticipate that PUDCA NPs have tremendous translational potential as bone regenerative agents.
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Affiliation(s)
- Yoshie Arai
- Department of Medical Biotechnology, Dongguk University, 04620 Seoul, South Korea
| | - Hyoeun Park
- Department of Medical Biotechnology, Dongguk University, 04620 Seoul, South Korea
| | - Sunghyun Park
- Department of Biomedical Science, CHA University, CHA Biocomplex, 13488 Gyeonggi-do, South Korea
| | - Dohyun Kim
- Department of Medical Biotechnology, Dongguk University, 04620 Seoul, South Korea
| | - Inho Baek
- Department of Medical Biotechnology, Dongguk University, 04620 Seoul, South Korea
| | - Lipjeong Jeong
- Department of BIN Convergence Technology, Jeonbuk National University, 54896 Jeonbuk, South Korea
| | - Byoung Ju Kim
- Department of Medical Biotechnology, Dongguk University, 04620 Seoul, South Korea
| | - Kwideok Park
- Center for Biomaterials, Korea Institute of Science and Technology (KIST), 02792 Seoul, South Korea
| | - Dongwon Lee
- Department of BIN Convergence Technology, Jeonbuk National University, 54896 Jeonbuk, South Korea.
| | - Soo-Hong Lee
- Department of Medical Biotechnology, Dongguk University, 04620 Seoul, South Korea.
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38
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Zhang C, Gullbrand SE, Schaer TP, Lau YK, Jiang Z, Dodge GR, Elliott DM, Mauck RL, Malhotra NR, Smith LJ. Inflammatory cytokine and catabolic enzyme expression in a goat model of intervertebral disc degeneration. J Orthop Res 2020; 38:2521-2531. [PMID: 32091156 PMCID: PMC7483272 DOI: 10.1002/jor.24639] [Citation(s) in RCA: 32] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/11/2019] [Revised: 01/28/2020] [Accepted: 02/19/2020] [Indexed: 02/04/2023]
Abstract
Intervertebral disc degeneration is implicated as a leading cause of low back pain. Persistent, local inflammation within the disc nucleus pulposus (NP) and annulus fibrosus (AF) is an important mediator of disc degeneration and negatively impacts the performance of therapeutic stem cells. There is a lack of validated large animal models of disc degeneration that recapitulate clinically relevant local inflammation. We recently described a goat model of disc degeneration in which increasing doses of chondroitinase ABC (ChABC) were used to reproducibly induce a spectrum of degenerative changes. The objective of this study was to extend the clinical relevance of this model by establishing whether these degenerative changes are associated with the local expression of inflammatory cytokines and catabolic enzymes. Degeneration was induced in goat lumbar discs using ChABC at different doses. After 12 weeks, degeneration severity was determined histologically and using quantitative magnetic resonance imaging (MRI). Expression levels of inflammatory cytokines (tumor necrosis factor-α [TNF-α], interleukin-1β [IL-1β], and IL-6) and catabolic enzymes (matrix metalloproteinases-1 [MMPs-1] and 13, and a disintegrin and metalloproteinase with thrombospondin type-1 motifs-4 [ADAMTS-4]) were assessed as the percentage of immunopositive cells in the NP and AF. With the exception of MMP-1, cytokine, and enzyme expression levels were significantly elevated in ChABC-treated discs in the NP and AF. Expression levels of TNF-α, IL1-β, and ADAMTS-4 were positively correlated with histological grade, while all cytokines and ADAMTS-4 were negatively correlated with MRI T2 and T1ρ scores. These results demonstrate that degenerate goat discs exhibit elevated expression of clinically relevant inflammatory mediators, and further validate this animal model as a platform for evaluating new therapeutic approaches for disc degeneration.
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Affiliation(s)
- Chenghao Zhang
- Translational Musculoskeletal Research Center, Corporal Michael J. Crescenz Philadelphia VA Medical Center, 3900 Woodland Avenue, Philadelphia, PA, USA
- Department of Neurosurgery, Perelman School of Medicine, University of Pennsylvania, 3450 Hamilton Walk, Philadelphia, PA, USA
- Department of Orthopaedic Surgery, Perelman School of Medicine, University of Pennsylvania, 3450 Hamilton Walk, Philadelphia, PA, USA, Philadelphia, PA, USA
| | - Sarah E. Gullbrand
- Translational Musculoskeletal Research Center, Corporal Michael J. Crescenz Philadelphia VA Medical Center, 3900 Woodland Avenue, Philadelphia, PA, USA
- Department of Orthopaedic Surgery, Perelman School of Medicine, University of Pennsylvania, 3450 Hamilton Walk, Philadelphia, PA, USA, Philadelphia, PA, USA
| | - Thomas P. Schaer
- Comparative Orthopaedic Research Laboratory, New Bolton Center, School of Veterinary Medicine, University of Pennsylvania, 382 W Street Rd, Kennett Square, PA, USA
| | - Yian Khai Lau
- Translational Musculoskeletal Research Center, Corporal Michael J. Crescenz Philadelphia VA Medical Center, 3900 Woodland Avenue, Philadelphia, PA, USA
- Department of Neurosurgery, Perelman School of Medicine, University of Pennsylvania, 3450 Hamilton Walk, Philadelphia, PA, USA
- Department of Orthopaedic Surgery, Perelman School of Medicine, University of Pennsylvania, 3450 Hamilton Walk, Philadelphia, PA, USA, Philadelphia, PA, USA
| | - Zhirui Jiang
- Translational Musculoskeletal Research Center, Corporal Michael J. Crescenz Philadelphia VA Medical Center, 3900 Woodland Avenue, Philadelphia, PA, USA
- Department of Neurosurgery, Perelman School of Medicine, University of Pennsylvania, 3450 Hamilton Walk, Philadelphia, PA, USA
- Department of Orthopaedic Surgery, Perelman School of Medicine, University of Pennsylvania, 3450 Hamilton Walk, Philadelphia, PA, USA, Philadelphia, PA, USA
| | - George R. Dodge
- Translational Musculoskeletal Research Center, Corporal Michael J. Crescenz Philadelphia VA Medical Center, 3900 Woodland Avenue, Philadelphia, PA, USA
- Department of Orthopaedic Surgery, Perelman School of Medicine, University of Pennsylvania, 3450 Hamilton Walk, Philadelphia, PA, USA, Philadelphia, PA, USA
| | - Dawn M. Elliott
- Department of Biomedical Engineering, University of Delaware, Newark, DE, USA
| | - Robert L. Mauck
- Translational Musculoskeletal Research Center, Corporal Michael J. Crescenz Philadelphia VA Medical Center, 3900 Woodland Avenue, Philadelphia, PA, USA
- Department of Orthopaedic Surgery, Perelman School of Medicine, University of Pennsylvania, 3450 Hamilton Walk, Philadelphia, PA, USA, Philadelphia, PA, USA
| | - Neil R. Malhotra
- Translational Musculoskeletal Research Center, Corporal Michael J. Crescenz Philadelphia VA Medical Center, 3900 Woodland Avenue, Philadelphia, PA, USA
| | - Lachlan J. Smith
- Translational Musculoskeletal Research Center, Corporal Michael J. Crescenz Philadelphia VA Medical Center, 3900 Woodland Avenue, Philadelphia, PA, USA
- Department of Neurosurgery, Perelman School of Medicine, University of Pennsylvania, 3450 Hamilton Walk, Philadelphia, PA, USA
- Department of Orthopaedic Surgery, Perelman School of Medicine, University of Pennsylvania, 3450 Hamilton Walk, Philadelphia, PA, USA, Philadelphia, PA, USA
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39
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Zhao SJ, Liu H, Chen J, Qian DF, Kong FQ, Jie J, Yin GY, Li QQ, Fan J. Macrophage GIT1 Contributes to Bone Regeneration by Regulating Inflammatory Responses in an ERK/NRF2-Dependent Way. J Bone Miner Res 2020; 35:2015-2031. [PMID: 32460388 PMCID: PMC7689802 DOI: 10.1002/jbmr.4099] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/13/2020] [Revised: 05/19/2020] [Accepted: 05/21/2020] [Indexed: 12/12/2022]
Abstract
Despite the best treatment, approximately 10% of fractures still face undesirable repair. Recently, many studies have focused on the importance of macrophages in bone repair; however, the cellular mechanisms by which they work are not yet fully understood. In this study, we explored the functions of macrophage G-protein-coupled receptor interacting protein 1 (GIT1) in healing a tibial monocortical defect model. Using GIT1flox/flox Lyz2-Cre (GIT1 CKO) mice, we observed that a GIT1 deficiency in the macrophages led to an exacerbation of interleukin 1β (IL1β) production, more M1-like macrophage infiltration, and impaired intramembranous ossification in vivo. The results of in vitro assays further indicated that the macrophage GIT1 plays a critical role in several cellular processes in response to lipopolysaccharide (LPS), such as anti-oxidation, IL1β production alleviation, and glycolysis control. Although GIT1 has been recognized as a scaffold protein, our data clarified that GIT1-mediated extracellular-signal-regulated kinase (ERK) phosphorylation could activate nuclear factor (erythroid-derived 2)-like 2 (NRF2) in macrophages after LPS treatment. Moreover, we demonstrated that macrophage GIT1-activated ERK/NRF2 negatively regulates the 6-phosphofructo-2-kinase/fructose-2, 6-biphosphatase 3 (PFKFB3), facilitating the decrease of glycolysis. Our findings uncovered a previously unrecognized role of GIT1 in regulating ERK/NRF2 in macrophages to control the inflammatory response, suggesting that macrophage GIT1 could be a potential target to improve bone regeneration. © 2020 The Authors. Journal of Bone and Mineral Research published by American Society for Bone and Mineral Research..
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Affiliation(s)
- Shu-Jie Zhao
- Department of Orthopedics, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Hao Liu
- Department of Orthopedics, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Jian Chen
- Department of Orthopedics, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Ding-Fei Qian
- Department of Orthopedics, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Fan-Qi Kong
- Department of Orthopedics, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Jian Jie
- Department of Orthopedics, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China.,Department of Orthopedics, Pukou Branch of Jiangsu Province Hospital (Nanjing Pukou Central Hospital), Nanjing, China
| | - Guo-Yong Yin
- Department of Orthopedics, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Qing-Qing Li
- Department of Orthopedics, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Jin Fan
- Department of Orthopedics, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
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40
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Zhang K, Yang X, Zhao Q, Li Z, Fu F, Zhang H, Zheng M, Zhang S. Molecular Mechanism of Stem Cell Differentiation into Adipocytes and Adipocyte Differentiation of Malignant Tumor. Stem Cells Int 2020; 2020:8892300. [PMID: 32849880 PMCID: PMC7441422 DOI: 10.1155/2020/8892300] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2020] [Revised: 07/07/2020] [Accepted: 07/27/2020] [Indexed: 02/07/2023] Open
Abstract
Adipogenesis is the process through which preadipocytes differentiate into adipocytes. During this process, the preadipocytes cease to proliferate, begin to accumulate lipid droplets, and develop morphologic and biochemical characteristics of mature adipocytes. Mesenchymal stem cells (MSCs) are a type of adult stem cells known for their high plasticity and capacity to generate mesodermal and nonmesodermal tissues. Many mature cell types can be generated from MSCs, including adipocyte, osteocyte, and chondrocyte. The differentiation of stem cells into multiple mature phenotypes is at the basis for tissue regeneration and repair. Cancer stem cells (CSCs) play a very important role in tumor development and have the potential to differentiate into multiple cell lineages. Accumulating evidence has shown that cancer cells can be induced to differentiate into various benign cells, such as adipocytes, fibrocytes, osteoblast, by a variety of small molecular compounds, which may provide new strategies for cancer treatment. Recent studies have reported that tumor cells undergoing epithelial-to-mesenchymal transition can be induced to differentiate into adipocytes. In this review, molecular mechanisms, signal pathways, and the roles of various biological processes in adipose differentiation are summarized. Understanding the molecular mechanism of adipogenesis and adipose differentiation of cancer cells may contribute to cancer treatments that involve inducing differentiation into benign cells.
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Affiliation(s)
- Kexin Zhang
- Department of Pathology, Tianjin Union Medical Center, Tianjin, China
- Nankai University School of Medicine, Nankai University, Tianjin, China
| | - Xudong Yang
- Tianjin Rehabilitation Center, Tianjin, China
| | - Qi Zhao
- Department of Pathology, Tianjin Union Medical Center, Tianjin, China
| | - Zugui Li
- Department of Pathology, Tianjin Union Medical Center, Tianjin, China
- Graduate School, Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Fangmei Fu
- Department of Pathology, Tianjin Union Medical Center, Tianjin, China
- Graduate School, Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Hao Zhang
- Department of Pathology, Tianjin Union Medical Center, Tianjin, China
- Graduate School, Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Minying Zheng
- Department of Pathology, Tianjin Union Medical Center, Tianjin, China
| | - Shiwu Zhang
- Department of Pathology, Tianjin Union Medical Center, Tianjin, China
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41
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Lukač N, Katavić V, Novak S, Šućur A, Filipović M, Kalajzić I, Grčević D, Kovačić N. What do we know about bone morphogenetic proteins and osteochondroprogenitors in inflammatory conditions? Bone 2020; 137:115403. [PMID: 32371019 DOI: 10.1016/j.bone.2020.115403] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/07/2020] [Revised: 04/10/2020] [Accepted: 04/28/2020] [Indexed: 02/07/2023]
Abstract
Osteochondroprogenitors are crucial for embryonic bone development and postnatal processes such as bone repair in response to fracture injury, and their dysfunction may contribute to insufficient repair of structural damage in inflammatory arthritides. In the fracture healing, the early inflammatory phase is crucial for normal callus development and new bone formation. This process involves a complex interplay of many molecules and cell types, responsible for recruitment, expansion and differentiation of osteochondroprogenitor populations. In inflammatory arthritides, inflammation induces bone resorption and causes insufficient bone formation, which leads to local and systemic bone loss. While bone loss is a predominant feature in rheumatoid arthritis, inflammation also induces pathologic bone formation at enthesial sites in seronegative spondyloarthropathies. Bone morphogenetic proteins (BMP) are involved in cell proliferation, differentiation and apoptosis, and have fundamental roles in maintenance of postnatal bone homeostasis. They are crucial regulators of the osteochondroprogenitor pool and drive their proliferation, differentiation, and lifespan during bone regeneration. In this review, we summarize the effects of inflammation on osteochondroprogenitor populations during fracture repair and in inflammatory arthritides, with special focus on inflammation-mediated modulation of BMP signaling. We also present data in which we describe a population of murine synovial osteochondroprogenitor cells, which are reduced in arthritis, and characterize their expression of genes involved in regulation of bone homeostasis, emphasizing the up-regulation of BMP pathways in early progenitor subset. Based on the presented data, it may be concluded that during an inflammatory response, innate immune cells induce osteochondroprogenitors by providing signals for their recruitment, by producing BMPs and other osteogenic factors for paracrine effects, and by secreting inflammatory cytokines that may positively regulate osteogenic pathways. On the other hand, inflammatory cells may secrete cytokines that interfere with osteogenic pathways, proapoptotic factors that reduce the pool of osteochondroprogenitor cells, as well as BMP and Wnt antagonists. The net effect is strongly context-dependent and influenced by the local milieu of cells, cytokines, and growth factors. Further elucidation of the interplay between inflammatory signals and BMP-mediated bone formation may provide valuable tools for therapeutic targeting.
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Affiliation(s)
- Nina Lukač
- Laboratory for Molecular Immunology, University of Zagreb School of Medicine, Zagreb, Croatia; Department of Anatomy, University of Zagreb School of Medicine, Zagreb, Croatia
| | - Vedran Katavić
- Laboratory for Molecular Immunology, University of Zagreb School of Medicine, Zagreb, Croatia; Department of Anatomy, University of Zagreb School of Medicine, Zagreb, Croatia
| | - Sanja Novak
- Department of Reconstructive Sciences, University of Connecticut Health Center, Farmington, CT, USA
| | - Alan Šućur
- Laboratory for Molecular Immunology, University of Zagreb School of Medicine, Zagreb, Croatia; Department of Physiology and Immunology, University of Zagreb School of Medicine, Zagreb, Croatia
| | - Maša Filipović
- Laboratory for Molecular Immunology, University of Zagreb School of Medicine, Zagreb, Croatia; Department of Physiology and Immunology, University of Zagreb School of Medicine, Zagreb, Croatia
| | - Ivo Kalajzić
- Department of Reconstructive Sciences, University of Connecticut Health Center, Farmington, CT, USA
| | - Danka Grčević
- Laboratory for Molecular Immunology, University of Zagreb School of Medicine, Zagreb, Croatia; Department of Physiology and Immunology, University of Zagreb School of Medicine, Zagreb, Croatia
| | - Nataša Kovačić
- Laboratory for Molecular Immunology, University of Zagreb School of Medicine, Zagreb, Croatia; Department of Anatomy, University of Zagreb School of Medicine, Zagreb, Croatia.
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Lynch K, Treacy O, Chen X, Murphy N, Lohan P, Islam MN, Donohoe E, Griffin MD, Watson L, McLoughlin S, O'Malley G, Ryan AE, Ritter T. TGF-β1-Licensed Murine MSCs Show Superior Therapeutic Efficacy in Modulating Corneal Allograft Immune Rejection In Vivo. Mol Ther 2020; 28:2023-2043. [PMID: 32531237 PMCID: PMC7474271 DOI: 10.1016/j.ymthe.2020.05.023] [Citation(s) in RCA: 46] [Impact Index Per Article: 9.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2019] [Revised: 03/14/2020] [Accepted: 05/26/2020] [Indexed: 12/13/2022] Open
Abstract
Mesenchymal stromal cells (MSCs) are a promising therapeutic option for multiple immune diseases/disorders; however, efficacy of MSC treatments can vary significantly. We present a novel licensing strategy to improve the immunosuppressive capacity of MSCs. Licensing murine MSCs with transforming growth factor-β1 (TGF-β MSCs) significantly improved their ability to modulate both the phenotype and secretome of inflammatory bone marrow-derived macrophages and significantly increased the numbers of regulatory T lymphocytes following co-culture assays. These TGF-β MSC-expanded regulatory T lymphocytes also expressed significantly higher levels of PD-L1 and CD73, indicating enhanced suppressive potential. Detailed analysis of T lymphocyte co-cultures revealed modulation of secreted factors, most notably elevated prostaglandin E2 (PGE2). Furthermore, TGF-β MSCs could significantly prolong rejection-free survival (69.2% acceptance rate compared to 21.4% for unlicensed MSC-treated recipients) in a murine corneal allograft model. Mechanistic studies revealed that (1) therapeutic efficacy of TGF-β MSCs is Smad2/3-dependent, (2) the enhanced immunosuppressive capacity of TGF-β MSCs is contact-dependent, and (3) enhanced secretion of PGE2 (via prostaglandin EP4 [E-type prostanoid 4] receptor) by TGF-β MSCs is the predominant mediator of Treg expansion and T cell activation and is associated with corneal allograft survival. Collectively, we provide compelling evidence for the use of TGF-β1 licensing as an unconventional strategy for enhancing MSC immunosuppressive capacity.
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Affiliation(s)
- Kevin Lynch
- Discipline of Pharmacology and Therapeutics, School of Medicine, College of Medicine, Nursing and Health Sciences, National University of Ireland, Galway, Galway, Ireland; Regenerative Medicine Institute (REMEDI), School of Medicine, College of Medicine, Nursing and Health Sciences, National University of Ireland Galway, Galway, Ireland
| | - Oliver Treacy
- Discipline of Pharmacology and Therapeutics, School of Medicine, College of Medicine, Nursing and Health Sciences, National University of Ireland, Galway, Galway, Ireland; Regenerative Medicine Institute (REMEDI), School of Medicine, College of Medicine, Nursing and Health Sciences, National University of Ireland Galway, Galway, Ireland
| | - Xizhe Chen
- Regenerative Medicine Institute (REMEDI), School of Medicine, College of Medicine, Nursing and Health Sciences, National University of Ireland Galway, Galway, Ireland; CÚRAM, SFI Research Centre for Medical Devices, National University of Ireland Galway, Galway, Ireland
| | - Nick Murphy
- Regenerative Medicine Institute (REMEDI), School of Medicine, College of Medicine, Nursing and Health Sciences, National University of Ireland Galway, Galway, Ireland
| | - Paul Lohan
- Regenerative Medicine Institute (REMEDI), School of Medicine, College of Medicine, Nursing and Health Sciences, National University of Ireland Galway, Galway, Ireland
| | - Md Nahidul Islam
- Regenerative Medicine Institute (REMEDI), School of Medicine, College of Medicine, Nursing and Health Sciences, National University of Ireland Galway, Galway, Ireland
| | - Ellen Donohoe
- Regenerative Medicine Institute (REMEDI), School of Medicine, College of Medicine, Nursing and Health Sciences, National University of Ireland Galway, Galway, Ireland
| | - Matthew D Griffin
- Regenerative Medicine Institute (REMEDI), School of Medicine, College of Medicine, Nursing and Health Sciences, National University of Ireland Galway, Galway, Ireland; CÚRAM, SFI Research Centre for Medical Devices, National University of Ireland Galway, Galway, Ireland
| | - Luke Watson
- Orbsen Therapeutics, National University of Ireland, Galway, Galway, Ireland
| | - Steven McLoughlin
- Regenerative Medicine Institute (REMEDI), School of Medicine, College of Medicine, Nursing and Health Sciences, National University of Ireland Galway, Galway, Ireland
| | - Grace O'Malley
- Discipline of Pharmacology and Therapeutics, School of Medicine, College of Medicine, Nursing and Health Sciences, National University of Ireland, Galway, Galway, Ireland; Regenerative Medicine Institute (REMEDI), School of Medicine, College of Medicine, Nursing and Health Sciences, National University of Ireland Galway, Galway, Ireland
| | - Aideen E Ryan
- Discipline of Pharmacology and Therapeutics, School of Medicine, College of Medicine, Nursing and Health Sciences, National University of Ireland, Galway, Galway, Ireland; Regenerative Medicine Institute (REMEDI), School of Medicine, College of Medicine, Nursing and Health Sciences, National University of Ireland Galway, Galway, Ireland; CÚRAM, SFI Research Centre for Medical Devices, National University of Ireland Galway, Galway, Ireland.
| | - Thomas Ritter
- Regenerative Medicine Institute (REMEDI), School of Medicine, College of Medicine, Nursing and Health Sciences, National University of Ireland Galway, Galway, Ireland; CÚRAM, SFI Research Centre for Medical Devices, National University of Ireland Galway, Galway, Ireland.
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Chu DT, Nguyen TT, Tien NLB, Tran DK, Jeong JH, Anh PG, Thanh VV, Truong DT, Dinh TC. Recent Progress of Stem Cell Therapy in Cancer Treatment: Molecular Mechanisms and Potential Applications. Cells 2020; 9:cells9030563. [PMID: 32121074 PMCID: PMC7140431 DOI: 10.3390/cells9030563] [Citation(s) in RCA: 108] [Impact Index Per Article: 21.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2020] [Revised: 02/26/2020] [Accepted: 02/26/2020] [Indexed: 02/07/2023] Open
Abstract
The insufficient and unspecific target of traditional therapeutic approaches in cancer treatment often leads to therapy resistance and cancer recurrence. Over the past decades, accumulating discoveries about stem cell biology have provided new potential approaches to cure cancer patients. Stem cells possess unique biological actions, including self-renewal, directional migration, differentiation, and modulatory effects on other cells, which can be utilized as regenerative medicine, therapeutic carriers, drug targeting, and generation of immune cells. In this review, we emphasize the mechanisms underlying the use of various types of stem cells in cancer treatment. In addition, we summarize recent progress in the clinical applications of stem cells, as well as common risks of this therapy. We finally give general directions for future studies, aiming to improve overall outcomes in the fight against cancer.
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Affiliation(s)
- Dinh-Toi Chu
- Department of Human and Animal Physiology, Faculty of Biology, Hanoi National University of Education, Hanoi 100000, Vietnam
- Correspondence: (D.-T.C.); (T.C.D.); Tel.: +84966409783 (D.-T.C.)
| | - Tiep Tien Nguyen
- College of Pharmacy, Yeungnam University, 280 Daehak-ro, Gyeongsan-si, Gyeongbuk-do 38541, Korea; (T.T.N.); (J.-H.J.)
| | - Nguyen Le Bao Tien
- Institute of Orthopaedics and Trauma Surgery, Viet Duc Hospital, Hanoi 100000, Vietnam; (N.L.B.T.); (V.V.T.)
| | - Dang-Khoa Tran
- Department of Anatomy, University of Medicine Pham Ngoc Thach, Ho Chi Minh City 700000, Vietnam;
| | - Jee-Heon Jeong
- College of Pharmacy, Yeungnam University, 280 Daehak-ro, Gyeongsan-si, Gyeongbuk-do 38541, Korea; (T.T.N.); (J.-H.J.)
| | - Pham Gia Anh
- Oncology Department, Viet Duc Hospital, Hanoi 100000, Vietnam;
| | - Vo Van Thanh
- Institute of Orthopaedics and Trauma Surgery, Viet Duc Hospital, Hanoi 100000, Vietnam; (N.L.B.T.); (V.V.T.)
- Department of Surgery, Hanoi Medical University, Hanoi 100000, Vietnam
| | - Dang Tien Truong
- Department of Anatomy, Vietnam Military Medical University, Hanoi 100000, Vietnam;
| | - Thien Chu Dinh
- Institute for Research and Development, Duy Tan University, Danang 550000, Vietnam
- Correspondence: (D.-T.C.); (T.C.D.); Tel.: +84966409783 (D.-T.C.)
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Cao H, Zhu X, Zhang J, Xu M, Ge L, Zhang C. Dose-dependent effects of tetramethylpyrazine on the characteristics of human umbilical cord mesenchymal stem cells for stroke therapy. Neurosci Lett 2020; 722:134797. [PMID: 32067986 DOI: 10.1016/j.neulet.2020.134797] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2019] [Revised: 01/25/2020] [Accepted: 01/27/2020] [Indexed: 12/15/2022]
Abstract
Umbilical cord mesenchymal stem cells (ucMSCs) may serve as a new source for cell therapy in stroke patients; however, the poor efficiency of viability, migration, and differentiation limit the application of ucMSCs. This study determined the dose-dependent effects of tetramethylpyrazine (TMP) on the characteristics of ucMSCs in vitro. The effect on proliferation was determined with Cell Counting kit-8 assays. Cell migration was analyzed with Transwell assays and western blot analysis. Differentiation of ucMSCs was evaluated according to markers and the expression of relevant proteins and genes. Secretion capacity was detected by ELISA analysis. TMP protected ucMSCs against H2O2 induced-oxidative damage but had no influence on ucMSC activity at a low concentration. Furthermore, ucMSC migration was improved by TMP via the SDF-1/CXCR4 axis. The observed effects were dose dependent. At a high dose, however, TMP induced the differentiation of ucMSCs into neuron-like cells that expressed neuron-specific markers. In addition, the secretion of cytokines was significantly increased by TMP. Therefore, TMP pre-treatment of ucMSCs may be an effective strategy to enhance the efficiency of ucMSC transplantation in stroke therapy.
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Affiliation(s)
- Huiling Cao
- Department of Laboratory Medicine, Affiliated Hospital of Nanjing University of Chinese Medicine, Jiangsu Province Hospital of Chinease Medicine, Nanjing, Jiangsu, PR China.
| | - Xiaofei Zhu
- Department of Laboratory Medicine, Affiliated Hospital of Nanjing University of Chinese Medicine, Jiangsu Province Hospital of Chinease Medicine, Nanjing, Jiangsu, PR China
| | - Jie Zhang
- Department of Laboratory Medicine, Affiliated Hospital of Nanjing University of Chinese Medicine, Jiangsu Province Hospital of Chinease Medicine, Nanjing, Jiangsu, PR China
| | - Min Xu
- Department of Laboratory Medicine, Affiliated Hospital of Nanjing University of Chinese Medicine, Jiangsu Province Hospital of Chinease Medicine, Nanjing, Jiangsu, PR China
| | - Liang Ge
- Department of Laboratory Medicine, Affiliated Hospital of Nanjing University of Chinese Medicine, Jiangsu Province Hospital of Chinease Medicine, Nanjing, Jiangsu, PR China
| | - Chunbing Zhang
- Department of Laboratory Medicine, Affiliated Hospital of Nanjing University of Chinese Medicine, Jiangsu Province Hospital of Chinease Medicine, Nanjing, Jiangsu, PR China
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Wang Y, Wang R, Yao B, Hu T, Li Z, Liu Y, Cui X, Cheng L, Song W, Huang S, Fu X. TNF-α suppresses sweat gland differentiation of MSCs by reducing FTO-mediated m 6A-demethylation of Nanog mRNA. SCIENCE CHINA. LIFE SCIENCES 2020; 63:80-91. [PMID: 31637575 DOI: 10.1007/s11427-019-9826-7] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/17/2019] [Accepted: 09/03/2019] [Indexed: 01/05/2023]
Abstract
An effect of inhibition of tumor necrosis factor-α (TNF-α) on differentiation of mesenchymal stromal cells (MSCs) has been demonstrated, but the exact mechanisms that govern MSCs differentiation remain to be further elucidated. Here, we show that TNF-α inhibits the differentiation of MSCs to sweat glands in a specific sweat gland-inducing environment, accompanied with reduced expression of Nanog, a core pluripotency factor. We elucidated that fat mass and obesity-associated protein (FTO)-mediated m6A demethylation is involved in the regulation of MSCs differentiation potential. Exposure of MSCs to TNF-α reduced expression of FTO, which demethylated Nanog mRNA. Reduced expression of FTO increased Nanog mRNA methylation, decreased Nanog mRNA and protein expression, and significantly inhibited MSCs capacity for differentiation to sweat gland cells. Our finding is the first to elucidate the functional importance of m6A modification in MSCs, providing new insights that the microenvironment can regulate the multipotency of MSCs at the post-transcriptional level. Moreover, to maintain differentiation capacity of MSCs by regulating m6A modification suggested a novel potential therapeutic target for stem cell-mediated regenerative medicine.
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Affiliation(s)
- Yihui Wang
- Tianjin Medical University, Tianjin, 300070, China
- Key Laboratory of Tissue Repair and Regeneration of PLA, and Beijing Key Research Laboratory of Skin Injury, Repair and Regeneration, Fourth Medical Center of General Hospital of PLA, Beijing, 100048, China
| | - Rui Wang
- Tianjin Medical University, Tianjin, 300070, China
- Key Laboratory of Tissue Repair and Regeneration of PLA, and Beijing Key Research Laboratory of Skin Injury, Repair and Regeneration, Fourth Medical Center of General Hospital of PLA, Beijing, 100048, China
| | - Bin Yao
- Key Laboratory of Tissue Repair and Regeneration of PLA, and Beijing Key Research Laboratory of Skin Injury, Repair and Regeneration, Fourth Medical Center of General Hospital of PLA, Beijing, 100048, China
| | - Tian Hu
- Key Laboratory of Tissue Repair and Regeneration of PLA, and Beijing Key Research Laboratory of Skin Injury, Repair and Regeneration, Fourth Medical Center of General Hospital of PLA, Beijing, 100048, China
- School of Medicine, Nankai University, Tianjin, 300052, China
| | - Zhao Li
- Wound Healing and Cell Biology Laboratory, Institute of Basic Medical Sciences, General Hospital of PLA, Beijing, 100853, China
| | - Yufan Liu
- Wound Healing and Cell Biology Laboratory, Institute of Basic Medical Sciences, General Hospital of PLA, Beijing, 100853, China
| | - Xiaoli Cui
- Key Laboratory of Tissue Repair and Regeneration of PLA, and Beijing Key Research Laboratory of Skin Injury, Repair and Regeneration, Fourth Medical Center of General Hospital of PLA, Beijing, 100048, China
| | - Liuhanghang Cheng
- Key Laboratory of Tissue Repair and Regeneration of PLA, and Beijing Key Research Laboratory of Skin Injury, Repair and Regeneration, Fourth Medical Center of General Hospital of PLA, Beijing, 100048, China
| | - Wei Song
- Key Laboratory of Tissue Repair and Regeneration of PLA, and Beijing Key Research Laboratory of Skin Injury, Repair and Regeneration, Fourth Medical Center of General Hospital of PLA, Beijing, 100048, China
| | - Sha Huang
- Key Laboratory of Tissue Repair and Regeneration of PLA, and Beijing Key Research Laboratory of Skin Injury, Repair and Regeneration, Fourth Medical Center of General Hospital of PLA, Beijing, 100048, China.
- Wound Healing and Cell Biology Laboratory, Institute of Basic Medical Sciences, General Hospital of PLA, Beijing, 100853, China.
| | - Xiaobing Fu
- Key Laboratory of Tissue Repair and Regeneration of PLA, and Beijing Key Research Laboratory of Skin Injury, Repair and Regeneration, Fourth Medical Center of General Hospital of PLA, Beijing, 100048, China.
- Wound Healing and Cell Biology Laboratory, Institute of Basic Medical Sciences, General Hospital of PLA, Beijing, 100853, China.
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Extracellular IL-37 promotes osteogenic differentiation of human bone marrow mesenchymal stem cells via activation of the PI3K/AKT signaling pathway. Cell Death Dis 2019; 10:753. [PMID: 31582734 PMCID: PMC6776644 DOI: 10.1038/s41419-019-1904-7] [Citation(s) in RCA: 56] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2019] [Revised: 07/24/2019] [Accepted: 08/11/2019] [Indexed: 12/11/2022]
Abstract
Interleukin (IL)-37, a pivotal anti-inflammatory cytokine and a fundamental inhibitor of innate immunity, has recently been shown to be abnormally expressed in several autoimmune-related orthopedic diseases, including rheumatoid arthritis, ankylosing spondylitis, and osteoporosis. However, the role of IL-37 during osteogenic differentiation of mesenchymal stem cells (MSCs) remains largely unknown. In this study, extracellular IL-37 significantly increased osteoblast-specific gene expression, the number of mineral deposits, and alkaline phosphatase activity of MSCs. Moreover, a signaling pathway was activated in the presence of IL-37. The enhanced osteogenic differentiation of MSCs due to supplementation of IL-37 was partially rescued by the presence of a PI3K/AKT signaling inhibitor. Using a rat calvarial bone defect model, IL-37 significantly improved bone healing. Collectively, these findings indicate that extracellular IL-37 enhanced osteogenesis of MSCs, at least in part by activation of the PI3K/AKT signaling pathway.
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Chen TH, Weber FE, Malina-Altzinger J, Ghayor C. Epigenetic drugs as new therapy for tumor necrosis factor-α-compromised bone healing. Bone 2019; 127:49-58. [PMID: 31152802 DOI: 10.1016/j.bone.2019.05.035] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/05/2019] [Revised: 05/20/2019] [Accepted: 05/27/2019] [Indexed: 02/07/2023]
Abstract
Impaired bone regeneration by excess inflammation leads to failure of bone healing. Current therapies display limited benefits making new treatments imperative. Our recent discoveries of the anti-inflammatory characteristics of bromodomain and extra terminal domain (BET) inhibitors, N-methylpyrrolidone (NMP) and N,N-Dimethylacetamide (DMA), implicate possible therapeutic use of epigenetic drugs in inflammation-impaired bone healing. Here, we investigated the effects of NMP and DMA on osteogenesis in vitro and ex vivo under the influence of TNFα, a key cytokine responsible for impaired fracture healing. NMP and DMA pre-treatment recovered TNFα-inhibited expression of essential osteoblastic genes, Alp, Runx2, and Osterix as well as mineralization in multipotent stem cells, but not in pre-osteoblasts and calvarial osteoblasts. The mechanism of action involves the recovery of TNFα-suppressed BMP-induced Smad signaling and the reduction of TNFα-triggered ERK pathway. In addition, ERK inhibitor treatment diminished the effect of TNFα on osteogenesis, which reinforces the role of ERK pathway in the adverse effect of TNFα. Furthermore, endochondral ossification was analyzed in an ex vivo bone culture model. TNFα largely abrogated BMP-promoted growth of mineralized bone while pre-treatment of NMP and DMA prevented the deleterious effect of TNFα. Taken together, these data shed light on developing low- affinity epigenetic drugs as new therapies for inflammation-compromised bone healing.
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Affiliation(s)
- Tse-Hsiang Chen
- University of Zurich, Center of Dental Medicine, Oral Biotechnology & Bioengineering, Plattenstrasse11, 8032 Zürich, Switzerland; Zurich Center for Integrative Human Physiology (ZIHP), University of Zurich, Switzerland
| | - Franz E Weber
- University of Zurich, Center of Dental Medicine, Oral Biotechnology & Bioengineering, Plattenstrasse11, 8032 Zürich, Switzerland; Zurich Center for Integrative Human Physiology (ZIHP), University of Zurich, Switzerland; CABMM, Center for Applied Biotechnology and Molecular Medicine, University of Zurich, Zürich, Switzerland
| | - Johann Malina-Altzinger
- Limmat Cleft and Craniofacial Centre, Zürich MKG, Hardturmstrasse 133, 8005 Zürich, Switzerland
| | - Chafik Ghayor
- University of Zurich, Center of Dental Medicine, Oral Biotechnology & Bioengineering, Plattenstrasse11, 8032 Zürich, Switzerland.
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Ni C, Zhou J, Kong N, Bian T, Zhang Y, Huang X, Xiao Y, Yang W, Yan F. Gold nanoparticles modulate the crosstalk between macrophages and periodontal ligament cells for periodontitis treatment. Biomaterials 2019; 206:115-132. [DOI: 10.1016/j.biomaterials.2019.03.039] [Citation(s) in RCA: 80] [Impact Index Per Article: 13.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2019] [Accepted: 03/23/2019] [Indexed: 12/12/2022]
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49
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Jiang Y, Wells A, Sylakowski K, Clark AM, Ma B. Adult Stem Cell Functioning in the Tumor Micro-Environment. Int J Mol Sci 2019; 20:ijms20102566. [PMID: 31130595 PMCID: PMC6566759 DOI: 10.3390/ijms20102566] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2019] [Revised: 05/18/2019] [Accepted: 05/23/2019] [Indexed: 12/14/2022] Open
Abstract
Tumor progression from an expanded cell population in a primary location to disseminated lethal growths subverts attempts at cures. It has become evident that these steps are driven in a large part by cancer cell-extrinsic signaling from the tumor microenvironment (TME), one cellular component of which is becoming more appreciated for potential modulation of the cancer cells directly and the TME globally. That cell is a heterogenous population referred to as adult mesenchymal stem cells/multipotent stromal cells (MSCs). Herein, we review emerging evidence as to how these cells, both from distant sources, mainly the bone marrow, or local resident cells, can impact the progression of solid tumors. These nascent investigations raise more questions than they answer but paint a picture of an orchestrated web of signals and interactions that can be modulated to impact tumor progression.
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Affiliation(s)
- Yuhan Jiang
- Department of Pathology, University of Pittsburgh, Pittsburgh, PA 15261, USA.
- School of Medicine, Tsinghua University, Beijing 100084, China.
| | - Alan Wells
- Department of Pathology, University of Pittsburgh, Pittsburgh, PA 15261, USA.
- Department of Bioengineering, University of Pittsburgh, Pittsburgh, PA 15260, USA.
- Department of Computational & Systems Biology, University of Pittsburgh, Pittsburgh, PA 15260, USA.
- UPMC Hillman Cancer Center, University of Pittsburgh, Pittsburgh, PA 15213, USA.
- VA Pittsburgh Healthcare System, Pittsburgh, PA 15213, USA.
| | - Kyle Sylakowski
- Department of Pathology, University of Pittsburgh, Pittsburgh, PA 15261, USA.
- VA Pittsburgh Healthcare System, Pittsburgh, PA 15213, USA.
| | - Amanda M Clark
- Department of Pathology, University of Pittsburgh, Pittsburgh, PA 15261, USA.
- VA Pittsburgh Healthcare System, Pittsburgh, PA 15213, USA.
| | - Bo Ma
- Department of Pathology, University of Pittsburgh, Pittsburgh, PA 15261, USA.
- VA Pittsburgh Healthcare System, Pittsburgh, PA 15213, USA.
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50
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Rodriguez LA, Mohammadipoor A, Alvarado L, Kamucheka RM, Asher AM, Cancio LC, Antebi B. Preconditioning in an Inflammatory Milieu Augments the Immunotherapeutic Function of Mesenchymal Stromal Cells. Cells 2019; 8:cells8050462. [PMID: 31096722 PMCID: PMC6562603 DOI: 10.3390/cells8050462] [Citation(s) in RCA: 27] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2019] [Revised: 05/09/2019] [Accepted: 05/13/2019] [Indexed: 02/06/2023] Open
Abstract
Multipotent mesenchymal stromal cells (MSCs) have emerged as potent therapeutic agents for multiple indications. However, recent evidence indicates that MSC function is compromised in the physiological post-injury milieu. In this study, bone marrow (BM)- and adipose-derived (AD)-MSCs were preconditioned in hypoxia with or without inflammatory mediators to potentiate their immunotherapeutic function in preparation for in vivo delivery. Human MSCs were cultured for 48 hours in either normoxia (21% O2) or hypoxia (2% O2) with or without the addition of Cytomix, thus creating 4 groups: 1) normoxia (21%); 2) Cytomix-normoxia (+21%); 3) hypoxia (2%); and 4) Cytomix-hypoxia (+2%). The 4 MSC groups were subjected to comprehensive evaluation of their characteristics and function. Preconditioning did not alter common MSC surface markers; nonetheless, Cytomix treatment triggered an increase in tissue factor (TF) expression. Moreover, the BM-MSCs and AD-MSCs from the +2% group were not able to differentiate to chondrocytes and osteoblasts, respectively. Following Cytomix preconditioning, the metabolism of MSCs was significantly increased while viability was decreased in AD-MSCs, but not in BM-MSCs. MSCs from both tissues showed a significant upregulation of key anti-inflammatory genes, increased secretion of IL-1 receptor antagonist (RA), and enhanced suppression of T-cell proliferation following the Cytomix treatment. Similarly, following a lipopolysaccharide challenge, the Cytomix-treated MSCs suppressed TNF-α secretion, while promoting the production of IL-10 and IL-1RA. These preconditioning approaches facilitate the production of MSCs with robust anti-inflammatory properties. AD-MSCs preconditioned with Cytomix under normoxia appear to be the most promising therapeutic candidates; however, safety concerns, such as thrombogenic disposition of cells due to TF expression, should be carefully considered prior to clinical translation.
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Affiliation(s)
- Luis A Rodriguez
- United States Army Institute of Surgical Research, San Antonio, TX 78234, USA.
| | - Arezoo Mohammadipoor
- United States Army Institute of Surgical Research, San Antonio, TX 78234, USA.
- Oak Ridge Institute for Science and Education, Oak Ridge, TN 37830, USA.
| | - Lucero Alvarado
- United States Army Institute of Surgical Research, San Antonio, TX 78234, USA.
- Oak Ridge Institute for Science and Education, Oak Ridge, TN 37830, USA.
- University of Texas at San Antonio, San Antonio, TX 78249, USA.
| | - Robin M Kamucheka
- United States Army Institute of Surgical Research, San Antonio, TX 78234, USA.
| | - Amber M Asher
- United States Army Institute of Surgical Research, San Antonio, TX 78234, USA.
- Oak Ridge Institute for Science and Education, Oak Ridge, TN 37830, USA.
| | - Leopoldo C Cancio
- United States Army Institute of Surgical Research, San Antonio, TX 78234, USA.
| | - Ben Antebi
- United States Army Institute of Surgical Research, San Antonio, TX 78234, USA.
- University of Texas at San Antonio, San Antonio, TX 78249, USA.
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