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Chen Y, Lin F, Zhang T, Xiao Z, Chen Y, Hua D, Wang Y, Wei J, Jin T, Lv X. Engineering Extracellular Vesicles Derived from 3D Cultivation of BMSCs Enriched with HGF Ameliorate Sepsis-Induced Lung Epithelial Barrier Damage. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2025; 12:e2500637. [PMID: 40041965 PMCID: PMC12021063 DOI: 10.1002/advs.202500637] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/11/2025] [Revised: 02/06/2025] [Indexed: 04/26/2025]
Abstract
Sepsis is a critical condition with high mortality, often leading to acute lung injury (ALI) due to uncontrolled inflammatory responses and alveolar epithelial damage. Extracellular vesicles (EVs), particularly mesenchymal stem cell-derived EVs, have shown therapeutic potential in sepsis-related organ dysfunction by transferring RNAs and proteins. However, their clinical use is limited by low efficacy and yield. To address this, 3D-cultured MSCs (3D-MSCs) are generated using MicroTissues 3D Petri Dish. These 3D-MSCs demonstrate improved protection and proliferation of MLE-12 cells in vitro. Mechanistic studies are conducted to explore the enhanced protective effects of 3D-MSCs derived EVs (3D-EVs) in a septic-ALI model. Proteomic and molecular analyses of 3D-EVs revealed that they are enriched in hepatocyte growth factor (HGF). HGF helps maintain the barrier function of damaged alveolar epithelium through the PI3K-AKT signaling pathway. Overall, 3D-EVs effectively ameliorate sepsis-induced ALI and enhance prognosis by enriching and delivering HGF, suggesting that their application represents a promising treatment strategy for septic ALI.
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Affiliation(s)
- Yong Chen
- Department of AnesthesiologyShanghai Pulmonary HospitalSchool of MedicineTongji UniversityShanghai200433China
- Shanghai Institute of Acupuncture and AnesthesiaShanghai200433China
- Department of AnesthesiologyThe First Affiliated Hospital of Wenzhou Medical UniversityWenzhou325000China
| | - Feihong Lin
- Department of AnesthesiologyShanghai Pulmonary HospitalSchool of MedicineTongji UniversityShanghai200433China
- Shanghai Institute of Acupuncture and AnesthesiaShanghai200433China
| | - Tong Zhang
- Department of AnesthesiologyShanghai Pulmonary HospitalSchool of MedicineTongji UniversityShanghai200433China
- Shanghai Institute of Acupuncture and AnesthesiaShanghai200433China
| | - Zhuoran Xiao
- Department of AnesthesiologyShanghai Pulmonary HospitalSchool of MedicineTongji UniversityShanghai200433China
- Shanghai Institute of Acupuncture and AnesthesiaShanghai200433China
| | - Yuanli Chen
- Department of AnesthesiologyShanghai Pulmonary HospitalSchool of MedicineTongji UniversityShanghai200433China
- Shanghai Institute of Acupuncture and AnesthesiaShanghai200433China
| | - Dongsheng Hua
- Department of AnesthesiologyShanghai Pulmonary HospitalSchool of MedicineTongji UniversityShanghai200433China
- Shanghai Institute of Acupuncture and AnesthesiaShanghai200433China
| | - Yu Wang
- Department of AnesthesiologyShanghai Pulmonary HospitalSchool of MedicineTongji UniversityShanghai200433China
- Shanghai Institute of Acupuncture and AnesthesiaShanghai200433China
| | - Juan Wei
- Department of AnesthesiologyShanghai Pulmonary HospitalSchool of MedicineTongji UniversityShanghai200433China
- Shanghai Institute of Acupuncture and AnesthesiaShanghai200433China
| | - Tian Jin
- Department of AnesthesiologyShanghai Pulmonary HospitalSchool of MedicineTongji UniversityShanghai200433China
- Shanghai Institute of Acupuncture and AnesthesiaShanghai200433China
| | - Xin Lv
- Department of AnesthesiologyShanghai Pulmonary HospitalSchool of MedicineTongji UniversityShanghai200433China
- Shanghai Institute of Acupuncture and AnesthesiaShanghai200433China
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Ma W, Tang S, Yao P, Zhou T, Niu Q, Liu P, Tang S, Chen Y, Gan L, Cao Y. Advances in acute respiratory distress syndrome: focusing on heterogeneity, pathophysiology, and therapeutic strategies. Signal Transduct Target Ther 2025; 10:75. [PMID: 40050633 PMCID: PMC11885678 DOI: 10.1038/s41392-025-02127-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2024] [Revised: 12/27/2024] [Accepted: 12/27/2024] [Indexed: 03/09/2025] Open
Abstract
In recent years, the incidence of acute respiratory distress syndrome (ARDS) has been gradually increasing. Despite advances in supportive care, ARDS remains a significant cause of morbidity and mortality in critically ill patients. ARDS is characterized by acute hypoxaemic respiratory failure with diffuse pulmonary inflammation and bilateral edema due to excessive alveolocapillary permeability in patients with non-cardiogenic pulmonary diseases. Over the past seven decades, our understanding of the pathology and clinical characteristics of ARDS has evolved significantly, yet it remains an area of active research and discovery. ARDS is highly heterogeneous, including diverse pathological causes, clinical presentations, and treatment responses, presenting a significant challenge for clinicians and researchers. In this review, we comprehensively discuss the latest advancements in ARDS research, focusing on its heterogeneity, pathophysiological mechanisms, and emerging therapeutic approaches, such as cellular therapy, immunotherapy, and targeted therapy. Moreover, we also examine the pathological characteristics of COVID-19-related ARDS and discuss the corresponding therapeutic approaches. In the face of challenges posed by ARDS heterogeneity, recent advancements offer hope for improved patient outcomes. Further research is essential to translate these findings into effective clinical interventions and personalized treatment approaches for ARDS, ultimately leading to better outcomes for patients suffering from ARDS.
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Affiliation(s)
- Wen Ma
- Department of Emergency Medicine, Institute of Disaster Medicine and Institute of Emergency Medicine, West China Hospital, Sichuan University, Chengdu, China
- Institute for Disaster Management and Reconstruction, Sichuan University-The Hong Kong Polytechnic University, Chengdu, China
| | - Songling Tang
- Department of Emergency Medicine, Institute of Disaster Medicine and Institute of Emergency Medicine, West China Hospital, Sichuan University, Chengdu, China
| | - Peng Yao
- Department of Emergency Medicine, Institute of Disaster Medicine and Institute of Emergency Medicine, West China Hospital, Sichuan University, Chengdu, China
| | - Tingyuan Zhou
- Department of Emergency Medicine, Institute of Disaster Medicine and Institute of Emergency Medicine, West China Hospital, Sichuan University, Chengdu, China
- Institute for Disaster Management and Reconstruction, Sichuan University-The Hong Kong Polytechnic University, Chengdu, China
| | - Qingsheng Niu
- Department of Emergency Medicine, Institute of Disaster Medicine and Institute of Emergency Medicine, West China Hospital, Sichuan University, Chengdu, China
| | - Peng Liu
- Department of Emergency Medicine, Institute of Disaster Medicine and Institute of Emergency Medicine, West China Hospital, Sichuan University, Chengdu, China
| | - Shiyuan Tang
- Department of Emergency Medicine, Institute of Disaster Medicine and Institute of Emergency Medicine, West China Hospital, Sichuan University, Chengdu, China
| | - Yao Chen
- Department of Emergency Medicine, Institute of Disaster Medicine and Institute of Emergency Medicine, West China Hospital, Sichuan University, Chengdu, China
| | - Lu Gan
- Department of Emergency Medicine, Institute of Disaster Medicine and Institute of Emergency Medicine, West China Hospital, Sichuan University, Chengdu, China.
| | - Yu Cao
- Department of Emergency Medicine, Institute of Disaster Medicine and Institute of Emergency Medicine, West China Hospital, Sichuan University, Chengdu, China.
- Institute for Disaster Management and Reconstruction, Sichuan University-The Hong Kong Polytechnic University, Chengdu, China.
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Liu G, Wang H, Zhang C, Li X, Mi Y, Chen Y, Xu L, Miao L, Long H, Liu Y. Tumor Necrosis Factor Receptor 1 Is Required for Human Umbilical Cord-Derived Mesenchymal Stem Cell-Mediated Rheumatoid Arthritis Therapy. Cell Transplant 2025; 34:9636897241301703. [PMID: 39831589 PMCID: PMC11748158 DOI: 10.1177/09636897241301703] [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: 05/12/2024] [Revised: 10/31/2024] [Accepted: 11/04/2024] [Indexed: 01/22/2025] Open
Abstract
Rheumatoid arthritis (RA) is a systemic, chronic inflammatory disease characterized by altered levels of inflammatory cytokines. One of the key cytokines involved in the pathogenesis of RA is tumor necrosis factor α (TNF-α), which plays a crucial role in the differentiation of T cells and B cells and serves as a primary trigger of inflammation and joint damage in RA. Human umbilical cord-derived mesenchymal stem cells (hUC-MSCs) have shown potential in alleviating the symptoms of RA. Previous in vitro studies indicate that TNF-α secreted by T cells can activate NF-κB in human MSCs, thereby triggering the immunoregulatory capacity of MSCs in a manner dependent on tumor necrosis factor receptor 1 (TNFR1). Inspired by these findings, we aimed to evaluate whether TNFR1 determine the therapeutic effects of hUC-MSCs on RA. First, we investigated whether TNFR1 is necessary for hUC-MSCs to inhibit TNF-α production of PBMCs, a source of elevated TNF-α in patients. Through coculture experiment, we confirmed that this inhibition was dependent on TNFR1. Subsequently, we administered hUC-MSCs or siTNFR1-MSCs to DBA/1J male mice with collagen-induced arthritis. The results indicated that hUC-MSCs significantly alleviated the pathological features of RA and suppressed the inflammatory cytokines IFN-γ, TNF-α, and IL-6 in peripheral blood, also in a manner dependent on TNFR1 either. Given the dramatic pathologic differences between hUC-MSCs and siTNFR1-MSCs treatments, we questioned whether production of growth factors and chemokines was significantly influenced by TNFR1. Consequently, we stimulated hUC-MSCs or siTNFR1-MSCs through IFN-γ, TNF-α, and IL-6, and profiled growth factors and chemokines in serum, which revealed significant changes of hepatocyte growth factor (HGF) and keratinocyte growth factor (KGF), as well as chemokines CXCL9, CXCL10, IL-8, and RANTES. In summary, our findings suggest that TNFR1 may determine whether hUC-MSCs will gain abilities of anti-inflammation and tissue regeneration.
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Affiliation(s)
- Guangyang Liu
- Stem Cell Biology and Regenerative Medicine Institution, Yi-Chuang Institute of Bio-Industry, Beijing, China
| | - Herui Wang
- Stem Cell Biology and Regenerative Medicine Institution, Yi-Chuang Institute of Bio-Industry, Beijing, China
| | - Chenliang Zhang
- Stem Cell Biology and Regenerative Medicine Institution, Yi-Chuang Institute of Bio-Industry, Beijing, China
| | - Xin Li
- Stem Cell Biology and Regenerative Medicine Institution, Yi-Chuang Institute of Bio-Industry, Beijing, China
| | - Yi Mi
- Stem Cell Biology and Regenerative Medicine Institution, Yi-Chuang Institute of Bio-Industry, Beijing, China
| | - Yaoyao Chen
- Stem Cell Biology and Regenerative Medicine Institution, Yi-Chuang Institute of Bio-Industry, Beijing, China
| | - Liqiang Xu
- Stem Cell Biology and Regenerative Medicine Institution, Yi-Chuang Institute of Bio-Industry, Beijing, China
| | - Li Miao
- Stem Cell Biology and Regenerative Medicine Institution, Yi-Chuang Institute of Bio-Industry, Beijing, China
| | - Haomiao Long
- Stem Cell Biology and Regenerative Medicine Institution, Yi-Chuang Institute of Bio-Industry, Beijing, China
| | - Yongjun Liu
- Stem Cell Biology and Regenerative Medicine Institution, Yi-Chuang Institute of Bio-Industry, Beijing, China
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Ghiasi M, Kheirandish Zarandi P, Dayani A, Salimi A, Shokri E. Potential therapeutic effects and nano-based delivery systems of mesenchymal stem cells and their isolated exosomes to alleviate acute respiratory distress syndrome caused by COVID-19. Regen Ther 2024; 27:319-328. [PMID: 38650667 PMCID: PMC11035022 DOI: 10.1016/j.reth.2024.03.015] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2023] [Revised: 03/03/2024] [Accepted: 03/15/2024] [Indexed: 04/25/2024] Open
Abstract
The severe respiratory effects of the coronavirus disease 2019 (COVID-19) pandemic have necessitated the immediate development of novel treatments. The majority of COVID-19-related fatalities are due to acute respiratory distress syndrome (ARDS). Consequently, this virus causes massive and aberrant inflammatory conditions, which must be promptly managed. Severe respiratory disorders, notably ARDS and acute lung injury (ALI), may be treated safely and effectively using cell-based treatments, mostly employing mesenchymal stem cells (MSCs). Since the high potential of these cells was identified, a great deal of research has been conducted on their use in regenerative medicine and complementary medicine. Multiple investigations have demonstrated that MSCs and their products, especially exosomes, inhibit inflammation. Exosomes serve a critical function in intercellular communication by transporting molecular cargo from donor cells to receiver cells. MSCs and their derived exosomes (MSCs/MSC-exosomes) may improve lung permeability, microbial and alveolar fluid clearance, and epithelial and endothelial repair, according to recent studies. This review focuses on COVID-19-related ARDS clinical studies involving MSCs/MSC-exosomes. We also investigated the utilization of Nano-delivery strategies for MSCs/MSC-exosomes and anti-inflammatory agents to enhance COVID-19 treatment.
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Affiliation(s)
- Mohsen Ghiasi
- Rajaie Cardiovascular Medical and Research Center, Iran University of Medical Sciences, Tehran, Iran
| | | | - Abdolreza Dayani
- Rajaie Cardiovascular Medical and Research Center, Iran University of Medical Sciences, Tehran, Iran
| | - Ali Salimi
- Nanobiotechnology Research Center, Baqiyatallah University of Medical Sciences, Tehran, Iran
| | - Ehsan Shokri
- Department of Nanotechnology, Agricultural Biotechnology Research Institute of Iran (ABRII), Agricultural Research, Education and Extension Organization (AREEO), Karaj, Iran
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Sun ZC, Liao R, Xian C, Lin R, Wang L, Fang Y, Zhang Z, Liu Y, Wu J. Natural pachypodol integrated, lung targeted and inhaled lipid nanomedicine ameliorates acute lung injury via anti-inflammation and repairing lung barrier. J Control Release 2024; 375:300-315. [PMID: 39265826 DOI: 10.1016/j.jconrel.2024.09.013] [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: 05/15/2024] [Revised: 07/29/2024] [Accepted: 09/09/2024] [Indexed: 09/14/2024]
Abstract
Acute lung injury (ALI) or acute respiratory distress syndrome (ARDS) is a high-mortality disease caused by multiple disorders such as COVID-19, influenza, and sepsis. Current therapies mainly rely on the inhalation of nitric oxide or injection of pharmaceutical drugs (e.g., glucocorticoids); however, their toxicity, side effects, or administration routes limit their clinical application. In this study, pachypodol (Pac), a hydrophobic flavonol with anti-inflammatory effects, was extracted from Pogostemon cablin Benth and intercalated in liposomes (Pac@liposome, Pac-lipo) to improve its solubility, biodistribution, and bioavailability, aiming at enhanced ALI/ARDS therapy. Nanosized Pac-lipo was confirmed to have stable physical properties, good biodistribution, and reliable biocompatibility. In vitro tests proved that Pac-lipo has anti-inflammatory property and protective effects on endothelial and epithelial barriers in lipopolysaccharide (LPS)-induced macrophages and endothelial cells, respectively. Further, the roles of Pac-lipo were validated on treating LPS-induced ALI in mice. Pac-lipo showed better effects than did Pac alone on relieving ALI phenotypes: It significantly attenuated lung index, improved pulmonary functions, inhibited cytokine expression such as TNF-α, IL-6, IL-1β, and iNOS in lung tissues, alleviated lung injury shown by HE staining, reduced protein content and total cell number in bronchoalveolar lavage fluid, and repaired lung epithelial and vascular endothelial barriers. As regards the underlying mechanisms, RNA sequencing results showed that the effects of the drugs were associated with numerous immune- and inflammation-related signaling pathways. Molecular docking and western blotting demonstrated that Pac-lipo inhibited the activation of the TLR4-MyD88-NF-κB/MAPK signaling pathway. Taken together, for the first time, our new drug (Pac-lipo) ameliorates ALI via inhibition of TLR4-MyD88-NF-κB/MAPK pathway-mediated inflammation and disruption of lung barrier. These findings may provide a promising strategy for ALI treatment in the clinic.
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Affiliation(s)
- Zhi-Chao Sun
- State Key Laboratory of Traditional Chinese Medicine Syndrome, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, 55 N, Neihuanxi Road, Guangzhou 510006, Guangdong, China
| | - Ran Liao
- State Key Laboratory of Traditional Chinese Medicine Syndrome, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, 55 N, Neihuanxi Road, Guangzhou 510006, Guangdong, China
| | - Caihong Xian
- Bioscience and Biomedical Engineering Thrust, Systems Hub, The Hong Kong University of Science and Technology (Guangzhou), Nansha, Guangzhou 511400, Guangdong, China; School of Biomedical Engineering, Sun Yat-sen University, Shenzhen 518107, China
| | - Ran Lin
- State Key Laboratory of Traditional Chinese Medicine Syndrome, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, 55 N, Neihuanxi Road, Guangzhou 510006, Guangdong, China
| | - Liying Wang
- Bioscience and Biomedical Engineering Thrust, Systems Hub, The Hong Kong University of Science and Technology (Guangzhou), Nansha, Guangzhou 511400, Guangdong, China; School of Biomedical Engineering, Sun Yat-sen University, Shenzhen 518107, China
| | - Yifei Fang
- Bioscience and Biomedical Engineering Thrust, Systems Hub, The Hong Kong University of Science and Technology (Guangzhou), Nansha, Guangzhou 511400, Guangdong, China; School of Biomedical Engineering, Sun Yat-sen University, Shenzhen 518107, China
| | - Zhongde Zhang
- State Key Laboratory of Traditional Chinese Medicine Syndrome, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, 55 N, Neihuanxi Road, Guangzhou 510006, Guangdong, China.
| | - Yuntao Liu
- State Key Laboratory of Traditional Chinese Medicine Syndrome, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, 55 N, Neihuanxi Road, Guangzhou 510006, Guangdong, China.
| | - Jun Wu
- Bioscience and Biomedical Engineering Thrust, Systems Hub, The Hong Kong University of Science and Technology (Guangzhou), Nansha, Guangzhou 511400, Guangdong, China; Division of Life Science, The Hong Kong University of Science and Technology, 999077, Hong Kong SAR.
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Chen YZ, Zhao L, Wei W, Gu J, Liu ZH, Shan WY, Dong J, Li C, Qin LQ, Xu JY. The Effect of Metformin on Radiation-Induced Lung Fibrosis in Mice. Dose Response 2024; 22:15593258241308051. [PMID: 39664837 PMCID: PMC11632958 DOI: 10.1177/15593258241308051] [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: 06/19/2024] [Revised: 10/28/2024] [Accepted: 11/17/2024] [Indexed: 12/13/2024] Open
Abstract
Introduction: Radiation-induced lung fibrosis (RILF) is a common complication of thoracic radiotherapy. Metformin has been suggested to have a radioprotective effect. Objective: This study explored the radioprotective effects of metformin on RILF and its mechanisms. Methods: C57BL/6J mice were randomly divided into control, ionizing radiation (IR), low-dose metformin (L-Met), and high-dose metformin (H-Met) groups. The IR, L-Met, and H-Met groups received 15 Gy chest irradiation. The L-Met and H-Met groups were administrated 100 or 200 mg/kg metformin from 3 days before irradiation and continued for 6 months. The mice were then sacrificed, and samples were collected for further analysis. Results: RILF was induced in the irradiated mice. Metformin improved lung pathology, inhibited collagen deposition, and reduced inflammatory factors such as high mobility group box 1 (HMGB1), interleukin-1 beta, interleukin-6, tumor necrosis factor alpha in lung tissue, lavage fluid, and serum. Western blot and quantitative real-time PCR analyses revealed that metformin downregulated HMGB1, toll-like receptor 4 (TLR4), and nuclear factor kappaB (NF-κB) expression. Additionally, metformin reversed the irradiation-induced reduction in the abundance of Lactobacillus and Lachnospiraceae at the genus level. Conclusion: Our findings indicated that metformin ameliorates RILF by downregulating the inflammatory-related HMGB1/TLR4/NF-κB pathway and improving intestinal flora disorder.
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Affiliation(s)
- Yu-Zhong Chen
- State Key Laboratory of Radiation Medicine and Protection, Collaborative Innovation Center of Radiation Medicine of Jiangsu Higher Education Institutions, School of Radiation Medicine and Protection, Suzhou Medical College of Soochow University, Suzhou, China
- Yancheng Municipal Center for Disease Control and Prevention, Yancheng, China
| | - Lin Zhao
- State Key Laboratory of Radiation Medicine and Protection, Collaborative Innovation Center of Radiation Medicine of Jiangsu Higher Education Institutions, School of Radiation Medicine and Protection, Suzhou Medical College of Soochow University, Suzhou, China
| | - Wei Wei
- State Key Laboratory of Radiation Medicine and Protection, Collaborative Innovation Center of Radiation Medicine of Jiangsu Higher Education Institutions, School of Radiation Medicine and Protection, Suzhou Medical College of Soochow University, Suzhou, China
| | - Jia Gu
- State Key Laboratory of Radiation Medicine and Protection, Collaborative Innovation Center of Radiation Medicine of Jiangsu Higher Education Institutions, School of Radiation Medicine and Protection, Suzhou Medical College of Soochow University, Suzhou, China
| | - Zhen-Hua Liu
- Department of Radiotherapy, The Yancheng Clinical College of Xuzhou Medical University, The First people’s Hospital of Yancheng, Yancheng, China
| | - Wen-Yue Shan
- State Key Laboratory of Radiation Medicine and Protection, Collaborative Innovation Center of Radiation Medicine of Jiangsu Higher Education Institutions, School of Radiation Medicine and Protection, Suzhou Medical College of Soochow University, Suzhou, China
| | - Jie Dong
- State Key Laboratory of Radiation Medicine and Protection, Collaborative Innovation Center of Radiation Medicine of Jiangsu Higher Education Institutions, School of Radiation Medicine and Protection, Suzhou Medical College of Soochow University, Suzhou, China
- The First Affiliated Hospital of Soochow University, Suzhou, China
| | - Chao Li
- Suzhou Kowloon Hospital, Shanghai Jiaotong University School of Medicine, Suzhou, China
| | - Li-Qiang Qin
- Department of Nutrition and Food Hygiene School of Public Health, Suzhou Medical College of Soochow University, Suzhou, China
| | - Jia-Ying Xu
- State Key Laboratory of Radiation Medicine and Protection, Collaborative Innovation Center of Radiation Medicine of Jiangsu Higher Education Institutions, School of Radiation Medicine and Protection, Suzhou Medical College of Soochow University, Suzhou, China
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Sang Y, Qiao L. Lung epithelial-endothelial-mesenchymal signaling network with hepatocyte growth factor as a hub is involved in bronchopulmonary dysplasia. Front Cell Dev Biol 2024; 12:1462841. [PMID: 39291265 PMCID: PMC11405311 DOI: 10.3389/fcell.2024.1462841] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2024] [Accepted: 08/23/2024] [Indexed: 09/19/2024] Open
Abstract
Bronchopulmonary dysplasia (BPD) is fundamentally characterized by the arrest of lung development and abnormal repair mechanisms, which result in impaired development of the alveoli and microvasculature. Hepatocyte growth factor (HGF), secreted by pulmonary mesenchymal and endothelial cells, plays a pivotal role in the promotion of epithelial and endothelial cell proliferation, branching morphogenesis, angiogenesis, and alveolarization. HGF exerts its beneficial effects on pulmonary vascular development and alveolar simplification primarily through two pivotal pathways: the stimulation of neovascularization, thereby enriching the pulmonary microvascular network, and the inhibition of the epithelial-mesenchymal transition (EMT), which is crucial for maintaining the integrity of the alveolar structure. We discuss HGF and its receptor c-Met, interact with various growth factors throughout the process of lung development and BPD, and form a signaling network with HGF as a hub, which plays the pivotal role in orchestrating and integrating epithelial, endothelial and mesenchymal.
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Affiliation(s)
- Yating Sang
- Pediatric Intensive Care Unit, West China Second University Hospital, Sichuan University, Chengdu, China
- Key Laboratory of Birth Defects and Related Diseases of Women and Children, Ministry of Education, Sichuan University, Chengdu, China
| | - Lina Qiao
- Pediatric Intensive Care Unit, West China Second University Hospital, Sichuan University, Chengdu, China
- Key Laboratory of Birth Defects and Related Diseases of Women and Children, Ministry of Education, Sichuan University, Chengdu, China
- NHC Key Laboratory of Chronobiology, Sichuan University, Chengdu, China
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Lin S, Chang Y, Lee W, Chiang C, Liu S, Lee H, Jeng L, Shyu W. Role of STAT3-FOXO3 Signaling in the Modulation of Neuroplasticity by PD-L1-HGF-Decorated Mesenchymal Stem Cell-Derived Exosomes in a Murine Stroke Model. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2024; 11:e2404882. [PMID: 39049677 PMCID: PMC11423231 DOI: 10.1002/advs.202404882] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/08/2024] [Revised: 06/28/2024] [Indexed: 07/27/2024]
Abstract
The limited therapeutic strategies available for stroke leave many patients disabled for life. This study assessed the potential of programmed death-ligand 1 (PD-L1) and hepatocyte growth factor (HGF)-engineered mesenchymal stem cell-derived exosomes (EXO-PD-L1-HGF) in enhancing neurological recovery post-stroke. EXO-PD-L1-HGF, which efficiently endocytosed into target cells, significantly diminishes the H2O2-induced neurotoxicity and increased the antiapoptotic proteins in vitro. EXO-PD-L1-HGF attenuates inflammation by inhibiting T-cell proliferation and increasing the number of CD8+CD122+IL-10+ regulatory T cells. Intravenous injection of EXO-PD-L1-HGF could target stromal cell-derived factor-1α (SDF-1α+) cells over the peri-infarcted area of the ischemic brain through CXCR4 upregulation and accumulation in neuroglial cells post-stroke. EXO-PD-L1-HGF facilitates endogenous nestin+ neural progenitor cell (NPC)-induced neurogenesis via STAT3-FOXO3 signaling cascade, which plays a pivotal role in cell survival and neuroprotection, thereby mitigating infarct size and enhancing neurological recovery in a murine stroke model. Moreover, increasing populations of the immune-regulatory CD19+IL-10+ and CD8+CD122+IL-10+ cells, together with reducing populations of proinflammatory cells, created an anti-inflammatory microenvironment in the ischemic brain. Thus, innovative approaches employing EXO-PD-L1-HGF intervention, which targets SDF-1α+ expression, modulates the immune system, and enhances the activation of resident nestin+ NPCs, might significantly alter the brain microenvironment and create a niche conducive to inducing neuroplastic regeneration post-stroke.
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Affiliation(s)
- Syuan‐Ling Lin
- Translational Medicine Research Center and Department of NeurologyChina Medical University HospitalTaichung404Taiwan
| | - Yi‐Wen Chang
- Cell Therapy CenterChina Medical University HospitalTaichung404Taiwan
- Department of Medical ResearchNational Taiwan University HospitalTaipei100Taiwan
| | - Wei Lee
- Cell Therapy CenterChina Medical University HospitalTaichung404Taiwan
| | - Chih‐Sheng Chiang
- Cell Therapy CenterChina Medical University HospitalTaichung404Taiwan
- Graduate Institute of Biomedical Sciences and New Drug Development CenterChina Medical UniversityTaichung404Taiwan
| | - Shih‐Ping Liu
- Translational Medicine Research Center and Department of NeurologyChina Medical University HospitalTaichung404Taiwan
- Graduate Institute of Biomedical Sciences and New Drug Development CenterChina Medical UniversityTaichung404Taiwan
| | - Hsu‐Tung Lee
- Graduate Institute of Medical SciencesNational Defense Medical CenterTaipei114Taiwan
- Department of Post‐Baccalaureate Medicine, College of MedicineNational Chung Hsing UniversityTaichung402Taiwan
- Division of neurosurgical Oncology Neurological InstituteTaichung Veterans General HospitalTaichung407Taiwan
| | - Long‐Bin Jeng
- Cell Therapy CenterChina Medical University HospitalTaichung404Taiwan
- Organ Transplantation CenterChina Medical University HospitalTaichung404Taiwan
| | - Woei‐Cherng Shyu
- Translational Medicine Research Center and Department of NeurologyChina Medical University HospitalTaichung404Taiwan
- Graduate Institute of Biomedical Sciences and New Drug Development CenterChina Medical UniversityTaichung404Taiwan
- Department of Occupational TherapyAsia UniversityTaichung413Taiwan
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Wang X, He W, Huang H, Han J, Wang R, Li H, Long Y, Wang G, Han X. Recent Advances in Hydrogel Technology in Delivering Mesenchymal Stem Cell for Osteoarthritis Therapy. Biomolecules 2024; 14:858. [PMID: 39062572 PMCID: PMC11274544 DOI: 10.3390/biom14070858] [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: 05/28/2024] [Revised: 07/06/2024] [Accepted: 07/13/2024] [Indexed: 07/28/2024] Open
Abstract
Osteoarthritis (OA), a chronic joint disease affecting over 500 million individuals globally, is characterized by the destruction of articular cartilage and joint inflammation. Conventional treatments are insufficient for repairing damaged joint tissue, necessitating novel therapeutic approaches. Mesenchymal stem cells (MSCs), with their potential for differentiation and self-renewal, hold great promise as a treatment for OA. However, challenges such as MSC viability and apoptosis in the ischemic joint environment hinder their therapeutic effectiveness. Hydrogels with biocompatibility and degradability offer a three-dimensional scaffold that support cell viability and differentiation, making them ideal for MSC delivery in OA treatment. This review discusses the pathological features of OA, the properties of MSCs, the challenges associated with MSC therapy, and methods for hydrogel preparation and functionalization. Furthermore, it highlights the advantages of hydrogel-based MSC delivery systems while providing insights into future research directions and the clinical potential of this approach.
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Affiliation(s)
- Xiangjiang Wang
- The Affiliated Qingyuan Hospital (Qingyuan People’s Hospital), Guangzhou Medical University, Qingyuan 511518, China; (X.W.); (W.H.); (J.H.); (R.W.); (H.L.); (Y.L.)
| | - Wentao He
- The Affiliated Qingyuan Hospital (Qingyuan People’s Hospital), Guangzhou Medical University, Qingyuan 511518, China; (X.W.); (W.H.); (J.H.); (R.W.); (H.L.); (Y.L.)
| | - Hao Huang
- Key Laboratory of Optoelectronic Devices and Systems of Ministry of Education and Guangdong Province, Collage of Physics and Optoelectronics Engineering, Shenzhen University, Shenzhen 518060, China;
| | - Jiali Han
- The Affiliated Qingyuan Hospital (Qingyuan People’s Hospital), Guangzhou Medical University, Qingyuan 511518, China; (X.W.); (W.H.); (J.H.); (R.W.); (H.L.); (Y.L.)
| | - Ruren Wang
- The Affiliated Qingyuan Hospital (Qingyuan People’s Hospital), Guangzhou Medical University, Qingyuan 511518, China; (X.W.); (W.H.); (J.H.); (R.W.); (H.L.); (Y.L.)
| | - Hongyi Li
- The Affiliated Qingyuan Hospital (Qingyuan People’s Hospital), Guangzhou Medical University, Qingyuan 511518, China; (X.W.); (W.H.); (J.H.); (R.W.); (H.L.); (Y.L.)
| | - Ying Long
- The Affiliated Qingyuan Hospital (Qingyuan People’s Hospital), Guangzhou Medical University, Qingyuan 511518, China; (X.W.); (W.H.); (J.H.); (R.W.); (H.L.); (Y.L.)
| | - Guiqing Wang
- The Affiliated Qingyuan Hospital (Qingyuan People’s Hospital), Guangzhou Medical University, Qingyuan 511518, China; (X.W.); (W.H.); (J.H.); (R.W.); (H.L.); (Y.L.)
| | - Xianjing Han
- The Affiliated Qingyuan Hospital (Qingyuan People’s Hospital), Guangzhou Medical University, Qingyuan 511518, China; (X.W.); (W.H.); (J.H.); (R.W.); (H.L.); (Y.L.)
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10
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Lin SL, Lee W, Liu SP, Chang YW, Jeng LB, Shyu WC. Novel Programmed Death Ligand 1-AKT-engineered Mesenchymal Stem Cells Promote Neuroplasticity to Target Stroke Therapy. Mol Neurobiol 2024; 61:3819-3835. [PMID: 38030932 DOI: 10.1007/s12035-023-03779-w] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2023] [Accepted: 11/06/2023] [Indexed: 12/01/2023]
Abstract
Although tissue plasminogen activator (t-PA) and endovascular thrombectomy are well-established treatments for acute ischemic stroke, over half of patients with stroke remain disabled for a long time. Thus, a significant unmet need exists to develop an effective strategy for treating acute stroke. We developed a combination of programmed cell death-ligand 1 (PD-L1) and AKT-modified umbilical cord mesenchymal stem cells (UMSC-PD-L1-AKT) implanted through intravenous (IV) and intracarotid (IA) routes to enhance therapeutic efficacy in a murine stroke model for overcoming the hypoxic environment of the ischemic brain, to prolong stem cell survival, and to attenuate systemic inflammation to protect neuroglial cells from ischemic injury. Higher cellular proliferation and survival upon exposure to toxic agents were observed in UMSC-PD-L1-AKT cells than in UMSCs in vitro. Moreover, increased attenuation of CFSE+ cell proliferation and increased survival of primary cortical cells were verified by the interaction with UMSC-PD-L1-AKT. Consistently, dual-route administration (IV + IA) of UMSC-PD-L1-AKT resulted in a significant reduction in infarction volume and improvement of neurological dysfunction in a stroke model. Furthermore, enhancing CD8+CD122+IL-10+ T-regulatory (Treg) cells and reducing CD11b+CD80+ microglial/macrophages and CD3+CD8+TNF-α+ and CD3+CD8+ IFN-α+ cytotoxic T cells induced an anti-inflammatory microenvironment to protect neuroglial cells in the ischemic brain. Collectively, therapeutic intervention using UMSC-PD-L1-AKT could provide a niche for inducing neuroplastic regeneration in brains after stroke.
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Affiliation(s)
- Syuan-Ling Lin
- Translational Medicine Research Center, China Medical University Hospital, Taichung, Taiwan
| | - Wei Lee
- Cell Therapy Center, China Medical University Hospital, Taichung, Taiwan
| | - Shih-Ping Liu
- Translational Medicine Research Center, China Medical University Hospital, Taichung, Taiwan
- Graduate Institute of Biomedical Science, China Medical University, Taichung, Taiwan
| | - Yi-Wen Chang
- Cell Therapy Center, China Medical University Hospital, Taichung, Taiwan.
| | - Long-Bin Jeng
- Cell Therapy Center, China Medical University Hospital, Taichung, Taiwan.
- Organ Transplantation Center, China Medical University Hospital, Taichung, Taiwan.
| | - Woei-Cherng Shyu
- Translational Medicine Research Center, China Medical University Hospital, Taichung, Taiwan.
- Graduate Institute of Biomedical Science, China Medical University, Taichung, Taiwan.
- Neuroscience and Brain Disease Center and New Drug Development Center, China Medical University, Taichung, Taiwan.
- Department of Occupational Therapy, Asia University, Taichung, Taiwan.
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11
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Zhang S, Liu Y, Zhang XL, Sun Y, Lu ZH. ANKRD22 aggravates sepsis-induced ARDS and promotes pulmonary M1 macrophage polarization. J Transl Autoimmun 2024; 8:100228. [PMID: 38225946 PMCID: PMC10788270 DOI: 10.1016/j.jtauto.2023.100228] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2023] [Revised: 12/11/2023] [Accepted: 12/13/2023] [Indexed: 01/17/2024] Open
Abstract
Acute respiratory distress syndrome (ARDS) is independently associated with a poor prognosis in patients with sepsis. Macrophage M1 polarization plays an instrumental role in this process. Therefore, the exploration of key molecules affecting acute lung injury and macrophage M1 polarization may provide therapeutic targets for the treatment of septic ARDS. Here, we identified that elevated levels of Ankyrin repeat domain-containing protein 22 (ANKRD22) were associated with poor prognosis and more pronounced M1 macrophage polarization in septic patients by analyzing high-throughput data. ANKRD22 expression was also significantly upregulated in the alveolar lavage fluid, peripheral blood, and lung tissue of septic ARDS model mice. Knockdown of ANKRD22 significantly attenuated acute lung injury in mice with sepsis-induced ARDS and reduced the M1 polarization of lung macrophages. Furthermore, deletion of ANKRD22 in macrophages inhibited M1 macrophage polarization and reduced levels of phosphorylated IRF3 and intracellular interferon regulatory factor 3 (IRF3) expression, while re-expression of ANKRD22 reversed these changes. Further experiments revealed that ANKRD22 promotes IRF3 activation by binding to mitochondrial antiviral-signaling protein (MAVS). In conclusion, these findings suggest that ANKRD22 promotes the M1 polarization of lung macrophages and exacerbates sepsis-induced ARDS.
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Affiliation(s)
- Shi Zhang
- Jiangsu Provincial Key Laboratory of Critical Care Medicine, Department of Critical Care Medicine, ZhongdaHospital, Southeast University, Nanjing, Jiangsu, China
- Department of Pulmonary and Critical Care Medicine, Jinan Central Hospital Affiliated to Shandong First Medical University, Jinan, China
| | - Yao Liu
- Emergency Department of Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, No. 321 Zhongshan Road, Gulou District, Nanjing, China
| | - Xiao-Long Zhang
- Department of Ultrasound, Jinan Central Hospital Affiliated to Shandong First Medical University, Jinan, China
| | - Yun Sun
- The First Department of Critical Care Medicine, The Second Affiliated Hospital of Anhui Medical University, 678 Furong Road, Hefei, Anhui Province, 230601, China
| | - Zhong-Hua Lu
- The First Department of Critical Care Medicine, The Second Affiliated Hospital of Anhui Medical University, 678 Furong Road, Hefei, Anhui Province, 230601, China
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12
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Fang Q, Wu W, Xiao Z, Zeng D, Liang R, Wang J, Yuan J, Su W, Xu X, Zheng Y, Lai T, Sun J, Fu Q, Zheng SG. Gingival-derived mesenchymal stem cells alleviate allergic asthma inflammation via HGF in animal models. iScience 2024; 27:109818. [PMID: 38766356 PMCID: PMC11099335 DOI: 10.1016/j.isci.2024.109818] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2024] [Revised: 03/25/2024] [Accepted: 04/24/2024] [Indexed: 05/22/2024] Open
Abstract
Allergic asthma is a chronic non-communicable disease characterized by lung tissue inflammation. Current treatments can alleviate the clinical symptoms to some extent, but there is still no cure. Recently, the transplantation of mesenchymal stem cells (MSCs) has emerged as a potential approach for treating allergic asthma. Gingival-derived mesenchymal stem cells (GMSCs), a type of MSC recently studied, have shown significant therapeutic effects in various experimental models of autoimmune diseases. However, their application in allergic diseases has yet to be fully elucidated. In this study, using an OVA-induced allergic asthma model, we demonstrated that GMSCs decrease CD11b+CD11c+ proinflammatory dendritic cells (DCs), reduce Th2 cells differentiation, and thus effectively diminish eosinophils infiltration. We also identified that the core functional factor, hepatocyte growth factor (HGF) secreted by GMSCs, mediated its effects in relieving airway inflammation. Taken together, our findings indicate GMSCs as a potential therapy for allergic asthma and other related diseases.
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Affiliation(s)
- Qiannan Fang
- Department of Immunology, School of Cell and Gene Therapy, Songjiang Research Institute, Shanghai Jiaotong University School of Medicine Affiliated Songjiang Hospital, Shanghai, China
- Medical Research Institute, Guangdong Provincial People’s Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, Guangdong, China
- Division of Rheumatology and Immunology, Department of Internal Medicine, The Ohio State University School of Medicine, Columbus, OH, USA
| | - Wenbin Wu
- Department of Clinical Immunology Center, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China
| | - Zexiu Xiao
- Department of Clinical Immunology Center, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China
| | - Donglan Zeng
- Department of Clinical Immunology Center, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China
| | - Rongzhen Liang
- Department of Immunology, School of Cell and Gene Therapy, Songjiang Research Institute, Shanghai Jiaotong University School of Medicine Affiliated Songjiang Hospital, Shanghai, China
| | - Julie Wang
- Department of Immunology, School of Cell and Gene Therapy, Songjiang Research Institute, Shanghai Jiaotong University School of Medicine Affiliated Songjiang Hospital, Shanghai, China
- Division of Rheumatology and Immunology, Department of Internal Medicine, The Ohio State University School of Medicine, Columbus, OH, USA
| | - Jia Yuan
- Division of Stomatology, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China
| | - Wenru Su
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangdong Provincial Key Laboratory of Ophthalmology and Visual Science, Guangzhou, Guangdong, China
| | - Xiang Xu
- Department of Stem Cell & Regenerative Medicine, Daping Hospital, Army Medical University, Chongqing, China
| | - Yue Zheng
- Department of Dermatology Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China
| | - Tianwen Lai
- The First Dongguan Affiliated Hospital, Guangdong Medical University, Dongguan, Guangdong, China
| | - Jianbo Sun
- The First Dongguan Affiliated Hospital, Guangdong Medical University, Dongguan, Guangdong, China
| | - Qingling Fu
- Otorhinolaryngology Department, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong, China
| | - Song Guo Zheng
- Department of Immunology, School of Cell and Gene Therapy, Songjiang Research Institute, Shanghai Jiaotong University School of Medicine Affiliated Songjiang Hospital, Shanghai, China
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13
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Yuan D, Bao Y, El-Hashash A. Mesenchymal stromal cell-based therapy in lung diseases; from research to clinic. AMERICAN JOURNAL OF STEM CELLS 2024; 13:37-58. [PMID: 38765802 PMCID: PMC11101986 DOI: 10.62347/jawm2040] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/10/2023] [Accepted: 03/02/2024] [Indexed: 05/22/2024]
Abstract
Recent studies demonstrated that mesenchymal stem cells (MSCs) are important for the cell-based therapy of diseased or injured lung due to their immunomodulatory and regenerative properties as well as limited side effects in experimental animal models. Preclinical studies have shown that MSCs have also a remarkable effect on the immune cells, which play major roles in the pathogenesis of multiple lung diseases, by modulating their activity, proliferation, and functions. In addition, MSCs can inhibit both the infiltrated immune cells and detrimental immune responses in the lung and can be used in treating lung diseases caused by a virus infection such as Tuberculosis and SARS-COV-2. Moreover, MSCs are a source for alveolar epithelial cells such as type 2 (AT2) cells. These MSC-derived functional AT2-like cells can be used to treat and diminish serious lung disorders, including acute lung injury, asthma, chronic obstructive pulmonary disease (COPD), and pulmonary fibrosis in animal models. As an alternative MSC-based therapy, extracellular vesicles that are derived from MSC-derived can be employed in regenerative medicine. Herein, we discussed the key research findings from recent clinical and preclinical studies on the functions of MSCs in treating some common and well-studied lung diseases. We also discussed the mechanisms underlying MSC-based therapy of well-studied lung diseases, and the recent employment of MSCs in both the attenuation of lung injury/inflammation and promotion of the regeneration of lung alveolar cells after injury. Finally, we described the role of MSC-based therapy in treating major pulmonary diseases such as pneumonia, COPD, asthma, and idiopathic pulmonary fibrosis (IPF).
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Affiliation(s)
- Dailin Yuan
- Zhejiang UniversityHangzhou 310058, Zhejiang, PR China
| | - Yufei Bao
- School of Biomedical Engineering, University of SydneyDarlington, NSW 2008, Australia
| | - Ahmed El-Hashash
- Texas A&M University, 3258 TAMU, College StationTX 77843-3258, USA
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14
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Kholodenko IV, Kholodenko RV, Yarygin KN. The Crosstalk between Mesenchymal Stromal/Stem Cells and Hepatocytes in Homeostasis and under Stress. Int J Mol Sci 2023; 24:15212. [PMID: 37894893 PMCID: PMC10607347 DOI: 10.3390/ijms242015212] [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: 09/23/2023] [Revised: 10/07/2023] [Accepted: 10/10/2023] [Indexed: 10/29/2023] Open
Abstract
Liver diseases, characterized by high morbidity and mortality, represent a substantial medical problem globally. The current therapeutic approaches are mainly aimed at reducing symptoms and slowing down the progression of the diseases. Organ transplantation remains the only effective treatment method in cases of severe liver pathology. In this regard, the development of new effective approaches aimed at stimulating liver regeneration, both by activation of the organ's own resources or by different therapeutic agents that trigger regeneration, does not cease to be relevant. To date, many systematic reviews and meta-analyses have been published confirming the effectiveness of mesenchymal stromal cell (MSC) transplantation in the treatment of liver diseases of various severities and etiologies. However, despite the successful use of MSCs in clinical practice and the promising therapeutic results in animal models of liver diseases, the mechanisms of their protective and regenerative action remain poorly understood. Specifically, data about the molecular agents produced by these cells and mediating their therapeutic action are fragmentary and often contradictory. Since MSCs or MSC-like cells are found in all tissues and organs, it is likely that many key intercellular interactions within the tissue niches are dependent on MSCs. In this context, it is essential to understand the mechanisms underlying communication between MSCs and differentiated parenchymal cells of each particular tissue. This is important both from the perspective of basic science and for the development of therapeutic approaches involving the modulation of the activity of resident MSCs. With regard to the liver, the research is concentrated on the intercommunication between MSCs and hepatocytes under normal conditions and during the development of the pathological process. The goals of this review were to identify the key factors mediating the crosstalk between MSCs and hepatocytes and determine the possible mechanisms of interaction of the two cell types under normal and stressful conditions. The analysis of the hepatocyte-MSC interaction showed that MSCs carry out chaperone-like functions, including the synthesis of the supportive extracellular matrix proteins; prevention of apoptosis, pyroptosis, and ferroptosis; support of regeneration; elimination of lipotoxicity and ER stress; promotion of antioxidant effects; and donation of mitochondria. The underlying mechanisms suggest very close interdependence, including even direct cytoplasm and organelle exchange.
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Affiliation(s)
- Irina V. Kholodenko
- Laboratory of Cell Biology, Orekhovich Institute of Biomedical Chemistry, 119121 Moscow, Russia
| | - Roman V. Kholodenko
- Laboratory of Molecular Immunology, Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, 117997 Moscow, Russia;
| | - Konstantin N. Yarygin
- Laboratory of Cell Biology, Orekhovich Institute of Biomedical Chemistry, 119121 Moscow, Russia
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15
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Martínez-Zarco BA, Jiménez-García MG, Tirado R, Ambrosio J, Hernández-Mendoza L. [Mesenchymal stem cells: Therapeutic option in ARDS, COPD, and COVID-19 patients]. REVISTA ALERGIA MÉXICO 2023; 70:89-101. [PMID: 37566772 DOI: 10.29262/ram.v70i1.1149] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2022] [Accepted: 03/30/2023] [Indexed: 08/13/2023] Open
Abstract
Acute respiratory distress syndrome (ARDS), chronic obstructive pulmonary disease (COPD) and COVID-19 have as a common characteristic the inflammatory lesion of the lung epithelium. The therapeutic options are associated with opportunistic infections, a hyperglycemic state, and adrenal involvement. Therefore, the search for new treatment strategies that reduce inflammation, and promote re-epithelialization of damaged tissue is very important. This work describes the relevant pathophysiological characteristics of these diseases and evaluates recent findings on the immunomodulatory, anti-inflammatory and regenerative effect of mesenchymal stem cells (MSC) and their therapeutic use. In Pubmed we selected the most relevant studies on the subject, published between 2003 and 2022 following the PRISMA guide. We conclude that MSCs are an important therapeutic option for regenerative treatment in COPD, ARDS, and COVID-19, because of their ability to differentiate into type II pneumocytes and maintain the size and function of lung tissue by replacing dead or damaged cells.
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Affiliation(s)
| | | | - Rocío Tirado
- Doctor en Ciencias Biomédicas, Departamento de Microbiología y Parasitología.Universidad Nacional Autónoma de México, Facultad de Medicina, Laboratorio de Biología del Citoesqueleto y Virología, Ciudad de México
| | - Javier Ambrosio
- Doctor en Ciencias Biomédicas, Departamento de Microbiología y Parasitología.Universidad Nacional Autónoma de México, Facultad de Medicina, Laboratorio de Biología del Citoesqueleto y Virología, Ciudad de México
| | - Lilian Hernández-Mendoza
- Doctor en Ciencias Biomédicas, Departamento de Microbiología y Parasitología.Universidad Nacional Autónoma de México, Facultad de Medicina, Laboratorio de Biología del Citoesqueleto y Virología, Ciudad de México.
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16
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Antigen-Specific T Cells and SARS-CoV-2 Infection: Current Approaches and Future Possibilities. Int J Mol Sci 2022; 23:ijms232315122. [PMID: 36499448 PMCID: PMC9737069 DOI: 10.3390/ijms232315122] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2022] [Revised: 11/25/2022] [Accepted: 11/26/2022] [Indexed: 12/05/2022] Open
Abstract
COVID-19, a significant global health threat, appears to be an immune-related disease. Failure of effective immune responses in initial stages of infection may contribute to development of cytokine storm and systemic inflammation with organ damage, leading to poor clinical outcomes. Disease severity and the emergence of new SARS-CoV-2 variants highlight the need for new preventative and therapeutic strategies to protect the immunocompromised population. Available data indicate that these people may benefit from adoptive transfer of allogeneic SARS-CoV-2-specific T cells isolated from convalescent individuals. This review first provides an insight into the mechanism of cytokine storm development, as it is directly related to the exhaustion of T cell population, essential for viral clearance and long-term antiviral immunity. Next, we describe virus-specific T lymphocytes as a promising and efficient approach for the treatment and prevention of severe COVID-19. Furthermore, other potential cell-based therapies, including natural killer cells, regulatory T cells and mesenchymal stem cells are mentioned. Additionally, we discuss fast and effective ways of producing clinical-grade antigen-specific T cells which can be cryopreserved and serve as an effective "off-the-shelf" approach for rapid treatment of SARS-CoV-2 infection in case of sudden patient deterioration.
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17
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Li Y, Cui S, Wu B, Gao J, Li M, Zhang F, Xia H. FGF5 alleviated acute lung injury via AKT signal pathway in endothelial cells. Biochem Biophys Res Commun 2022; 634:152-158. [PMID: 36244113 PMCID: PMC9527228 DOI: 10.1016/j.bbrc.2022.09.112] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2022] [Revised: 09/23/2022] [Accepted: 09/28/2022] [Indexed: 11/25/2022]
Abstract
Acute lung injury (ALI), with high morbidity and mortality, is mainly resulted by infectious or non-infectious inflammatory stimulators, and it will further evolve into acute respiratory distress syndrome if not controlled. Fibroblast growth factors (FGFs) consist of more than 23 kinds of members, which are involved in various pathophysiological processes of body. However, the effect of FGF5, one member of FGFs, is still not certain in lipopolysaccharide (LPS)-induced ALI. In this study, we explored the possible impacts of FGF5 in LPS-induced ALI and primarily focused on endothelial cell, which was one of the most vulnerable cells in septic ALI. In the mouse group of FGF5 overexpression, LPS-induced lung injuries were mitigated, as well as the pyroptosis levels of pulmonary vascular endothelial cells. Additionally, in vitro human umbilical vein endothelial cells (HUVECs), our results showed that the level of cell pyroptosis was ameliorated with FGF5 overexpression, and AKT signal was activated with the overexpression of FGF5, whereas after administration of MK2206, an inhibitor of AKT signal, the protection of FGF5 was inhibited. Therefore, these results suggested that FGF5 exerted protective effects in endothelial cells exposed to LPS, and this protection of FGF5 could be attributed to activated AKT signal.
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Affiliation(s)
- Yuhua Li
- Intensive Care Unit, Wuhan Children's Hospital (Wuhan Maternal and Child Healthcare Hospital), Tongji Medical College, Huazhong University of Science & Technology, Wuhan, China
| | - Shengyu Cui
- Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, 430060, China
| | - Bing Wu
- Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, 430060, China
| | - Jixian Gao
- Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, 430060, China
| | - Ming Li
- Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, 430060, China
| | - Furong Zhang
- Intensive Care Unit, Wuhan Children's Hospital (Wuhan Maternal and Child Healthcare Hospital), Tongji Medical College, Huazhong University of Science & Technology, Wuhan, China.
| | - Hao Xia
- Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, 430060, China.
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18
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Liu C, Xiao K, Xie L. Advances in mesenchymal stromal cell therapy for acute lung injury/acute respiratory distress syndrome. Front Cell Dev Biol 2022; 10:951764. [PMID: 36036014 PMCID: PMC9399751 DOI: 10.3389/fcell.2022.951764] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2022] [Accepted: 07/19/2022] [Indexed: 11/29/2022] Open
Abstract
Acute lung injury (ALI)/acute respiratory distress syndrome (ARDS) develops rapidly and has high mortality. ALI/ARDS is mainly manifested as acute or progressive hypoxic respiratory failure. At present, there is no effective clinical intervention for the treatment of ALI/ARDS. Mesenchymal stromal cells (MSCs) show promise for ALI/ARDS treatment due to their biological characteristics, easy cultivation, low immunogenicity, and abundant sources. The therapeutic mechanisms of MSCs in diseases are related to their homing capability, multidirectional differentiation, anti-inflammatory effect, paracrine signaling, macrophage polarization, the polarization of the MSCs themselves, and MSCs-derived exosomes. In this review, we discuss the pathogenesis of ALI/ARDS along with the biological characteristics and mechanisms of MSCs in the treatment of ALI/ARDS.
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Affiliation(s)
- Chang Liu
- School of Medicine, Nankai University, Tianjin, China
- Center of Pulmonary and Critical Care Medicine, Chinese People’s Liberation Army (PLA) General Hospital, Beijing, China
- Medical School of Chinese People’s Liberation Army (PLA), Beijing, China
| | - Kun Xiao
- Center of Pulmonary and Critical Care Medicine, Chinese People’s Liberation Army (PLA) General Hospital, Beijing, China
- Medical School of Chinese People’s Liberation Army (PLA), Beijing, China
- *Correspondence: Kun Xiao, ; Lixin Xie,
| | - Lixin Xie
- School of Medicine, Nankai University, Tianjin, China
- Center of Pulmonary and Critical Care Medicine, Chinese People’s Liberation Army (PLA) General Hospital, Beijing, China
- Medical School of Chinese People’s Liberation Army (PLA), Beijing, China
- *Correspondence: Kun Xiao, ; Lixin Xie,
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19
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Meng HF, Jin J, Wang H, Wang LS, Wu CT. Recent advances in the therapeutic efficacy of hepatocyte growth factor gene-modified mesenchymal stem cells in multiple disease settings. J Cell Mol Med 2022; 26:4745-4755. [PMID: 35922965 PMCID: PMC9465188 DOI: 10.1111/jcmm.17497] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2022] [Revised: 06/16/2022] [Accepted: 07/08/2022] [Indexed: 11/30/2022] Open
Abstract
Mesenchymal stem cell (MSC) therapy is considered a new treatment for a wide range of diseases and injuries, but challenges remain, such as poor survival, homing and engraftment rates, thus limiting the therapeutic efficacy of the transplanted MSCs. Many strategies have been developed to enhance the therapeutic efficacy of MSCs, such as preconditioning, co-transplantation with graft materials and gene modification. Hepatocyte growth factor (HGF) is secreted by MSCs, which plays an important role in MSC therapy. It has been reported that the modification of the HGF gene is beneficial to the therapeutic efficacy of MSCs, including diseases of the heart, lung, liver, urinary system, bone and skin, lower limb ischaemia and immune-related diseases. This review focused on studies involving HGF/MSCs both in vitro and in vivo. The characteristics of HGF/MSCs were summarized, and the mechanisms of their improved therapeutic efficacy were analysed. Furthermore, some insights are provided for HGF/MSCs' clinical application based on our understanding of the HGF gene and MSC therapy.
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Affiliation(s)
- Hong-Fang Meng
- School of Chemical Engineering and Technology, Tianjin University, Tianjin, China.,Beijing Key Laboratory for Radiobiology, Beijing Institute of Radiation Medicine, Beijing, China
| | - Jide Jin
- Beijing Key Laboratory for Radiobiology, Beijing Institute of Radiation Medicine, Beijing, China
| | - Hua Wang
- Beijing Key Laboratory for Radiobiology, Beijing Institute of Radiation Medicine, Beijing, China
| | - Li-Sheng Wang
- Beijing Key Laboratory for Radiobiology, Beijing Institute of Radiation Medicine, Beijing, China
| | - Chu-Tse Wu
- School of Chemical Engineering and Technology, Tianjin University, Tianjin, China.,Beijing Key Laboratory for Radiobiology, Beijing Institute of Radiation Medicine, Beijing, China
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20
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Tan MI, Alfarafisa NM, Septiani P, Barlian A, Firmansyah M, Faizal A, Melani L, Nugrahapraja H. Potential Cell-Based and Cell-Free Therapy for Patients with COVID-19. Cells 2022; 11:2319. [PMID: 35954162 PMCID: PMC9367488 DOI: 10.3390/cells11152319] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2022] [Revised: 07/20/2022] [Accepted: 07/26/2022] [Indexed: 02/01/2023] Open
Abstract
Since it was first reported, the novel coronavirus disease 2019 (COVID-19) remains an unresolved puzzle for biomedical researchers in different fields. Various treatments, drugs, and interventions were explored as treatments for COVID. Nevertheless, there are no standard and effective therapeutic measures. Meanwhile, mesenchymal stem cell (MSC) therapy offers a new approach with minimal side effects. MSCs and MSC-based products possess several biological properties that potentially alleviate COVID-19 symptoms. Generally, there are three classifications of stem cell therapy: cell-based therapy, tissue engineering, and cell-free therapy. This review discusses the MSC-based and cell-free therapies for patients with COVID-19, their potential mechanisms of action, and clinical trials related to these therapies. Cell-based therapies involve the direct use and injection of MSCs into the target tissue or organ. On the other hand, cell-free therapy uses secreted products from cells as the primary material. Cell-free therapy materials can comprise cell secretomes and extracellular vesicles. Each therapeutic approach possesses different benefits and various risks. A better understanding of MSC-based and cell-free therapies is essential for supporting the development of safe and effective COVID-19 therapy.
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Affiliation(s)
- Marselina Irasonia Tan
- School of Life Sciences and Technology, Institut Teknologi Bandung, Bandung 40132, Indonesia; (P.S.); (A.B.); (M.F.); (A.F.); (L.M.); (H.N.)
| | - Nayla Majeda Alfarafisa
- Department of Biomedical Sciences, Faculty of Medicine, Universitas Padjadjaran, Sumedang 45363, Indonesia;
| | - Popi Septiani
- School of Life Sciences and Technology, Institut Teknologi Bandung, Bandung 40132, Indonesia; (P.S.); (A.B.); (M.F.); (A.F.); (L.M.); (H.N.)
| | - Anggraini Barlian
- School of Life Sciences and Technology, Institut Teknologi Bandung, Bandung 40132, Indonesia; (P.S.); (A.B.); (M.F.); (A.F.); (L.M.); (H.N.)
| | - Mochamad Firmansyah
- School of Life Sciences and Technology, Institut Teknologi Bandung, Bandung 40132, Indonesia; (P.S.); (A.B.); (M.F.); (A.F.); (L.M.); (H.N.)
| | - Ahmad Faizal
- School of Life Sciences and Technology, Institut Teknologi Bandung, Bandung 40132, Indonesia; (P.S.); (A.B.); (M.F.); (A.F.); (L.M.); (H.N.)
| | - Lili Melani
- School of Life Sciences and Technology, Institut Teknologi Bandung, Bandung 40132, Indonesia; (P.S.); (A.B.); (M.F.); (A.F.); (L.M.); (H.N.)
| | - Husna Nugrahapraja
- School of Life Sciences and Technology, Institut Teknologi Bandung, Bandung 40132, Indonesia; (P.S.); (A.B.); (M.F.); (A.F.); (L.M.); (H.N.)
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21
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Zavvar M, Yahyapoor A, Baghdadi H, Zargaran S, Assadiasl S, Abdolmohammadi K, Hossein Abooei A, Reza Sattarian M, JalaliFarahani M, Zarei N, Farahvash A, Fatahi Y, Deniz G, Zarebavani M, Nicknam MH. COVID-19 immunotherapy: Treatment based on the immune cell-mediated approaches. Int Immunopharmacol 2022; 107:108655. [PMID: 35248946 PMCID: PMC8872837 DOI: 10.1016/j.intimp.2022.108655] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2021] [Revised: 02/21/2022] [Accepted: 02/22/2022] [Indexed: 02/07/2023]
Abstract
Multiple efforts are currently underway to control and treat severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), causing coronavirus disease 2019 (COVID-19) worldwide. Despite all efforts, the virus that emerged in Wuhan city has rapidly spread globally and led to a public health emergency of international concern (PHEIC) due to the lack of approved antiviral therapy. Nevertheless, SARS-CoV-2 has had a significant influence on the evolution of cellular therapeutic approaches. Adoptive immune cell therapy is innovative and offers either promising prophylactic or therapy for patients with moderate-to-severe COVID-19. This approach is aimed at developing safety and providing secure and effective therapy in combination with standard therapy for all COVID-19 infected individuals. Based on the effective results of previous studies on both inflammatory and autoimmune diseases, various immune cell therapies against COVID-19 have been reviewed and discussed. It must be considered that the application of cell therapy for treatment and to eliminate infected respiratory cells could result in excessive inflammation, so this treatment must be used in combination with other treatments, despite its many beneficial efforts.
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22
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Hepatocyte growth factor protects pulmonary endothelial barrier against oxidative stress and mitochondria-dependent apoptosis. Chin Med J (Engl) 2022; 135:837-848. [PMID: 35671182 PMCID: PMC9276181 DOI: 10.1097/cm9.0000000000001916] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022] Open
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23
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Cellular therapies for the treatment and prevention of SARS-CoV-2 infection. Blood 2022; 140:208-221. [PMID: 35240679 PMCID: PMC8896869 DOI: 10.1182/blood.2021012249] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2022] [Accepted: 03/01/2022] [Indexed: 12/15/2022] Open
Abstract
Patients with blood disorders who are immune suppressed are at increased risk for infection with severe acute respiratory syndrome coronavirus 2. Sequelae of infection can include severe respiratory disease and/or prolonged duration of viral shedding. Cellular therapies may protect these vulnerable patients by providing antiviral cellular immunity and/or immune modulation. In this recent review of the field, phase 1/2 trials evaluating adoptive cellular therapies with virus-specific T cells or natural killer cells are described along with trials evaluating the safety, feasibility, and preliminary efficacy of immune modulating cellular therapies including regulatory T cells and mesenchymal stromal cells. In addition, the immunologic basis for these therapies is discussed.
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24
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Hu X, Zhang YA, Chen B, Jin Z, Lin ML, Li M, Mei HX, Lu JC, Gong YQ, Jin SW, Zheng SX. Protectin DX promotes the inflammatory resolution via activating COX-2/L-PGDS-PGD 2 and DP 1 receptor in acute respiratory distress syndrome. Int Immunopharmacol 2022; 102:108348. [PMID: 34920958 PMCID: PMC8578004 DOI: 10.1016/j.intimp.2021.108348] [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: 07/21/2021] [Revised: 10/23/2021] [Accepted: 11/03/2021] [Indexed: 11/29/2022]
Abstract
PURPOSE Acute respiratory distress syndrome (ARDS) is characterized by uncontrollable inflammation. Cyclooxygenase-2(COX-2) and its metabolite prostaglandins are known to promote the inflammatory resolution of ARDS. Recently, a newly discovered endogenous lipid mediator, Protectin DX (PDX), was also shown to mediate the resolution of inflammation. However, the regulatory of PDX on the pro-resolving COX-2 in ARDS remains unknown. MATERIAL AND METHODS PDX (5 μg/kg) was injected into rats intravenously 12 h after the lipopolysaccharide (LPS, 3 mg/kg) challenge. Primary rat lung fibroblasts were incubated with LPS (1 μg/ml) and/or PDX (100 nM). Lung pathological changes examined using H&E staining. Protein levels of COX-2, PGDS and PGES were evaluated using western blot. Inflammatory cytokines were tested by qPCR, and the concentration of prostaglandins measured by using ELISA. RESULTS Our study revealed that, COX-2 and L-PGDS has biphasic activation characteristics that LPS could induce induced by LPS both in vivo and in vitro.. The secondary peak of COX-2, L-PGDS-PGD2 promoted the inflammatory resolution in ARDS model with the DP1 receptor being activated and PDX up-regulated the inflammatory resolutionvia enhancing the secondary peak of COX-2/L-PGDS-PGD2 and activating the DP1 receptor. CONCLUSION PDX promoted the resolution of inflammation of ARDS model via enhancing the expression of secondary peak of COX-2/L-PGDS-PGD2 and activating the DP1 receptor. PDX shows promising therapeutic potential in the clinical management of ARDS.
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Affiliation(s)
- Xin Hu
- Department of Anesthesia and Critical Care, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, 325027, People's Republic of China
| | - Ye-An Zhang
- Department of Anesthesia and Critical Care, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, 325027, People's Republic of China
| | - Ben Chen
- Department of Anesthesia and Critical Care, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, 325027, People's Republic of China
| | - Zi Jin
- Department of Anesthesia and Critical Care, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, 325027, People's Republic of China
| | - Mei-Lin Lin
- Department of Anesthesia and Critical Care, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, 325027, People's Republic of China
| | - Ming Li
- Department of Anesthesia and Critical Care, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, 325027, People's Republic of China
| | - Hong-Xia Mei
- Department of Anesthesia and Critical Care, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, 325027, People's Republic of China
| | - Jia-Chao Lu
- Department of Anesthesia and Critical Care, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, 325027, People's Republic of China
| | - Yu-Qiang Gong
- Department of Anesthesia and Critical Care, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, 325027, People's Republic of China.
| | - Sheng-Wei Jin
- Department of Anesthesia and Critical Care, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, 325027, People's Republic of China.
| | - Sheng-Xing Zheng
- Department of Anesthesia and Critical Care, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, 325027, People's Republic of China.
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25
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Bao H, Li Y, Yu C, Li X, Wang Y, Gao L, Huang J, Zhang Z. DNA-coated gold nanoparticles for tracking hepatocyte growth factor secreted by transplanted mesenchymal stem cells in pulmonary fibrosis therapy. Biomater Sci 2021; 10:368-375. [PMID: 34897301 DOI: 10.1039/d1bm01362a] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/11/2023]
Abstract
The identification of paracrine factors secreted by transplanted mesenchymal stem cells (MSCs) during the treatment of idiopathic pulmonary fibrosis (IPF) is essential for understanding the role of MSCs in therapy. Herein, we report a facile and efficient strategy for in vivo tracking the secretion of hepatocyte growth factor (HGF) in MSCs during IPF therapy. In our strategy, a novel nanoflare tracer consisting of gold nanoparticles (AuNPs), complementary sequences and dye-labeled recognition sequences is developed. Briefly, the AuNPs are functionalized with oligonucleotide complementary sequences hybridized to the organic dye-labeled recognition sequences, where the organic fluorophores are in close proximity to the AuNPs. In the absence of targets, the dye and AuNPs are separated from each other, inducing the quenching of the fluorescence signal. However, in the presence of targets, the recognition sequences gradually fall off from the AuNPs, causing the fluorescence signal to rise. In brief, in vivo monitoring of the dynamic expression of HGF mRNA in transplanted MSCs during IPF therapy in the current work may provide new insight into the paracrine process of the transplanted MSCs, thereby advancing the MSC-based IPF therapy toward clinical applications.
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Affiliation(s)
- Hongying Bao
- School of Nano-Tech and Nano-Bionics, University of Science and Technology of China, Hefei, 230026, China.,CAS Key Laboratory of Nano-Bio Interface, Division of Nanobiomedicine, Suzhou Institute of Nano-Tech and Nano-Bionics, Chinese Academy of Sciences, Suzhou 215123, China.
| | - Yuxuan Li
- School of Nano-Tech and Nano-Bionics, University of Science and Technology of China, Hefei, 230026, China.,CAS Key Laboratory of Nano-Bio Interface, Division of Nanobiomedicine, Suzhou Institute of Nano-Tech and Nano-Bionics, Chinese Academy of Sciences, Suzhou 215123, China.
| | - Chenggong Yu
- CAS Key Laboratory of Nano-Bio Interface, Division of Nanobiomedicine, Suzhou Institute of Nano-Tech and Nano-Bionics, Chinese Academy of Sciences, Suzhou 215123, China.
| | - Xiaodi Li
- School of Nano-Tech and Nano-Bionics, University of Science and Technology of China, Hefei, 230026, China.,CAS Key Laboratory of Nano-Bio Interface, Division of Nanobiomedicine, Suzhou Institute of Nano-Tech and Nano-Bionics, Chinese Academy of Sciences, Suzhou 215123, China.
| | - Yujie Wang
- CAS Key Laboratory of Nano-Bio Interface, Division of Nanobiomedicine, Suzhou Institute of Nano-Tech and Nano-Bionics, Chinese Academy of Sciences, Suzhou 215123, China.
| | - Li Gao
- School of Life Science, Jiangsu University, Zhenjiang 212013, China
| | - Jie Huang
- School of Nano-Tech and Nano-Bionics, University of Science and Technology of China, Hefei, 230026, China.,CAS Key Laboratory of Nano-Bio Interface, Division of Nanobiomedicine, Suzhou Institute of Nano-Tech and Nano-Bionics, Chinese Academy of Sciences, Suzhou 215123, China.
| | - Zhijun Zhang
- School of Nano-Tech and Nano-Bionics, University of Science and Technology of China, Hefei, 230026, China.,CAS Key Laboratory of Nano-Bio Interface, Division of Nanobiomedicine, Suzhou Institute of Nano-Tech and Nano-Bionics, Chinese Academy of Sciences, Suzhou 215123, China.
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26
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Mori H, Huq MA, Islam MM, Takeyama N. Neutrophil extracellular traps are associated with altered human pulmonary artery endothelial barrier function. EUR J INFLAMM 2021. [DOI: 10.1177/20587392211062386] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
Abstract
Introduction: Acute respiratory response syndrome (ARDS) leads to increased permeability of the endothelial-epithelial barrier, which in turn promotes edema formation and hypoxemic respiratory failure. Although activated neutrophils are thought to play a significant role in mediating ARDS, at present the contribution of neutrophil extracellular traps (NETs) to lung endothelial barrier function is unclear. Methods: To clarify their role, we co-cultured in vitro NETs induced by phorbol myristate acetate (PMA)–activated neutrophils with lung endothelial cell monolayers and examined the barrier function of lung endothelial cells by immunofluorescence microscopy and albumin permeability in a double-chamber culture method. Results: Co-culture with stimulated neutrophils increased the albumin permeability of the human pulmonary artery endothelial cell (HPAEC) monolayer and altered cytoskeleton F-actin and vascular endothelial-cadherin in cell-cell junctions. Hyperpermeability to albumin and histological alterations were prevented by inhibition of NET formation with peptidyl arginine deiminase inhibitor or a neutrophil elastase inhibitor and were also prevented by increased degradation of NET structure with DNase. Conclusion: This in vitro experiment shows that altered HPAEC barrier function and increased albumin permeability are caused by the direct effect of PMA-induced NETs and their components. NET formation may be involved in the increased vascular permeability of the lung, which is a common feature in ARDS of various etiologies. These insights may help generate novel approaches for medical interventions.
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Affiliation(s)
- Hisatake Mori
- Department of Emergency and Critical Care Medicine, Aichi Medical University, Aichi, Japan
| | - Muhammad Aminul Huq
- Department of Emergency and Critical Care Medicine, Aichi Medical University, Aichi, Japan
| | - Md. Monirul Islam
- Department of Emergency and Critical Care Medicine, Aichi Medical University, Aichi, Japan
| | - Naoshi Takeyama
- Department of Emergency and Critical Care Medicine, Aichi Medical University, Aichi, Japan
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27
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mTORC2 Activation Mediated by Mesenchymal Stem Cell-Secreted Hepatocyte Growth Factors for the Recovery of Lipopolysaccharide-Induced Vascular Endothelial Barrier. Stem Cells Int 2021; 2021:9981589. [PMID: 34707661 PMCID: PMC8545561 DOI: 10.1155/2021/9981589] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2021] [Revised: 07/26/2021] [Accepted: 08/03/2021] [Indexed: 01/11/2023] Open
Abstract
Acute lung injury (ALI)/acute respiratory distress syndrome (ARDS) is characterized by pulmonary microvascular endothelial barrier dysfunction. Mesenchymal stem cell-secreted hepatocyte growth factor (HGF) has positive effects of lipopolysaccharide- (LPS-) induced pulmonary endothelial barrier. Studies have exhibited the mammalian TORC1 (mTORC1) signaling is of potent angiogenesis effects. The mTOR protein kinase has two distinct multiprotein complexes mTORC1 and mTORC2 that regulate different branches of the mTOR network. However, detailed mTORC2 mechanisms of HGF protective effects remain poorly defined. Therefore, the aim of this study was to determine whether mTORC2 mediated protective effects of MSC-secreted HGF against LPS-induced pulmonary microvascular endothelial barrier dysfunction activated like mTORC1 activation. We introduced MSC-PMVEC coculture transwell system and recombinant murine HGF on LPS-induced endothelial cell barrier dysfunction in vitro and then explored potential mechanisms by lentivirus vector-mediated HGF, mTORC1 (raptor), and mTORC2 (rictor) gene knockdown modification. Endothelial paracellular and transcellular permeability, adherent junction protein (VE-Cadherin), cell proliferation, apoptosis, and mTOR-associated proteins were tested. These revealed that HGF could promote quick reestablishment of adherent junction VE-cadherin and decrease endothelial paracellular and transcellular permeability during LSP-induced endothelial dysfunction with the involvement of mTORC2 (rictor) and mTORC1 (raptor) pathways. Raptor and rictor knockdown in LPS-induced PMEVECs with stimulation of HGF increased apoptosis ratio, activated Cleaved-Caspase-3 expression, and downregulated cell proliferation. Moreover, mTORC2/Akt but not mTORC2/PKC had significance on HGF endothelial protective effects. Taken together, these highlight activation mTORC2 pathway could also contribute to vascular endothelial barrier recovery by MSC-secreted HGF in LPS stimulation.
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28
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Xu Z, Huang Y, Zhou J, Deng X, He W, Liu X, Li Y, Zhong N, Sang L. Current Status of Cell-Based Therapies for COVID-19: Evidence From Mesenchymal Stromal Cells in Sepsis and ARDS. Front Immunol 2021; 12:738697. [PMID: 34659231 PMCID: PMC8517471 DOI: 10.3389/fimmu.2021.738697] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2021] [Accepted: 09/13/2021] [Indexed: 12/29/2022] Open
Abstract
The severe respiratory consequences of the coronavirus disease 2019 (COVID-19) pandemic have prompted the urgent need for novel therapies. Cell-based therapies, primarily using mesenchymal stromal cells (MSCs), have demonstrated safety and potential efficacy in the treatment of critical illness, particularly sepsis and acute respiratory distress syndrome (ARDS). However, there are limited preclinical data for MSCs in COVID-19. Recent studies have shown that MSCs could decrease inflammation, improve lung permeability, enhance microbe and alveolar fluid clearance, and promote lung epithelial and endothelial repair. In addition, MSC-based therapy has shown promising effects in preclinical studies and phase 1 clinical trials in sepsis and ARDS. Here, we review recent advances related to MSC-based therapy in the context of sepsis and ARDS and evaluate the potential value of MSCs as a therapeutic strategy for COVID-19.
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Affiliation(s)
- Zhiheng Xu
- State Key Laboratory of Respiratory Diseases, Department of Critical Care Medicine, Guangzhou Institute of Respiratory Health, First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China.,Guangzhou Medical University, Guangzhou, China
| | - Yongbo Huang
- State Key Laboratory of Respiratory Diseases, Department of Critical Care Medicine, Guangzhou Institute of Respiratory Health, First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China.,Guangzhou Medical University, Guangzhou, China
| | - Jianmeng Zhou
- School of Public Health, Southern Medical University, Guangzhou, China
| | - Xiumei Deng
- State Key Laboratory of Respiratory Diseases, Department of Critical Care Medicine, Guangzhou Institute of Respiratory Health, First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China.,Guangzhou Medical University, Guangzhou, China
| | - Weiqun He
- State Key Laboratory of Respiratory Diseases, Department of Critical Care Medicine, Guangzhou Institute of Respiratory Health, First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China.,Guangzhou Medical University, Guangzhou, China
| | - Xiaoqing Liu
- State Key Laboratory of Respiratory Diseases, Department of Critical Care Medicine, Guangzhou Institute of Respiratory Health, First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China.,Guangzhou Medical University, Guangzhou, China
| | - Yimin Li
- State Key Laboratory of Respiratory Diseases, Department of Critical Care Medicine, Guangzhou Institute of Respiratory Health, First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China.,Guangzhou Medical University, Guangzhou, China
| | - Nanshan Zhong
- State Key Laboratory of Respiratory Diseases, Department of Critical Care Medicine, Guangzhou Institute of Respiratory Health, First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China.,Guangzhou Medical University, Guangzhou, China
| | - Ling Sang
- State Key Laboratory of Respiratory Diseases, Department of Critical Care Medicine, Guangzhou Institute of Respiratory Health, First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China.,Guangzhou Medical University, Guangzhou, China.,Guangzhou Laboratory, Guangzhou, China
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29
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Chen XY, Chen YY, Lin W, Chen CH, Wen YC, Hsiao TC, Chou HC, Chung KF, Chuang HC. Therapeutic Potential of Human Umbilical Cord-Derived Mesenchymal Stem Cells in Recovering From Murine Pulmonary Emphysema Under Cigarette Smoke Exposure. Front Med (Lausanne) 2021; 8:713824. [PMID: 34646841 PMCID: PMC8502916 DOI: 10.3389/fmed.2021.713824] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2021] [Accepted: 08/31/2021] [Indexed: 01/08/2023] Open
Abstract
Human umbilical cord-derived mesenchymal stem cells (hUC-MSCs) were shown to have potential for immunoregulation and tissue repair. The objective of this study was to investigate the effects of hUC-MSCs on emphysema in chronic obstructive pulmonary disease (COPD). The C57BL/6JNarl mice were exposed to cigarette smoke (CS) for 4 months followed by administration of hUC-MSCs at 3 × 106 (low dose), 1 × 107 (medium dose), and 3 × 107 cells/kg body weight (high dose). The hUC-MSCs caused significant decreases in emphysema severity by measuring the mean linear intercept (MLI) and destructive index (DI). A decrease in neutrophils (%) and an increase in lymphocytes (%) in bronchoalveolar lavage fluid (BALF) were observed in emphysematous mice after hUC-MSC treatment. Lung levels of interleukin (IL)-1β, C-X-C motif chemokine ligand 1 (CXCL1)/keratinocyte chemoattractant (KC), and matrix metalloproteinase (MMP)-12 significantly decreased after hUC-MSC administration. Significant reductions in tumor necrosis factor (TNF)-α, IL-1β, and IL-17A in serum occurred after hUC-MSC administration. Notably, the cell viability of lung fibroblasts improved with hUC-MSCs after being treated with CS extract (CSE). Furthermore, the hUC-MSCs-conditioned medium (hUC-MSCs-CM) restored the contractile force, and increased messenger RNA expressions of elastin and fibronectin by lung fibroblasts. In conclusion, hUC-MSCs reduced inflammatory responses and emphysema severity in CS-induced emphysematous mice.
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Affiliation(s)
- Xiao-Yue Chen
- Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei, Taiwan.,School of Respiratory Therapy, College of Medicine, Taipei Medical University, Taipei, Taiwan
| | - Yi-Ying Chen
- School of Respiratory Therapy, College of Medicine, Taipei Medical University, Taipei, Taiwan
| | - Willie Lin
- Meridigen Biotech Co., Ltd., Taipei, Taiwan
| | | | | | - Ta-Chih Hsiao
- Graduate Institute of Environmental Engineering, National Taiwan University, Taipei, Taiwan
| | - Hsiu-Chu Chou
- Department of Anatomy and Cell Biology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan
| | - Kian Fan Chung
- National Heart and Lung Institute, Imperial College London, London, United Kingdom
| | - Hsiao-Chi Chuang
- School of Respiratory Therapy, College of Medicine, Taipei Medical University, Taipei, Taiwan.,Division of Pulmonary Medicine, Department of Internal Medicine, Shuang Ho Hospital, Taipei Medical University, New Taipei City, Taiwan.,Cell Physiology and Molecular Image Research Center, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan
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30
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Wang M, Zhou T, Zhang Z, Liu H, Zheng Z, Xie H. Current therapeutic strategies for respiratory diseases using mesenchymal stem cells. MedComm (Beijing) 2021; 2:351-380. [PMID: 34766151 PMCID: PMC8554668 DOI: 10.1002/mco2.74] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2020] [Revised: 03/15/2021] [Accepted: 03/18/2021] [Indexed: 02/06/2023] Open
Abstract
Mesenchymal stromal/stem cells (MSCs) have a great potential to proliferate, undergo multi-directional differentiation, and exert immunoregulatory effects. There is already much enthusiasm for their therapeutic potentials for respiratory inflammatory diseases. Although the mechanism of MSCs-based therapy has been well explored, only a few articles have summarized the key advances in this field. We hereby provide a review over the latest progresses made on the MSCs-based therapies for four types of inflammatory respiratory diseases, including idiopathic pulmonary fibrosis, acute respiratory distress syndrome, chronic obstructive pulmonary disease, and asthma, and the uncovery of their underlying mechanisms from the perspective of biological characteristics and functions. Furthermore, we have also discussed the advantages and disadvantages of the MSCs-based therapies and prospects for their optimization.
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Affiliation(s)
- Ming‐yao Wang
- Laboratory of Stem Cell and Tissue EngineeringOrthopedic Research InstituteMed‐X Center for MaterialsState Key Laboratory of Biotherapy and Cancer CenterWest China HospitalSichuan University and Collaborative Innovation Center of BiotherapyChengduChina
| | - Ting‐yue Zhou
- Laboratory of Stem Cell and Tissue EngineeringOrthopedic Research InstituteMed‐X Center for MaterialsState Key Laboratory of Biotherapy and Cancer CenterWest China HospitalSichuan University and Collaborative Innovation Center of BiotherapyChengduChina
| | - Zhi‐dong Zhang
- Laboratory of Stem Cell and Tissue EngineeringOrthopedic Research InstituteMed‐X Center for MaterialsState Key Laboratory of Biotherapy and Cancer CenterWest China HospitalSichuan University and Collaborative Innovation Center of BiotherapyChengduChina
| | - Hao‐yang Liu
- Laboratory of Stem Cell and Tissue EngineeringOrthopedic Research InstituteMed‐X Center for MaterialsState Key Laboratory of Biotherapy and Cancer CenterWest China HospitalSichuan University and Collaborative Innovation Center of BiotherapyChengduChina
| | - Zhi‐yao Zheng
- Laboratory of Stem Cell and Tissue EngineeringOrthopedic Research InstituteMed‐X Center for MaterialsState Key Laboratory of Biotherapy and Cancer CenterWest China HospitalSichuan University and Collaborative Innovation Center of BiotherapyChengduChina
| | - Hui‐qi Xie
- Laboratory of Stem Cell and Tissue EngineeringOrthopedic Research InstituteMed‐X Center for MaterialsState Key Laboratory of Biotherapy and Cancer CenterWest China HospitalSichuan University and Collaborative Innovation Center of BiotherapyChengduChina
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31
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Sütlüoğlu H, Özdemir Ö. May mesenchymal stem cell transplantation be a solution for COVID-19 induced cytokine storm? World J Transplant 2021; 11:344-355. [PMID: 34447671 PMCID: PMC8371495 DOI: 10.5500/wjt.v11.i8.344] [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: 02/22/2021] [Revised: 06/16/2021] [Accepted: 08/10/2021] [Indexed: 02/06/2023] Open
Abstract
The recently emergent disease caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), transmitted by droplets and aerosols, was named coronavirus disease 2019 (COVID-19) by World Health Organization. Predominantly, the disease progress is asymptomatic or mild, but one-fifth of the patients advance to severe or critical illness. In severe COVID-19 patients, type-2 T helper cells release numerous cytokines; this excessive immune response is named as cytokine storm. The cytokine storm, which is the hallmark of the COVID-19 induced by the disease and aggravates due to lack of proper immune response, similar to SARS and Middle East respiratory syndrome (MERS), and the disease status may progress forward to acute respiratory distress syndrome (ARDS), systemic inflammatory response syndrome, multi-organ dysfunction syndrome, and death. Mesenchymal stromal cell transplantation is up-and-coming in treating many diseases such as HIV, hepatitis B, influenza, coronavirus diseases (SARS, MERS), lung injuries, and ARDS. Upon closer inspection on respiratory diseases, COVID-19, influenza, SARS, and MERS have similarities in pathogenesis, especially cytokine and immune response profiles. These comparable features in terms of the cytokine storm will provide hints for the treatment of COVID-19.
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Affiliation(s)
- Hüseyin Sütlüoğlu
- Faculty of Medicine, Sakarya University, Adapazarı 54100, Sakarya, Turkey
| | - Öner Özdemir
- Division of Pediatric Allergy and Immunology, Sakarya University Medical Faculty, Adapazarı 54100, Sakarya, Turkey
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Zani-Ruttenstock E, Antounians L, Khalaj K, Figueira RL, Zani A. The Role of Exosomes in the Treatment, Prevention, Diagnosis, and Pathogenesis of COVID-19. Eur J Pediatr Surg 2021; 31:326-334. [PMID: 34161984 DOI: 10.1055/s-0041-1731294] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
The novel coronavirus disease 2019 (COVID-19) pandemic, caused by the severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2), continues to be a major health concern. In search for novel treatment strategies against COVID-19, exosomes have attracted the attention of scientists and pharmaceutical companies worldwide. Exosomes are small extracellular vesicles, secreted by all types of cells, and considered as key mediators of intercellular communication and stem-cell paracrine signaling. Herein, we reviewed the most recent literature about the role of exosomes as potential agents for treatment, prevention, diagnosis, and pathogenesis of COVID-19. Several studies and ongoing clinical trials have been investigating the anti-inflammatory, immunomodulatory, and reparative effects of exosomes derived from mesenchymal stem/stromal cells for COVID-19-related acute lung injury. Other studies reported that exosomes play a key role in convalescent plasma therapy for COVID-19, and that they could be of use for the treatment of COVID-19 Kawasaki's-like multisystem inflammatory syndrome and as drug delivery nanocarriers for antiviral therapy. Harnessing some advantageous aspects of exosome biology, such as their endogenous origin, capability of crossing biological barriers, high stability in circulation, and low toxicity and immunogenicity, several companies have been testing exosome-based vaccines against SARS-CoV-2. As they carry cargos that mimic the status of parent cells, exosomes can be isolated from a variety of sources, including plasma, and employed as biomarkers of COVID-19. Lastly, there is growing evidence supporting the role of exosomes in COVID-19 infection, spread, reactivation, and reinfection. The lessons learned using exosomes for COVID-19 will help determine their efficacy and applicability in other clinical conditions.
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Affiliation(s)
- Elke Zani-Ruttenstock
- Division of General and Thoracic Surgery, Hospital for Sick Children, Toronto, Ontario, Canada
| | - Lina Antounians
- Division of General and Thoracic Surgery, Hospital for Sick Children, Toronto, Ontario, Canada.,Developmental and Stem Cell Biology Program, Hospital for Sick Children, Toronto, Ontario, Canada
| | - Kasra Khalaj
- Division of General and Thoracic Surgery, Hospital for Sick Children, Toronto, Ontario, Canada.,Developmental and Stem Cell Biology Program, Hospital for Sick Children, Toronto, Ontario, Canada
| | - Rebeca L Figueira
- Division of General and Thoracic Surgery, Hospital for Sick Children, Toronto, Ontario, Canada.,Developmental and Stem Cell Biology Program, Hospital for Sick Children, Toronto, Ontario, Canada
| | - Augusto Zani
- Division of General and Thoracic Surgery, Hospital for Sick Children, Toronto, Ontario, Canada.,Developmental and Stem Cell Biology Program, Hospital for Sick Children, Toronto, Ontario, Canada.,Department of Surgery, University of Toronto, Toronto, Ontario, Canada
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Moradinasab S, Pourbagheri-Sigaroodi A, Zafari P, Ghaffari SH, Bashash D. Mesenchymal stromal/stem cells (MSCs) and MSC-derived extracellular vesicles in COVID-19-induced ARDS: Mechanisms of action, research progress, challenges, and opportunities. Int Immunopharmacol 2021; 97:107694. [PMID: 33932694 PMCID: PMC8079337 DOI: 10.1016/j.intimp.2021.107694] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2021] [Revised: 04/11/2021] [Accepted: 04/17/2021] [Indexed: 02/06/2023]
Abstract
In late 2019, a novel coronavirus (SARS-CoV-2) emerged in Wuhan city, Hubei province, China. Rapidly escalated into a worldwide pandemic, it has caused an unprecedented and devastating situation on the global public health and society economy. The severity of recent coronavirus disease, abbreviated to COVID-19, seems to be mostly associated with the patients' immune response. In this vein, mesenchymal stromal/stem cells (MSCs) have been suggested as a worth-considering option against COVID-19 as their therapeutic properties are mainly displayed in immunomodulation and anti-inflammatory effects. Indeed, administration of MSCs can attenuate cytokine storm and enhance alveolar fluid clearance, endothelial recovery, and anti-fibrotic regeneration. Despite advantages attributed to MSCs application in lung injuries, there are still several issues __foremost probability of malignant transformation and incidence of MSCs-related coagulopathy__ which should be resolved for the successful application of MSC therapy in COVID-19. In the present study, we review the historical evidence of successful use of MSCs and MSC-derived extracellular vesicles (EVs) in the treatment of acute respiratory distress syndrome (ARDS). We also take a look at MSCs mechanisms of action in the treatment of viral infections, and then through studying both the dark and bright sides of this approach, we provide a thorough discussion if MSC therapy might be a promising therapeutic approach in COVID-19 patients.
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Affiliation(s)
- Susan Moradinasab
- Iranian Blood Transfusion Research Center, High Institute for Research and Education in Transfusion Medicine, Tehran, Iran
| | - Atieh Pourbagheri-Sigaroodi
- Department of Hematology and Blood Banking, School of Allied Medical Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Parisa Zafari
- Department of Immunology, Faculty of Medicine, Mazandaran University of Medical Sciences, Sari, Iran
| | - Seyed H Ghaffari
- Hematology, Oncology and Stem Cell Transplantation Research Center, Shariati Hospital, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Davood Bashash
- Department of Hematology and Blood Banking, School of Allied Medical Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
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The Role of MSC in Wound Healing, Scarring and Regeneration. Cells 2021; 10:cells10071729. [PMID: 34359898 PMCID: PMC8305394 DOI: 10.3390/cells10071729] [Citation(s) in RCA: 211] [Impact Index Per Article: 52.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2021] [Revised: 07/02/2021] [Accepted: 07/03/2021] [Indexed: 02/06/2023] Open
Abstract
Tissue repair and regeneration after damage is not completely understood, and current therapies to support this process are limited. The wound healing process is associated with cell migration and proliferation, extracellular matrix remodeling, angiogenesis and re-epithelialization. In normal conditions, a wound will lead to healing, resulting in reparation of the tissue. Several risk factors, chronic inflammation, and some diseases lead to a deficient wound closure, producing a scar that can finish with a pathological fibrosis. Mesenchymal stem/stromal cells (MSCs) are widely used for their regenerative capacity and their possible therapeutically potential. Derived products of MSCs, such as exosomes or extravesicles, have shown a therapeutic potential similar to MSCs, and these cell-free products may be interesting in clinics. MSCs or their derivative products have shown paracrine beneficial effects, regulating inflammation, modifying the fibroblast activation and production of collagen and promoting neovascularization and re-epithelialization. This review describes the effects of MSCs and their derived products in each step of the wound repair process. As well, it reviews the pre-clinical and clinical use of MSCs to benefit in skin wound healing in diabetic associated wounds and in pathophysiological fibrosis.
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Sharma A, Chakraborty A, Jaganathan BG. Review of the potential of mesenchymal stem cells for the treatment of infectious diseases. World J Stem Cells 2021; 13:568-593. [PMID: 34249228 PMCID: PMC8246252 DOI: 10.4252/wjsc.v13.i6.568] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/08/2021] [Revised: 04/07/2021] [Accepted: 06/03/2021] [Indexed: 02/06/2023] Open
Abstract
The therapeutic value of mesenchymal stem cells (MSCs) for the treatment of infectious diseases and the repair of disease-induced tissue damage has been explored extensively. MSCs inhibit inflammation, reduce pathogen load and tissue damage encountered during infectious diseases through the secretion of antimicrobial factors for pathogen clearance and they phagocytose certain bacteria themselves. MSCs dampen tissue damage during infection by downregulating the levels of pro-inflammatory cytokines, and inhibiting the excessive recruitment of neutrophils and proliferation of T cells at the site of injury. MSCs aid in the regeneration of damaged tissue by differentiating into the damaged cell types or by releasing paracrine factors that direct tissue regeneration, differentiation, and wound healing. In this review, we discuss in detail the various mechanisms by which MSCs help combat pathogens, tissue damage associated with infectious diseases, and challenges in utilizing MSCs for therapy.
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Affiliation(s)
- Amit Sharma
- Stem Cell and Cancer Biology Group, Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati, Guwahati 781039, India
| | - Anuja Chakraborty
- Stem Cell and Cancer Biology Group, Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati, Guwahati 781039, India
| | - Bithiah Grace Jaganathan
- Stem Cell and Cancer Biology Group, Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati, Guwahati 781039, India
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Ciccocioppo R, Gibellini D, Astori G, Bernardi M, Bozza A, Chieregato K, Elice F, Ugel S, Caligola S, De Sanctis F, Canè S, Fiore A, Trovato R, Vella A, Petrova V, Amodeo G, Santimaria M, Mazzariol A, Frulloni L, Ruggeri M, Polati E, Bronte V. The immune modulatory effects of umbilical cord-derived mesenchymal stromal cells in severe COVID-19 pneumonia. Stem Cell Res Ther 2021; 12:316. [PMID: 34078447 PMCID: PMC8170427 DOI: 10.1186/s13287-021-02376-9] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2020] [Accepted: 05/09/2021] [Indexed: 12/11/2022] Open
Abstract
Coronavirus disease 2019 (COVID-19) may result in a life-threatening condition due to a hyperactive immune reaction to severe acute respiratory syndrome-coronavirus-2 infection, for which no effective treatment is available. Based on the potent immunomodulatory properties of mesenchymal stromal cells (MSCs), a growing number of trials are ongoing. This prompted us to carry out a thorough immunological study in a patient treated with umbilical cord-derived MSCs and admitted to the Intensive Care Unit for COVID-19-related pneumonia. The exploratory analyses were assessed on both peripheral blood and bronchoalveolar fluid lavage samples at baseline and after cellular infusion by means of single-cell RNA sequencing, flow cytometry, ELISA, and functional assays. Remarkably, a normalization of circulating T lymphocytes count paralleled by a reduction of inflammatory myeloid cells, and a decrease in serum levels of pro-inflammatory cytokines, mostly of interleukin-6 and tumor necrosis factor-α, were observed. In addition, a drop of plasma levels of those chemokines essential for neutrophil recruitment became evident that paralleled the decrease of lung-infiltrating inflammatory neutrophils. Finally, circulating monocytes and low-density gradient neutrophils acquired immunosuppressive function. This scenario was accompanied by an amelioration of respiratory, renal, inflammatory, and pro-thrombotic indexes. Our results provide the first immunological data possibly related to the use of umbilical cord-derived MSCs in severe COVID-19 context.
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Affiliation(s)
- Rachele Ciccocioppo
- Gastroenterology Unit, Department of Medicine, A.O.U.I. Policlinico G.B. Rossi & University of Verona, Piazzale L.A. Scuro, 10, 37134, Verona, Italy.
| | - Davide Gibellini
- Microbiology Section, Department of Diagnostics and Public Health, University of Verona, Verona, Italy
| | - Giuseppe Astori
- Laboratory of Advanced Cellular Therapies, Hematology Unit, San Bortolo Hospital, A.U.L.S.S. 8 "Berica", Vicenza, Italy
| | - Martina Bernardi
- Laboratory of Advanced Cellular Therapies, Hematology Unit, San Bortolo Hospital, A.U.L.S.S. 8 "Berica", Vicenza, Italy
| | - Angela Bozza
- Laboratory of Advanced Cellular Therapies, Hematology Unit, San Bortolo Hospital, A.U.L.S.S. 8 "Berica", Vicenza, Italy
| | - Katia Chieregato
- Laboratory of Advanced Cellular Therapies, Hematology Unit, San Bortolo Hospital, A.U.L.S.S. 8 "Berica", Vicenza, Italy
| | - Francesca Elice
- Hematology Unit, San Bortolo Hospital, A.U.L.S.S. 8 "Berica", Vicenza, Italy
| | - Stefano Ugel
- Immunology Unit, Department of Medicine, A.O.U.I. Policlinico G.B. Rossi & University of Verona, Verona, Italy
| | - Simone Caligola
- Immunology Unit, Department of Medicine, A.O.U.I. Policlinico G.B. Rossi & University of Verona, Verona, Italy
| | - Francesco De Sanctis
- Immunology Unit, Department of Medicine, A.O.U.I. Policlinico G.B. Rossi & University of Verona, Verona, Italy
| | - Stefania Canè
- Immunology Unit, Department of Medicine, A.O.U.I. Policlinico G.B. Rossi & University of Verona, Verona, Italy
| | - Alessandra Fiore
- Immunology Unit, Department of Medicine, A.O.U.I. Policlinico G.B. Rossi & University of Verona, Verona, Italy
| | - Rosalinda Trovato
- Immunology Unit, Department of Medicine, A.O.U.I. Policlinico G.B. Rossi & University of Verona, Verona, Italy
| | - Antonio Vella
- Immunology Unit, Department of Medicine, A.O.U.I. Policlinico G.B. Rossi & University of Verona, Verona, Italy
| | - Varvara Petrova
- Immunology Unit, Department of Medicine, A.O.U.I. Policlinico G.B. Rossi & University of Verona, Verona, Italy
| | - Giuseppe Amodeo
- Gastroenterology Unit, Department of Medicine, A.O.U.I. Policlinico G.B. Rossi & University of Verona, Piazzale L.A. Scuro, 10, 37134, Verona, Italy
| | - Monica Santimaria
- Nuclear Medicine Unit, San Bortolo Hospital, A.U.L.S.S. 8 "Berica", Vicenza, Italy
| | - Annarita Mazzariol
- Microbiology Section, Department of Diagnostics and Public Health, University of Verona, Verona, Italy
| | - Luca Frulloni
- Gastroenterology Unit, Department of Medicine, A.O.U.I. Policlinico G.B. Rossi & University of Verona, Piazzale L.A. Scuro, 10, 37134, Verona, Italy
| | - Marco Ruggeri
- Hematology Unit, San Bortolo Hospital, A.U.L.S.S. 8 "Berica", Vicenza, Italy
| | - Enrico Polati
- Intensive Care Unit, Department of Surgery, Dentistry, Maternity and Infant, A.O.U.I. Ospedale Maggiore & University of Verona, Verona, Italy
| | - Vincenzo Bronte
- Immunology Unit, Department of Medicine, A.O.U.I. Policlinico G.B. Rossi & University of Verona, Verona, Italy
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Shahani P, Datta I. Mesenchymal stromal cell therapy for coronavirus disease 2019: which? when? and how much? Cytotherapy 2021; 23:861-873. [PMID: 34053857 PMCID: PMC8084615 DOI: 10.1016/j.jcyt.2021.04.004] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2020] [Revised: 03/27/2021] [Accepted: 04/10/2021] [Indexed: 12/27/2022]
Abstract
Mesenchymal stromal cells (MSCs) are under active consideration as a treatment strategy for controlling the hyper-inflammation and slow disease progression associated with coronavirus disease 2019 (COVID-19). The possible mechanism of protection through their immunoregulatory and paracrine action has been reviewed extensively. However, the importance of process control in achieving consistent cell quality, maximum safety and efficacy—for which the three key questions are which, when and how much—remains unaddressed. Any commonality, if it exists, in ongoing clinical trials has yet to be analyzed and reviewed. In this review, the authors have therefore compiled study design data from ongoing clinical trials to address the key questions of “which” with regard to tissue source, donor profile, isolation technique, culture conditions, long-term culture and cryopreservation of MSCs; “when” with regard to defining the transplantation window by identifying and staging patients based on their pro-inflammatory profile; and “how much” with regard to the number of cells in a single administration, number of doses and route of transplantation. To homogenize MSC therapy for COVID-19 on a global scale and to make it readily available in large numbers, a shared understanding and uniform agreement with respect to these fundamental issues are essential.
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Affiliation(s)
- Pradnya Shahani
- Department of Biophysics, National Institute of Mental Health and Neurosciences, Bengaluru, India
| | - Indrani Datta
- Department of Biophysics, National Institute of Mental Health and Neurosciences, Bengaluru, India.
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HGF-Modified Dental Pulp Stem Cells Mitigate the Inflammatory and Fibrotic Responses in Paraquat-Induced Acute Respiratory Distress Syndrome. Stem Cells Int 2021; 2021:6662831. [PMID: 33747095 PMCID: PMC7943272 DOI: 10.1155/2021/6662831] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2020] [Revised: 12/07/2020] [Accepted: 02/01/2021] [Indexed: 12/15/2022] Open
Abstract
Paraquat (PQ) poisoning can cause acute lung injury and progress to pulmonary fibrosis and eventually death without effective therapy. Mesenchymal stem cells (MSCs) and hepatocyte growth factor (HGF) have been shown to partially reverse this damage. MSCs can be derived from bone marrow (BM-MSCs), adipose tissue (AD-MSCs), umbilical cord (UC-MSCs), dental pulp (DPSCs), and other sources. The biological characteristics of MSCs are specific to the tissue source. To develop an effective treatment for PQ poisoning, we compared the anti-inflammatory and antifibrotic effects of UC-MSCs and DPSCs and chose and modified a suitable source with HGF to investigate their therapeutic effects in vitro and in vivo. In this study, MSCs' supernatant was beneficial to the viability and proliferation of human lung epithelial cell BEAS-2B. Inflammatory and fibrosis-related cytokines were analyzed by real-time PCR. The results showed that MSCs' supernatant could suppress the expression of proinflammatory and profibrotic cytokines and increase the expression of anti-inflammatory and antifibrotic cytokines in BEAS-2B cells and human pulmonary fibroblast MRC-5. Extracellular vesicles (EVs) derived from MSCs performed more effectively than MSCs' supernatant. The effect of DPSCs was stronger than that of UC-MSCs and was further strengthened by HGF modification. PQ-poisoned mice were established, and UC-MSCs, DPSCs, and DPSCs-HGF were administered. Histopathological assessments revealed that DPSCs-HGF mitigated lung inflammation and collagen accumulation more effectively than the other treatments. DPSCs-HGF reduced lung permeability and increased the survival rate of PQ mice from 20% to 50%. Taken together, these results indicated that DPSCs can suppress inflammation and fibrosis in human lung cells better than UC-MSCs. The anti-inflammatory and antifibrotic effects were significantly enhanced by HGF modification. DPSCs-HGF ameliorated pulmonitis and pulmonary fibrosis in PQ mice, effectively improving the survival rate, which might be mediated by paracrine mechanisms. The results suggested that DPSCs-HGF transplantation was a potential therapeutic approach for PQ poisoning.
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Peng F, Liang C, Chang W, Sun Q, Xie J, Qiu H, Yang Y. Prognostic Significance of Plasma Hepatocyte Growth Factor in Sepsis. J Intensive Care Med 2021; 37:352-358. [PMID: 33611982 DOI: 10.1177/0885066621993423] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
BACKGROUND To assess any correlation of plasma hepatocyte growth factor (HGF) levels with relevant endothelial cell injury parameters and determine the prognostic value in septic patients. METHODS A prospective, observational study was conducted in patients with sepsis admitted to the Department of Critical Care Medicine at the Zhongda Hospital from November 2017 to March 2018. Plasma HGF levels were measured by enzyme-linked immunosorbent assay in the first 24 h after admission (day 1) and on day 3. The primary endpoint was defined as all-cause 28-day mortality. Furthermore, we analyzed the correlation of HGF with relevant endothelial cell injury markers. RESULTS Eighty-six patients admitted with sepsis were included. HGF levels of nonsurvivors were elevated compared to those of survivors on day 1 (1940.62 ± 74.66 pg/mL vs. 1635.61 ± 47.49 pg/mL; P = 0.002) and day 3 (1824.82 ± 137.52 pg/mL vs. 1309.77 ± 83.49 pg/mL; P = 0.001) and showed a strong correlation with von Willebrand factor (r = 0.45, P < 0.0001), lactate (r = 0.35, P = 0.0011), pulmonary vascular permeability index (r = 0.38, P = 0.0241), first 24 h fluid administration (r = 0.38, P < 0.0001), and sequential organ failure assessment score (r = 0.40, P = 0.0001). Plasma HGF levels were able to prognostically discriminate between survivors and nonsurvivors on day 1 (AUC: 0.72, 95%CI: 0.60-0.84) and day 3 (AUC: 0.77, 95%CI: 0.63-0.91). CONCLUSIONS HGF levels are associated with sepsis and correlated with established markers of endothelial cell injury. Elevated HGF levels in sepsis patients are an efficient indicator of poor prognosis. TRIAL REGISTRATION The study was registered in Clinical Trial (Registration Number: NCT02883231).
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Affiliation(s)
- Fei Peng
- Department of Critical Care Medicine, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, People's Republic of China
| | - Chenglong Liang
- Department of Critical Care Medicine, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, People's Republic of China
| | - Wei Chang
- Department of Critical Care Medicine, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, People's Republic of China
| | - Qin Sun
- Department of Critical Care Medicine, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, People's Republic of China
| | - Jianfeng Xie
- Department of Critical Care Medicine, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, People's Republic of China
| | - Haibo Qiu
- Department of Critical Care Medicine, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, People's Republic of China
| | - Yi Yang
- Department of Critical Care Medicine, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, People's Republic of China
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Siddesh SE, Gowda DM, Jain R, Gulati A, Patil GS, Anudeep TC, Jeyaraman N, Muthu S, Jeyaraman M. Placenta-derived mesenchymal stem cells (P-MSCs) for COVID-19 pneumonia-a regenerative dogma. Stem Cell Investig 2021; 8:3. [PMID: 33688491 PMCID: PMC7937692 DOI: 10.21037/sci-2020-034] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2020] [Accepted: 01/20/2021] [Indexed: 02/05/2023]
Abstract
With a robust rise in the number of COVID-19 cases, the World Health Organization (WHO) has declared COVID-19 as a pandemic on 11th March 2020. COVID-19 pandemic has invited global researchers from various biomedical and biotechnological researchers to plan various treatment modalities for combating this pandemic crisis. At present, there is the unavailability of specific treatment modality; however, researchers have thrown light into the exploration of mesenchymal stem cells (MSCs) to therapeutically perquisite in ameliorating immune-mediated progressive worsening in COVID-19 infected patients. Cellular therapy (CT) has revolutionized the treatment of untreatable diseases with a better clinical and functional outcome. Placenta, being considered as medical waste, contains a variety of stem cells, and hence placenta-derived MSCs (P-MSCs) owe potentiality for extrapolation to combat COVID-19 pandemic. The usage of P-MSCs in combating the COVID-19 pandemic has plausible challenges in terms of isolation, harvesting, expansion, characterization, and involvement of ethical concerns. This article provides an insight into dealing COVID-19 pandemic with P-MSCs as cell-based therapy embracing immunomodulatory and immune-privileged potentials and future prospects. Advocating prospective randomized controlled clinical trials ethically will concretely supplement for its efficacy and safety concerns.
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Affiliation(s)
| | - Dheemant Muniswamy Gowda
- Department of Dermatology, Rajarajeswari Medical College and Hospital, Bengaluru, Karnataka, India
| | - Rashmi Jain
- School of Medical Sciences and Research, Sharda University, Greater Noida, Uttar Pradesh, India
- Indian Stem Cell Study Group ISCSG, Lucknow, Uttar Pradesh, India
| | - Arun Gulati
- Indian Stem Cell Study Group ISCSG, Lucknow, Uttar Pradesh, India
- Department of Orthopaedics, Kalpana Chawla Government Medical College and Hospital, Karnal, Haryana, India
| | | | - Talagavadi Channaiah Anudeep
- Indian Stem Cell Study Group ISCSG, Lucknow, Uttar Pradesh, India
- Department of Plastic Surgery, Topiwala National Medical College and BYL Nair Ch. Hospital, Mumbai, Maharashtra, India
| | - Naveen Jeyaraman
- Indian Stem Cell Study Group ISCSG, Lucknow, Uttar Pradesh, India
- Department of Orthopaedics, Kasturba Medical College, MAHE University, Manipal, Karnataka, India
| | - Sathish Muthu
- Indian Stem Cell Study Group ISCSG, Lucknow, Uttar Pradesh, India
- Orthopaedic Research Group, Coimbatore, Tamil Nadu, India
| | - Madhan Jeyaraman
- Indian Stem Cell Study Group ISCSG, Lucknow, Uttar Pradesh, India
- Department of Orthopaedics, School of Medical Sciences and Research, Sharda University, Greater Noida, Uttar Pradesh, India
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Mahendiratta S, Bansal S, Sarma P, Kumar H, Choudhary G, Kumar S, Prakash A, Sehgal R, Medhi B. Stem cell therapy in COVID-19: Pooled evidence from SARS-CoV-2, SARS-CoV, MERS-CoV and ARDS: A systematic review. Biomed Pharmacother 2021; 137:111300. [PMID: 33529945 PMCID: PMC7843034 DOI: 10.1016/j.biopha.2021.111300] [Citation(s) in RCA: 18] [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: 12/08/2020] [Revised: 01/12/2021] [Accepted: 01/18/2021] [Indexed: 12/29/2022] Open
Abstract
BACKGROUND SARS-CoV-2, which majorly affects the lungs and respiratory tract is thought due to dysregulation of the immune system which causes an immense imbalance of the cytokines. However, till now no standard treatment has been developed in treating the disease. On the other hand, it becomes important to prevent the acute respiratory tract infection due to COVID-19 which is the most dangerous phase leading to increased mortality. Hence this systematic review has been framed by pooling the available data of the use of stem cells in SARS-CoV-2, SARS-CoV, MERS-CoV and ARDS. METHODS 6 literature databases (PubMed, EMBASE, Scopus, Google Scholar, Clinicaltrials.gov, and Clinical trial registry of India) were searched for relevant studies till 10th August 2020 using keywords stem cells, mesenchymal stem cells, cell therapy, SARS CoV-2, SARS Coronavirus, Coronavirus 2, COVID-19, nCoV-19, Novel Coronavirus, MERS CoV, ARDS, acute respiratory distress syndrome. RESULTS The observations of this systematic review suggest capability of MSCs in reducing the systemic inflammation and protecting against SARS-CoV-2 as evidenced by the available clinical data. CONCLUSION MSCs can overcome the clinical challenges currently faced by SARS-CoV-2 infected patients, specifically who are seriously ill and not responding to conventional therapies. Though the available clinical data is motivating, still predicting the therapeutic potential of MSCs will be too early in COVID-19. Hence, further studies in a larger cohort of patients becomes a prerequisite to validate their potential efficacy.
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Affiliation(s)
- Saniya Mahendiratta
- Department of Pharmacology, Postgraduate Institute of Medical Education and Research, Chandigarh, India.
| | - Seema Bansal
- Post Graduate Institute of Medical Education and Research, Chandigarh, India.
| | - Phulen Sarma
- Department of Pharmacology, Postgraduate Institute of Medical Education and Research, Chandigarh, India.
| | - Harish Kumar
- Department of Pharmacology, Postgraduate Institute of Medical Education and Research, Chandigarh, India.
| | - Gajendra Choudhary
- Department of Pharmacology, Postgraduate Institute of Medical Education and Research, Chandigarh, India.
| | | | - Ajay Prakash
- Department of Pharmacology, Postgraduate Institute of Medical Education and Research, Chandigarh, India.
| | - Rakesh Sehgal
- Dept. of Parasitology, Postgraduate Institute of Medical Education and Research, Chandigarh, India.
| | - Bikash Medhi
- Department of Pharmacology, Postgraduate Institute of Medical Education and Research, Chandigarh, India.
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Gorman E, Millar J, McAuley D, O'Kane C. Mesenchymal stromal cells for acute respiratory distress syndrome (ARDS), sepsis, and COVID-19 infection: optimizing the therapeutic potential. Expert Rev Respir Med 2020; 15:301-324. [PMID: 33172313 DOI: 10.1080/17476348.2021.1848555] [Citation(s) in RCA: 39] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Introduction: Mesenchymal stromal (stem) cell (MSC) therapies are emerging as a promising therapeutic intervention in patients with Acute Respiratory Distress Syndrome (ARDS) and sepsis due to their reparative, immunomodulatory, and antimicrobial properties.Areas covered: This review provides an overview of Mesenchymal stromal cells (MSCs) and their mechanisms of effect in ARDS and sepsis. The preclinical and clinical evidence to support MSC therapy in ARDS and sepsis is discussed. The potential for MSC therapy in COVID-19 ARDS is discussed with insights from respiratory viral models and early clinical reports of MSC therapy in COVID-19. Strategies to optimize the therapeutic potential of MSCs in ARDS and sepsis are considered including preconditioning, altered gene expression, and alternative cell-free MSC-derived products, such as extracellular vesicles and conditioned medium.Expert opinion: MSC products present considerable therapeutic promise for ARDS and sepsis. Preclinical investigations report significant benefits and early phase clinical studies have not highlighted safety concerns. Optimization of MSC function in preclinical models of ARDS and sepsis has enhanced their beneficial effects. MSC-derived products, as cell-free alternatives, may provide further advantages in this field. These strategies present opportunity for the clinical development of MSCs and MSC-derived products with enhanced therapeutic efficacy.
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Affiliation(s)
- Ellen Gorman
- School of Medicine Dentistry and Biomedical Science, Queen's University Belfast, UK
| | - Jonathan Millar
- Division of Functional Genetics and Development, Roslin Institute, University of Edinburgh, Edinburgh, UK
| | - Danny McAuley
- School of Medicine Dentistry and Biomedical Science, Queen's University Belfast, UK
| | - Cecilia O'Kane
- School of Medicine Dentistry and Biomedical Science, Queen's University Belfast, UK
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Therapeutic Potential of Mesenchymal Stem Cells and Their Secretome in the Treatment of SARS-CoV-2-Induced Acute Respiratory Distress Syndrome. ACTA ACUST UNITED AC 2020; 2020:1939768. [PMID: 33274176 PMCID: PMC7678745 DOI: 10.1155/2020/1939768] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2020] [Accepted: 11/06/2020] [Indexed: 12/22/2022]
Abstract
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the etiological agent responsible for the development of a new coronavirus disease (COVID-19), is a highly transmittable virus which, in just ten months, infected more than 40 million people in 214 countries worldwide. After inhalation, aerosols containing SARS-CoV-2 penetrate to the depths of the lungs and cause severe pneumonia, alveolar injury, and life-threatening acute respiratory distress syndrome (ARDS). Since there are no specific drugs or vaccines available to cure or prevent COVID-19 infection and COVID-19-related ARDS, a new therapeutic agent which will support oxygen supply and, at the same time, efficiently alleviate SARS-CoV-2-induced lung inflammation is urgently needed. Due to their potent immuno- and angiomodulatory characteristics, mesenchymal stem cells (MSCs) may increase oxygen supply in the lungs and may efficiently alleviate ongoing lung inflammation, including SARS-CoV-2-induced ARDS. In this review article, we described molecular mechanisms that are responsible for MSC-based modulation of immune cells which play a pathogenic role in the development of SARS-CoV-2-induced ARDS and we provided a brief outline of already conducted and ongoing clinical studies that increase our understanding about the therapeutic potential of MSCs and their secretome in the therapy of COVID-19-related ARDS.
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Zhu Y, Geng S, Li Q, Jiang H. Transplantation of Mesenchymal Stem Cells: A Potential Adjuvant Therapy for COVID-19. Front Bioeng Biotechnol 2020; 8:557652. [PMID: 33224928 PMCID: PMC7674275 DOI: 10.3389/fbioe.2020.557652] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2020] [Accepted: 10/16/2020] [Indexed: 01/08/2023] Open
Abstract
Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) is the causative pathogen for coronavirus disease-2019 (COVID-19), which has posed an increasing serious public health threat. However, still there are no approved antiviral agents or vaccines available yet. Mesenchymal stem cells (MSCs) are emerging as a novel promising adjuvant therapy for the attenuation of COVID-19 based on its putative pathogenesis. MSCs may exert anti-inflammatory, immunomodulatory, anti-apoptotic, as well as regenerative effects through a series of mechanisms. Remarkably, MSCs may be resistant to virus infection, which is fundamental for the treatment of COVID-19. The beneficial therapeutic effects of MSCs have been preliminarily proved to be safe and efficacious for the treatment of COVID-19 in current clinical trials. This work aims to review the beneficial effects of MSCs in treating ALI/ARDS, which provides novel insight into the potential therapeutic strategies against COVID-19. However, further research is warranted regarding both safety and efficacy of MSCs.
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Affiliation(s)
- Yingqian Zhu
- Department of Geriatrics, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China.,Department of General Medicine, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China
| | - Shasha Geng
- Department of Geriatrics, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China.,Department of General Medicine, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China
| | - Qingqing Li
- Department of Geriatrics, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China.,Department of General Medicine, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China
| | - Hua Jiang
- Department of Geriatrics, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China.,Department of General Medicine, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China
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Taghavi-Farahabadi M, Mahmoudi M, Soudi S, Hashemi SM. Hypothesis for the management and treatment of the COVID-19-induced acute respiratory distress syndrome and lung injury using mesenchymal stem cell-derived exosomes. Med Hypotheses 2020; 144:109865. [PMID: 32562911 PMCID: PMC7242964 DOI: 10.1016/j.mehy.2020.109865] [Citation(s) in RCA: 48] [Impact Index Per Article: 9.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2020] [Accepted: 05/21/2020] [Indexed: 12/31/2022]
Abstract
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a member of the coronaviridae that causes respiratory disorders. After infection, large amounts of inflammatory cytokines are secreted, known as the cytokine storm. These cytokines can cause pulmonary damage induced by inflammation resulting in acute respiratory distress syndrome (ARDS), and even death. One of the therapeutic approaches for treatment of ARDS is a mesenchymal stem cell (MSC). MSCs suppress inflammation and reduce lung injury through their immunomodulatory properties. MSCs also have the potential to prevent apoptosis of the lung cells and regenerate them. But our suggestion is using MSCs-derived exosomes. Because these exosomes apply the same immunomodulatory and tissue repair effects of MSCs and they don't have problems associated to cell maintenance and injections. For investigation the hypothesis, MSCs should be isolated from tissues and characterized. Then, the exosomes should be isolated from the supernatants and characterized. These exosomes should be injected into a transgenic animal for COVID-19. In the final section, lung function assessment, histological examination, micro-CT, differential leukocyte, viral load analysis, cytokine assay, and CRP level analysis can be investigated. COVID-19 treatment is currently focused on supportive therapies and no vaccine has been developed for it. So, numerous researches are needed to find potential therapies. Since the pathogenesis of this disease was identified in previous studies and can cause lung injury with ARDS, investigation of the therapeutic approaches that can suppress inflammation, cytokine storm and ARDS can be helpful in finding a novel therapeutic approach for this disease.
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Affiliation(s)
- Mahsa Taghavi-Farahabadi
- Department of Immunology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Mohammad Mahmoudi
- Department of Immunology, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Sara Soudi
- Department of immunology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran
| | - Seyed Mahmoud Hashemi
- Department of Immunology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran; Department of Tissue Engineering and Applied Cell Sciences, School of Advanced Technologies in Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran; Urogenital Stem Cell Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
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Mechanically Stretched Mesenchymal Stem Cells Can Reduce the Effects of LPS-Induced Injury on the Pulmonary Microvascular Endothelium Barrier. Stem Cells Int 2020; 2020:8861407. [PMID: 33178288 PMCID: PMC7647750 DOI: 10.1155/2020/8861407] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2020] [Revised: 10/10/2020] [Accepted: 10/16/2020] [Indexed: 12/18/2022] Open
Abstract
Mesenchymal stem cells (MSCs) may improve the treatment of acute respiratory distress syndrome (ARDS). However, few studies have investigated the effects of mechanically stretched -MSCs (MS-MSCs) in in vitro models of ARDS. The aim of this study was to evaluate the potential therapeutic effects of MS-MSCs on pulmonary microvascular endothelium barrier injuries induced by LPS. We introduced a cocultured model of pulmonary microvascular endothelial cell (EC) and MSC medium obtained from MSCs with or without mechanical stretch. We found that Wright-Giemsa staining revealed that MSC morphology changed significantly and cell plasma shrank separately after mechanical stretch. Cell proliferation of the MS-MSC groups was much lower than the untreated MSC group; expression of cell surface markers did not change significantly. Compared to the medium from untreated MSCs, inflammatory factors elevated statistically in the medium from MS-MSCs. Moreover, the paracellular permeability of endothelial cells treated with LPS was restored with a medium from MS-MSCs, while LPS-induced EC apoptosis decreased. In addition, protective effects on the remodeling of intercellular junctions were observed when compared to LPS-treated endothelial cells. These data demonstrated that the MS-MSC groups had potential therapeutic effects on the LPS-treated ECs; these results might be useful in the treatment of ARDS.
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Qin H, Zhao A. Mesenchymal stem cell therapy for acute respiratory distress syndrome: from basic to clinics. Protein Cell 2020; 11:707-722. [PMID: 32519302 PMCID: PMC7282699 DOI: 10.1007/s13238-020-00738-2] [Citation(s) in RCA: 94] [Impact Index Per Article: 18.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2020] [Accepted: 05/12/2020] [Indexed: 01/08/2023] Open
Abstract
The 2019 novel coronavirus disease (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has occurred in China and around the world. SARS-CoV-2-infected patients with severe pneumonia rapidly develop acute respiratory distress syndrome (ARDS) and die of multiple organ failure. Despite advances in supportive care approaches, ARDS is still associated with high mortality and morbidity. Mesenchymal stem cell (MSC)-based therapy may be an potential alternative strategy for treating ARDS by targeting the various pathophysiological events of ARDS. By releasing a variety of paracrine factors and extracellular vesicles, MSC can exert anti-inflammatory, anti-apoptotic, anti-microbial, and pro-angiogenic effects, promote bacterial and alveolar fluid clearance, disrupt the pulmonary endothelial and epithelial cell damage, eventually avoiding the lung and distal organ injuries to rescue patients with ARDS. An increasing number of experimental animal studies and early clinical studies verify the safety and efficacy of MSC therapy in ARDS. Since low cell engraftment and survival in lung limit MSC therapeutic potentials, several strategies have been developed to enhance their engraftment in the lung and their intrinsic, therapeutic properties. Here, we provide a comprehensive review of the mechanisms and optimization of MSC therapy in ARDS and highlighted the potentials and possible barriers of MSC therapy for COVID-19 patients with ARDS.
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Affiliation(s)
- Hua Qin
- Research Center for Tissue Repair and Regeneration Affiliated to the Medical Innovation Research Department, PLA General Hospital and PLA Medical College, Beijing, 100853, China.
| | - Andong Zhao
- Research Center for Tissue Repair and Regeneration Affiliated to the Medical Innovation Research Department, PLA General Hospital and PLA Medical College, Beijing, 100853, China
- Tianjin Medical University, Tianjin, 300070, China
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Peng F, Chang W, Sun Q, Xu X, Xie J, Qiu H, Yang Y. HGF alleviates septic endothelial injury by inhibiting pyroptosis via the mTOR signalling pathway. Respir Res 2020; 21:215. [PMID: 32795289 PMCID: PMC7427898 DOI: 10.1186/s12931-020-01480-3] [Citation(s) in RCA: 25] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2020] [Accepted: 08/03/2020] [Indexed: 12/16/2022] Open
Abstract
Background Endothelial injury is one of the predominant pathophysiological characteristics of sepsis and is the major cause of sepsis-induced multiple organ failure. Endothelial pyroptosis is a fatal mechanism of endothelial injury in sepsis, and specific, effective therapies are lacking. Although hepatocyte growth factor (HGF) has been shown to have anti-apoptotic and anti-necrotic effects, whether it prevents pyroptosis to improve endothelial injury in sepsis remains unclear. Methods Recombinant HGF was intravenously injected into mice with sepsis caused by caecal ligation puncture (CLP). Histopathological examination and transmission electron microscopy (TEM) were used to measure lung vascular endothelial injury. Lipopolysaccharide (LPS) was transfected into EA.hy926 cells to induce endothelial pyroptosis, and the cells were treated with HGF in the presence of inhibitors of c-Met and mTOR, namely, PHA-665752 and rapamycin, respectively. The mTOR signalling pathway and mitochondrial physiology were assessed using Western blot and flow cytometry. Results Intravenous HGF effectively alleviated pulmonary vascular endothelial injury and acute lung injury in the septic mice. The TEM results of lung tissue revealed that HGF attenuated pulmonary vascular endothelial pyroptosis, which was confirmed in vitro. Transfected LPS induced the pyroptosis of EA.hy926 cells and damaged their paracellular permeability, and these effects were ameliorated by treating the cells with recombinant HGF. The protective effect of HGF against pyroptosis was dependent on c-Met/mTOR signalling. mTOR activation effectively protected mitochondrial physiology and decreased reactive oxygen species (ROS) production in EA.hy926 cells in vitro. Conclusions These results demonstrated that HGF protected mitochondrial physiology by activating mTOR signalling to partially ameliorate endothelial pyroptosis and attenuate vascular endothelial injury and acute lung injury in sepsis animal model.
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Affiliation(s)
- Fei Peng
- Jiangsu Provincial Key Laboratory of Critical Care Medicine, Department of Critical Care Medicine, Zhongda Hospital, School of Medicine, Southeast University, 87 Dingjiaqiao Rd, Nanjing, 210009, People's Republic of China
| | - Wei Chang
- Jiangsu Provincial Key Laboratory of Critical Care Medicine, Department of Critical Care Medicine, Zhongda Hospital, School of Medicine, Southeast University, 87 Dingjiaqiao Rd, Nanjing, 210009, People's Republic of China
| | - Qin Sun
- Jiangsu Provincial Key Laboratory of Critical Care Medicine, Department of Critical Care Medicine, Zhongda Hospital, School of Medicine, Southeast University, 87 Dingjiaqiao Rd, Nanjing, 210009, People's Republic of China
| | - Xinyi Xu
- Jiangsu Provincial Key Laboratory of Critical Care Medicine, Department of Critical Care Medicine, Zhongda Hospital, School of Medicine, Southeast University, 87 Dingjiaqiao Rd, Nanjing, 210009, People's Republic of China
| | - Jianfeng Xie
- Jiangsu Provincial Key Laboratory of Critical Care Medicine, Department of Critical Care Medicine, Zhongda Hospital, School of Medicine, Southeast University, 87 Dingjiaqiao Rd, Nanjing, 210009, People's Republic of China
| | - Haibo Qiu
- Jiangsu Provincial Key Laboratory of Critical Care Medicine, Department of Critical Care Medicine, Zhongda Hospital, School of Medicine, Southeast University, 87 Dingjiaqiao Rd, Nanjing, 210009, People's Republic of China
| | - Yi Yang
- Jiangsu Provincial Key Laboratory of Critical Care Medicine, Department of Critical Care Medicine, Zhongda Hospital, School of Medicine, Southeast University, 87 Dingjiaqiao Rd, Nanjing, 210009, People's Republic of China.
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Qu Y, Zhang L, He D, Xu N, Tang Y, Shao Y, Shen J. Protective role of mesenchymal stem cells transfected with miRNA-378a-5p in phosgene inhalation lung injury. Biochem Biophys Res Commun 2020; 530:189-195. [PMID: 32828284 DOI: 10.1016/j.bbrc.2020.06.112] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2020] [Accepted: 06/23/2020] [Indexed: 02/08/2023]
Abstract
Phosgene-induced lung injury is an important type of acute lung injury (ALI). Currently, no effective clinical treatment has been developed yet. Our previous study revealed that expressions of 6 miRNAs were significantly increased in phosgene-induced lung injury. The screened miRNA with the most significant effect on hepatocyte growth factor (HGF) expression by mesenchymal stem cells (MSCs) was transfected into MSCs. This study aimed to investigate whether the transfected MSCs had better therapeutic effects than MSCs alone. MSCs were co-cultured with miRNA mimics for 24h and 48h. HGF expression in culture supernatant was detected by ELISA. HGF expression in MSCs was detected by Western blot after being co-cultured with the selected miRNA inhibitor. The transfected MSCs were given to rats suffering from phosgene-induced lung injury. Expressions of TNF-α, IL-6, IL-1β and IL-10, were assayed by ELISA. SP-C mRNA level was tested by RT-PCR. VE-CAD expression was tested by Western blot. We found that miRNA-378a-5p most increased HGF expression among the six miRNAs. After transfection of MSCs with miRNA-378a-5p inhibitor, HGF expression was decreased. Compared with untreated MSCs, MSCs transfected with miRNA-378a-5p exhibited more significant decreases in lung injury score, white blood cell count and protein content while restoring respiratory indexes. Meanwhile, expressions of TNF-α, IL-6, IL-1β were decreased while those of IL-10, SP-C and VE-cadherin were increased. In conclusion, MSCs transfected with miRNA-378a-5p were more effective in treating phosgene-induced lung injury by repairing the secretion of alveolar epithelial cells and improving the permeability of vascular endothelial cells compared with MSCs alone.
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Affiliation(s)
- Yubei Qu
- Department of Intensive Care Unit, Center of Emergency & Intensive Care Unit, Jinshan Hospital, Fudan University, Shanghai, China; Department of Intensive Care Unit, Medical Research Center of Chemical Injury, Jinshan Hospital, Fudan University, Shanghai, China; Department of Intensive Care Unit, Medical Center of Radiation Injury, Jinshan Hospital, Fudan University, Shanghai, China
| | - Lin Zhang
- Department of Intensive Care Unit, Center of Emergency & Intensive Care Unit, Jinshan Hospital, Fudan University, Shanghai, China; Department of Intensive Care Unit, Medical Research Center of Chemical Injury, Jinshan Hospital, Fudan University, Shanghai, China; Department of Intensive Care Unit, Medical Center of Radiation Injury, Jinshan Hospital, Fudan University, Shanghai, China
| | - Daikun He
- Department of Intensive Care Unit, Center of Emergency & Intensive Care Unit, Jinshan Hospital, Fudan University, Shanghai, China; Department of Intensive Care Unit, Medical Research Center of Chemical Injury, Jinshan Hospital, Fudan University, Shanghai, China; Department of Intensive Care Unit, Medical Center of Radiation Injury, Jinshan Hospital, Fudan University, Shanghai, China
| | - Ning Xu
- Department of Intensive Care Unit, Center of Emergency & Intensive Care Unit, Jinshan Hospital, Fudan University, Shanghai, China; Department of Intensive Care Unit, Medical Research Center of Chemical Injury, Jinshan Hospital, Fudan University, Shanghai, China; Department of Intensive Care Unit, Medical Center of Radiation Injury, Jinshan Hospital, Fudan University, Shanghai, China
| | - Yuedong Tang
- Department of Intensive Care Unit, Center of Emergency & Intensive Care Unit, Jinshan Hospital, Fudan University, Shanghai, China; Department of Intensive Care Unit, Medical Research Center of Chemical Injury, Jinshan Hospital, Fudan University, Shanghai, China; Department of Intensive Care Unit, Medical Center of Radiation Injury, Jinshan Hospital, Fudan University, Shanghai, China
| | - Yiru Shao
- Department of Intensive Care Unit, Center of Emergency & Intensive Care Unit, Jinshan Hospital, Fudan University, Shanghai, China; Department of Intensive Care Unit, Medical Research Center of Chemical Injury, Jinshan Hospital, Fudan University, Shanghai, China; Department of Intensive Care Unit, Medical Center of Radiation Injury, Jinshan Hospital, Fudan University, Shanghai, China
| | - Jie Shen
- Department of Intensive Care Unit, Center of Emergency & Intensive Care Unit, Jinshan Hospital, Fudan University, Shanghai, China; Department of Intensive Care Unit, Medical Research Center of Chemical Injury, Jinshan Hospital, Fudan University, Shanghai, China; Department of Intensive Care Unit, Medical Center of Radiation Injury, Jinshan Hospital, Fudan University, Shanghai, China.
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Lu Z, Meng S, Chang W, Fan S, Xie J, Guo F, Yang Y, Qiu H, Liu L. Mesenchymal stem cells activate Notch signaling to induce regulatory dendritic cells in LPS-induced acute lung injury. J Transl Med 2020; 18:241. [PMID: 32546185 PMCID: PMC7298963 DOI: 10.1186/s12967-020-02410-z] [Citation(s) in RCA: 35] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/29/2020] [Accepted: 06/06/2020] [Indexed: 12/12/2022] Open
Abstract
Background Mesenchymal stem cells (MSCs) have been shown to alleviate acute lung injury (ALI) and induce the production of regulatory dendritic cells (DCregs), but the potential link between these two cell types remains unclear. The goal of this study was to investigate the effect and mechanism of MSC-induced regulatory dendritic cells in ALI mice. Material/methods In vivo experiments, C57BL/6 wild-type male mice were sacrificed at different times after intratracheal injection of LPS to observe changes in lung DC maturation and pathological damage. MSCs, DCregs or/and carboxyfluorescein diacetate succinimidyl ester (CFSE)-labeled DCs were administered to the mice by tail vein, and flow cytometry was performed to measure the phenotype of lung DCs and T cells. Lung injury was estimated by the lung wet weight/body weight ratio and histopathological analysis. In vitro, Western blotting or flow cytometry was used to detect the expression of Notch ligand or receptor in MSCs or DCs after coculture or LPS stimulation. Finally, in vivo and in vitro, we used the Notch signaling inhibitor DAPT to verify the effect of the Notch pathway on MSC-induced DCregs and their pulmonary protection. Results We showed significant accumulation and maturation of lung DCs 2 h after intratracheal injection of LPS, which were positively correlated with the lung pathological injury score. MSC treatment alleviated ALI lung injury, accompanied by a decrease in the number and maturity of classical DCs in the lungs. CFSE-labeled DCs migrated to the lungs of ALI mice more than those of the normal group, and the elimination of CFSE-labeled DCs in the blood was slower. MSCs inhibited the migration of CFSE-labeled DCs to the lung and promoted their elimination in the blood. DCregs, which are obtained by contact coculture of mDCs with MSCs, expressed reduced levels of MHCII, CD86, CD40 and increased levels of PD-L1, and had a reduced ability to stimulate lymphocyte proliferation and activation (expression of CD44 and CD69). mDCs expressing Notch2 significantly increased after coculture with MSCs or rhJagged1, and MSCs expressed more Jagged1 after LPS stimulation. After stimulation of mDCs with recombinant Jagged1, DCs with low expression of MHCII, CD86 and CD40 were also induced, and the effects of both rhJagged1 and MSCs on DCs were blocked by the Notch inhibitor DAPT. Intra-airway DAPT reversed the inhibitory effect of mesenchymal stem cells on DC recruitment to the lungs and its maturation. Conclusions Our results suggested that the recruitment and maturation of lung DCs is an important process in early ALI, MSCs attenuate LPS-induced ALI by inducing the production of DCregs by activating Notch signaling.
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Affiliation(s)
- Zhonghua Lu
- Department of Critical Care Medicine, Zhongda Hospital, School of Medicine, Southeast University, 87 Dingjia Bridge, Hunan Road, Gu Lou District, Nanjing, 210009, China
| | - Shanshan Meng
- Department of Critical Care Medicine, Zhongda Hospital, School of Medicine, Southeast University, 87 Dingjia Bridge, Hunan Road, Gu Lou District, Nanjing, 210009, China
| | - Wei Chang
- Department of Critical Care Medicine, Zhongda Hospital, School of Medicine, Southeast University, 87 Dingjia Bridge, Hunan Road, Gu Lou District, Nanjing, 210009, China
| | - Shanwen Fan
- Department of Critical Care Medicine, Zhongda Hospital, School of Medicine, Southeast University, 87 Dingjia Bridge, Hunan Road, Gu Lou District, Nanjing, 210009, China
| | - Jianfeng Xie
- Department of Critical Care Medicine, Zhongda Hospital, School of Medicine, Southeast University, 87 Dingjia Bridge, Hunan Road, Gu Lou District, Nanjing, 210009, China
| | - Fengmei Guo
- Department of Critical Care Medicine, Zhongda Hospital, School of Medicine, Southeast University, 87 Dingjia Bridge, Hunan Road, Gu Lou District, Nanjing, 210009, China
| | - Yi Yang
- Department of Critical Care Medicine, Zhongda Hospital, School of Medicine, Southeast University, 87 Dingjia Bridge, Hunan Road, Gu Lou District, Nanjing, 210009, China
| | - Haibo Qiu
- Department of Critical Care Medicine, Zhongda Hospital, School of Medicine, Southeast University, 87 Dingjia Bridge, Hunan Road, Gu Lou District, Nanjing, 210009, China
| | - Ling Liu
- Department of Critical Care Medicine, Zhongda Hospital, School of Medicine, Southeast University, 87 Dingjia Bridge, Hunan Road, Gu Lou District, Nanjing, 210009, China.
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