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Park KS, Lässer C, Lötvall J. Extracellular vesicles and the lung: from disease pathogenesis to biomarkers and treatments. Physiol Rev 2025; 105:1733-1821. [PMID: 40125970 DOI: 10.1152/physrev.00032.2024] [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: 08/14/2024] [Revised: 10/14/2024] [Accepted: 03/12/2025] [Indexed: 03/25/2025] Open
Abstract
Nanosized extracellular vesicles (EVs) are released by all cells to convey cell-to-cell communication. EVs, including exosomes and microvesicles, carry an array of bioactive molecules, such as proteins and RNAs, encapsulated by a membrane lipid bilayer. Epithelial cells, endothelial cells, and various immune cells in the lung contribute to the pool of EVs in the lung microenvironment and carry molecules reflecting their cellular origin. EVs can maintain lung health by regulating immune responses, inducing tissue repair, and maintaining lung homeostasis. They can be detected in lung tissues and biofluids such as bronchoalveolar lavage fluid and blood, offering information about disease processes, and can function as disease biomarkers. Here, we discuss the role of EVs in lung homeostasis and pulmonary diseases such as asthma, chronic obstructive pulmonary disease, cystic fibrosis, pulmonary fibrosis, and lung injury. The mechanistic involvement of EVs in pathogenesis and their potential as disease biomarkers are discussed. Finally, the pulmonary field benefits from EVs as clinical therapeutics in severe pulmonary inflammatory disease, as EVs from mesenchymal stem cells attenuate severe respiratory inflammation in multiple clinical trials. Further, EVs can be engineered to carry therapeutic molecules for enhanced and broadened therapeutic opportunities, such as the anti-inflammatory molecule CD24. Finally, we discuss the emerging opportunity of using different types of EVs for treating severe respiratory conditions.
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Affiliation(s)
- Kyong-Su Park
- Krefting Research Centre, Institute of Medicine at the Sahlgrenska Academy, University of Gothenburg, Göteborg, Sweden
| | - Cecilia Lässer
- Krefting Research Centre, Institute of Medicine at the Sahlgrenska Academy, University of Gothenburg, Göteborg, Sweden
| | - Jan Lötvall
- Krefting Research Centre, Institute of Medicine at the Sahlgrenska Academy, University of Gothenburg, Göteborg, Sweden
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Zhang Z, Shan XY, Liang C, Zhao L, Shan XQ. Microvesicles derived from mesenchymal stem cells: A promising therapeutic strategy for acute respiratory distress syndrome-related pulmonary fibrosis? World J Stem Cells 2025; 17:101036. [PMID: 39866898 PMCID: PMC11752460 DOI: 10.4252/wjsc.v17.i1.101036] [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: 09/03/2024] [Revised: 11/24/2024] [Accepted: 12/16/2024] [Indexed: 01/20/2025] Open
Abstract
Pulmonary fibrosis significantly contributes to the pathogenesis of acute respiratory distress syndrome (ARDS), markedly increasing patient mortality. Despite the established anti-fibrotic effects of mesenchymal stem cells (MSCs), numerous challenges hinder their clinical application. A recent study demonstrated that microvesicles (MVs) from MSCs (MSC-MVs) could attenuate ARDS-related pulmonary fibrosis and enhance lung function via hepatocyte growth factor mRNA transcription. This discovery presents a promising strategy for managing ARDS-associated pulmonary fibrosis. This article initially examines the safety and efficacy of MSCs from both basic science and clinical perspectives, subsequently exploring the potential and obstacles of employing MSC-MVs as a novel therapeutic approach. Additionally, it provides perspectives on future research into the application of MSC-MVs in ARDS-associated pulmonary fibrosis.
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Affiliation(s)
- Zhao Zhang
- The First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin 300381, China
| | - Xin-Yun Shan
- Shandong Medical College, Jinan 276000, Shandong Province, China
| | - Ce Liang
- Hebei Normal University of Science and Technology, Qinhuangdao 066004, Hebei Province, China
| | - Lan Zhao
- Tianjin Institute of Acupuncture and Moxibustion, The First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin 300381, China.
| | - Xiao-Qian Shan
- The First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin 300381, China
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3
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Wang X, Guo J, Dai Q. Mesenchymal stem cell-derived extracellular vesicles in systemic sclerosis: role and therapeutic directions. Front Cell Dev Biol 2024; 12:1492821. [PMID: 39483335 PMCID: PMC11524835 DOI: 10.3389/fcell.2024.1492821] [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: 09/08/2024] [Accepted: 10/07/2024] [Indexed: 11/03/2024] Open
Abstract
Systemic sclerosis (SSc) is a complex autoimmune disease with clinical symptoms of vascular damage, immune disorders, and fibrosis, presenting significant treatment challenges and limited therapeutic options. Mesenchymal stem cell-derived extracellular vesicles (MSC-EVs) have been demonstrated in numerous studies as more effective than MSCs in treating autoimmune diseases. Recent studies demonstrate that MSC-EVs can significantly ameliorate the symptoms of SSc and mitigate pathological changes such as vascular injury, immune dysregulation, and fibrosis. These findings underscore the promising therapeutic potential of MSC-EVs in the treatment of SSc. MSC-EVs promote angiogenesis, modulate immune dysfunction, and combat fibrosis. This article summarizes the therapeutic applications and possible mechanisms of MSC-EVs for SSc, thereby offering a novel therapeutic direction for the treatment of SSc.
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Affiliation(s)
- Xuan Wang
- Department of Rheumatology and Immunology, The Second Affiliated Hospital of Wannan Medical College, Wuhu, China
| | - Jiaying Guo
- Department of Geriatric Medicine, The Second Affiliated Hospital of Wannan Medical College, Wuhu, China
| | - Qiangfu Dai
- Department of Rheumatology and Immunology, The Second Affiliated Hospital of Wannan Medical College, Wuhu, China
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Patel AA, Mohamed AH, Rizaev J, Mallick AK, Qasim MT, Abdulmonem WA, Jamal A, Hattiwale HM, Kamal MA, Ahmad F. Application of mesenchymal stem cells derived from the umbilical cord or Wharton's jelly and their extracellular vesicles in the treatment of various diseases. Tissue Cell 2024; 89:102415. [PMID: 38851032 DOI: 10.1016/j.tice.2024.102415] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2024] [Revised: 04/26/2024] [Accepted: 05/20/2024] [Indexed: 06/10/2024]
Abstract
Mesenchymal stem cells (MSCs) originating from the umbilical cord (UC) or Wharton's jelly (WJ) have attracted substantial interest due to their potential to augment therapeutic approaches for a wide range of disorders. These cells demonstrate a wide range of capabilities in the process of differentiating into a multitude of cell types. Additionally, they possess a significant capacity for proliferation and are conveniently accessible. Furthermore, they possess a status of being immune-privileged, exhibit minimal tumorigenic characteristics, and raise minimal ethical concerns. Consequently, they are well-suited candidates for tissue regeneration and the treatment of diseases. Additionally, UC-derived MSCs offer a substantial yield compared to other sources. The therapeutic effects of these MSCs are closely associated with the release of nanosized extracellular vesicles (EVs), including exosomes and microvesicles (MVs), containing lipids, microRNAs, and proteins that facilitate intercellular communication. Due to their reduced tumorigenic and immunogenic characteristics, in addition to their convenient manipulability, EVs have arisen as a viable alternative for the management of disorders. The favorable characteristics of UC-MSCs or WJ-MSCs and their EVs have generated significant attention in clinical investigations encompassing diverse pathologies. Therefore, we present a review encompassing current preclinical and clinical investigations, examining the implications of UC-MSCs in diverse diseases, including those affecting bone, cartilage, skin, liver, kidney, neural, lung, cardiovascular, muscle, and retinal tissues, as well as conditions like cancer, diabetes, sepsis, and others.
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Affiliation(s)
- Ayyub Ali Patel
- Clinical Biochemistry Department, College of Medicine, King Khalid University, Abha, Saudi Arabia
| | - Asma'a H Mohamed
- Biomedical Engineering Department, College of Engineering and Technologies, Al-Mustaqbal University, Hilla, Babil 51001, Iraq.
| | - Jasur Rizaev
- Department of Public Health and Healthcare management, Rector, Samarkand State Medical University, 18, Amir Temur Street, Samarkand, Uzbekistan
| | - Ayaz Khurram Mallick
- Clinical Biochemistry Department, College of Medicine, King Khalid University, Abha, Saudi Arabia
| | - Maytham T Qasim
- College of Health and Medical Technology, Al-Ayen University, Thi-Qar 64001, Iraq
| | - Waleed Al Abdulmonem
- Department of Pathology, College of Medicine, Qassim University, Buraidah, Saudi Arabia
| | - Azfar Jamal
- Department of Biology, College of Science Al-Zulfi, Majmaah University, Al-Majmaah 11952, Saudi Arabia; Health and Basic Science Research Centre, Majmaah University, Al-Majmaah 11952, Saudi Arabia
| | - Haroonrashid M Hattiwale
- Department of Basic Medical Sciences, College of Medicine, Majmaah University, Al-Majmaah 11952, Saudi Arabia.
| | - Mohammad Azhar Kamal
- Department of Pharmaceutics, College of Pharmacy, Prince Sattam Bin Abdulaziz University, Alkharj 11942, Saudi Arabia
| | - Fuzail Ahmad
- College of Applied Sciences, Almaarefa University, Diriya, Riyadh 13713, Saudi Arabia
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Ahmed SH, AlMoslemany MA, Witwer KW, Tehamy AG, El-Badri N. Stem Cell Extracellular Vesicles as Anti-SARS-CoV-2 Immunomodulatory Therapeutics: A Systematic Review of Clinical and Preclinical Studies. Stem Cell Rev Rep 2024; 20:900-930. [PMID: 38393666 PMCID: PMC11087360 DOI: 10.1007/s12015-023-10675-2] [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] [Accepted: 12/28/2023] [Indexed: 02/25/2024]
Abstract
BACKGROUND COVID-19 rapidly escalated into a worldwide pandemic with elevated infectivity even from asymptomatic patients. Complications can lead to severe pneumonia and acute respiratory distress syndrome (ARDS), which are the main contributors to death. Because of their regenerative and immunomodulatory capacities, stem cells and their derived extracellular vesicles (EVs) are perceived as promising therapies against severe pulmonary conditions, including those associated with COVID-19. Herein, we evaluate the safety and efficacy of stem cell EVs in treating COVID-19 and complicating pneumonia, acute lung injury, and ARDS. We also cover relevant preclinical studies to recapitulate the current progress in stem cell EV-based therapy. METHODS Using PubMed, Cochrane Central Register of Controlled Trials, Scopus, and Web of Science, we searched for all English-language published studies (2000-2023) that used stem cell EVs as a therapy for COVID-19, ARDS, or pneumonia. The risk of bias (ROB) was assessed for all studies. RESULTS Forty-eight studies met our inclusion criteria. Various-sized EVs derived from different types of stem cells were reported as a potentially safe and effective therapy to attenuate the cytokine storm induced by COVID-19. EVs alleviated inflammation and regenerated the alveolar epithelium by decreasing apoptosis, proinflammatory cytokines, neutrophil infiltration, and M2 macrophage polarization. They also prevented fibrin production and promoted the production of anti-inflammatory cytokines and endothelial cell junction proteins. CONCLUSION Similar to their parental cells, stem cell EVs mediate lung tissue regeneration by targeting multiple pathways and thus hold promise in promoting the recovery of COVID-19 patients and improving the survival rate of severely affected patients.
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Affiliation(s)
- Sarah Hamdy Ahmed
- Center of Excellence for Stem Cells and Regenerative Medicine (CESC), Zewail City of Science and Technology, October Gardens, Giza, 6th of October City, 12582, Egypt
- Biotechnology/Biomolecular Chemistry Department, Faculty of Science, Cairo University, Giza, 12613, Egypt
| | - Mohamed Atef AlMoslemany
- Center of Excellence for Stem Cells and Regenerative Medicine (CESC), Zewail City of Science and Technology, October Gardens, Giza, 6th of October City, 12582, Egypt
| | - Kenneth Whitaker Witwer
- Department of Molecular and Comparative Pathobiology, The Johns Hopkins University School of Medicine, Baltimore, MD, USA
- Department of Neurology and Neurosurgery, The Johns Hopkins University School of Medicine, Baltimore, MD, USA
- Richman Family Precision Medicine Center of Excellence in Alzheimer's Disease, The Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Ahmed Gamal Tehamy
- Center of Excellence for Stem Cells and Regenerative Medicine (CESC), Zewail City of Science and Technology, October Gardens, Giza, 6th of October City, 12582, Egypt
| | - Nagwa El-Badri
- Center of Excellence for Stem Cells and Regenerative Medicine (CESC), Zewail City of Science and Technology, October Gardens, Giza, 6th of October City, 12582, Egypt.
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Zhang X, Cheng Z, Zeng M, He Z. The efficacy of extracellular vesicles for acute lung injury in preclinical animal models: a meta-analysis. BMC Pulm Med 2024; 24:128. [PMID: 38481171 PMCID: PMC10935944 DOI: 10.1186/s12890-024-02910-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2023] [Accepted: 02/15/2024] [Indexed: 03/17/2024] Open
Abstract
BACKGROUND With the increasing research on extracellular vesicles (EVs), EVs have received widespread attention as biodiagnostic markers and therapeutic agents for a variety of diseases. Stem cell-derived EVs have also been recognized as a new viable therapy for acute lung injury (ALI) and acute respiratory distress syndrome (ARDS). To assess their efficacy, we conducted a meta-analysis of existing preclinical experimental animal models of EVs for ALI treatment. METHODS The database was systematically interrogated for pertinent data encompassing the period from January 2010 to April 2022 concerning interventions involving extracellular vesicles (EVs) in animal models of acute lung injury (ALI). The lung injury score was selected as the primary outcome measure for statistical analysis. Meta-analyses were executed utilizing RevMan 5.3 and State15.1 software tools. RESULTS The meta-analyses comprised 31 studies, exclusively involving animal models of acute lung injury (ALI), categorized into two cohorts based on the presence or absence of extracellular vesicle (EV) intervention. The statistical outcomes from these two study groups revealed a significant reduction in lung injury scores with the administration of stem and progenitor cell-derived EVs (SMD = -3.63, 95% CI [-4.97, -2.30], P < 0.05). Conversely, non-stem cell-derived EVs were associated with an elevation in lung injury scores (SMD = -4.34, 95% CI [3.04, 5.63], P < 0.05). EVs originating from stem and progenitor cells demonstrated mitigating effects on alveolar neutrophil infiltration, white blood cell counts, total cell counts in bronchoalveolar lavage fluid (BALF), lung wet-to-dry weight ratios (W/D), and total protein in BALF. Furthermore, pro-inflammatory mediators exhibited down-regulation, while anti-inflammatory mediators demonstrated up-regulation. Conversely, non-stem cell-derived EVs exacerbated lung injury. CONCLUSION In preclinical animal models of acute lung injury (ALI), the administration of extracellular vesicles (EVs) originating from stem and progenitor cells demonstrably enhances pulmonary function. This ameliorative effect is attributed to the mitigation of pulmonary vascular permeability and the modulation of immune homeostasis, collectively impeding the progression of inflammation. In stark contrast, the utilization of EVs derived from non-stem progenitor cells exacerbates the extent of lung injury. These findings substantiate the potential utility of EVs as a novel therapeutic avenue for addressing acute lung injury.
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Affiliation(s)
- Xuefeng Zhang
- The Third Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Zongyong Cheng
- The Second Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Menghao Zeng
- The Third Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Zhihui He
- Department of Critical Care Medicine, the Third Xiangya Hospital, Central South University, Changsha, Hunan, China.
- 138 Tongzibo Road, Yuelu District, Changsha, Hunan, 410013, China.
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7
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Quaglia M, Fanelli V, Merlotti G, Costamagna A, Deregibus MC, Marengo M, Balzani E, Brazzi L, Camussi G, Cantaluppi V. Dual Role of Extracellular Vesicles in Sepsis-Associated Kidney and Lung Injury. Biomedicines 2022; 10:biomedicines10102448. [PMID: 36289710 PMCID: PMC9598620 DOI: 10.3390/biomedicines10102448] [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: 08/29/2022] [Revised: 09/25/2022] [Accepted: 09/27/2022] [Indexed: 11/16/2022] Open
Abstract
Extracellular vesicles form a complex intercellular communication network, shuttling a variety of proteins, lipids, and nucleic acids, including regulatory RNAs, such as microRNAs. Transfer of these molecules to target cells allows for the modulation of sets of genes and mediates multiple paracrine and endocrine actions. EVs exert broad pro-inflammatory, pro-oxidant, and pro-apoptotic effects in sepsis, mediating microvascular dysfunction and multiple organ damage. This deleterious role is well documented in sepsis-associated acute kidney injury and acute respiratory distress syndrome. On the other hand, protective effects of stem cell-derived extracellular vesicles have been reported in experimental models of sepsis. Stem cell-derived extracellular vesicles recapitulate beneficial cytoprotective, regenerative, and immunomodulatory properties of parental cells and have shown therapeutic effects in experimental models of sepsis with kidney and lung involvement. Extracellular vesicles are also likely to play a role in deranged kidney-lung crosstalk, a hallmark of sepsis, and may be key to a better understanding of shared mechanisms underlying multiple organ dysfunction. In this review, we analyze the state-of-the-art knowledge on the dual role of EVs in sepsis-associated kidney/lung injury and repair. PubMed library was searched from inception to July 2022, using a combination of medical subject headings (MeSH) and keywords related to EVs, sepsis, acute kidney injury (AKI), acute lung injury (ALI), and acute respiratory distress syndrome (ARDS). Key findings are summarized into two sections on detrimental and beneficial mechanisms of actions of EVs in kidney and lung injury, respectively. The role of EVs in kidney-lung crosstalk is then outlined. Efforts to expand knowledge on EVs may pave the way to employ them as prognostic biomarkers or therapeutic targets to prevent or reduce organ damage in sepsis.
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Affiliation(s)
- Marco Quaglia
- Nephrology and Kidney Transplantation Unit, Department of Translational Medicine, University of Piemonte Orientale (UPO), 28100 Novara, Italy
| | - Vito Fanelli
- Department of Anaesthesia, Critical Care and Emergency, Città della Salute e della Scienza Hospital, University of Torino, 10126 Torino, Italy
| | - Guido Merlotti
- Nephrology and Kidney Transplantation Unit, Department of Translational Medicine, University of Piemonte Orientale (UPO), 28100 Novara, Italy
| | - Andrea Costamagna
- Department of Anaesthesia, Critical Care and Emergency, Città della Salute e della Scienza Hospital, University of Torino, 10126 Torino, Italy
| | | | - Marita Marengo
- Nephrology and Dialysis Unit, ASL CN1, 12038 Savigliano, Italy
| | - Eleonora Balzani
- Department of Anaesthesia, Critical Care and Emergency, Città della Salute e della Scienza Hospital, University of Torino, 10126 Torino, Italy
| | - Luca Brazzi
- Department of Anaesthesia, Critical Care and Emergency, Città della Salute e della Scienza Hospital, University of Torino, 10126 Torino, Italy
| | - Giovanni Camussi
- Department of Medical Sciences, University of Torino, 10126 Torino, Italy
- Correspondence: (G.C.); (V.C.)
| | - Vincenzo Cantaluppi
- Nephrology and Kidney Transplantation Unit, Department of Translational Medicine, University of Piemonte Orientale (UPO), 28100 Novara, Italy
- Correspondence: (G.C.); (V.C.)
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Su R, Zhang Y, Zhang J, Wang H, Luo Y, Chan HF, Tao Y, Chen Z, Li M. Nanomedicine to advance the treatment of bacteria-induced acute lung injury. J Mater Chem B 2021; 9:9100-9115. [PMID: 34672317 DOI: 10.1039/d1tb01770e] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Bacteria-induced acute lung injury (ALI) is associated with a high mortality rate due to the lack of an effective treatment. Patients often rely on supportive care such as low tidal volume ventilation to alleviate the symptoms. Nanomedicine has recently received much attention owing to its premium benefits of delivering drugs in a sustainable and controllable manner while minimizing the potential side effects. It can effectively improve the prognosis of bacteria-induced ALI through targeted delivery of drugs, regulation of multiple inflammatory pathways, and combating antibiotic resistance. Hence, in this review, we first discuss the pathogenesis of ALI and its potential therapeutics. In particular, the state-of-the-art nanomedicines for the treatment of bacteria-induced ALI are highlighted, including their administration routes, in vivo distribution, and clearance. Furthermore, the available bacteria-induced ALI animal models are also summarized. In the end, future perspectives of nanomedicine for ALI treatment are proposed.
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Affiliation(s)
- Ruonan Su
- Center for Nanomedicine, Department of Pediatrics and Department of Allergy, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou 510630, China. .,Laboratory of Biomaterials and Translational Medicine, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou 510630, China
| | - Yu Zhang
- Department of Biological and Environmental Engineering, Cornell University, Ithaca 14853, USA
| | - Jiabin Zhang
- Center for Nanomedicine, Department of Pediatrics and Department of Allergy, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou 510630, China.
| | - Haixia Wang
- Center for Nanomedicine, Department of Pediatrics and Department of Allergy, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou 510630, China. .,Laboratory of Biomaterials and Translational Medicine, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou 510630, China
| | - Yun Luo
- Department of Urology, The Third Affiliated Hospital, Sun Yat-Sen University, Guangzhou 510630, China
| | - Hon Fai Chan
- Institute for Tissue Engineering and Regenerative Medicine, School of Biomedical Science, The Chinese University of Hong Kong, Hong Kong 999077, China
| | - Yu Tao
- Center for Nanomedicine, Department of Pediatrics and Department of Allergy, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou 510630, China. .,Laboratory of Biomaterials and Translational Medicine, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou 510630, China
| | - Zhuanggui Chen
- Center for Nanomedicine, Department of Pediatrics and Department of Allergy, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou 510630, China.
| | - Mingqiang Li
- Center for Nanomedicine, Department of Pediatrics and Department of Allergy, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou 510630, China. .,Laboratory of Biomaterials and Translational Medicine, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou 510630, China.,Guangdong Provincial Key Laboratory of Liver Disease Research, Guangzhou 510630, China
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9
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Tieu A, Hu K, Gnyra C, Montroy J, Fergusson DA, Allan DS, Stewart DJ, Thébaud B, Lalu MM. Mesenchymal stromal cell extracellular vesicles as therapy for acute and chronic respiratory diseases: A meta-analysis. J Extracell Vesicles 2021; 10:e12141. [PMID: 34596349 PMCID: PMC8485337 DOI: 10.1002/jev2.12141] [Citation(s) in RCA: 39] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2021] [Revised: 07/30/2021] [Accepted: 08/23/2021] [Indexed: 12/15/2022] Open
Abstract
Preclinical studies suggest mesenchymal stromal cell extracellular vesicles (MSC-EVs) reduce inflammation and improve organ function in lung diseases; however, an objective analysis of all available data is needed prior to translation. Using rigorous meta-research methods, we determined the effectiveness of MSC-EVs for preclinical respiratory diseases and identified experimental conditions that may further refine this therapy. A systematic search of MEDLINE/Embase identified 1167 records. After screening, 52 articles were included for data extraction and evaluated for risk of bias and quality of reporting in study design. A random effects meta-analysis was conducted for acute lung injury (ALI; N = 23), bronchopulmonary dysplasia (BPD; N = 8) and pulmonary arterial hypertension (PAH; N = 7). Subgroup analyses identified EV methods/characteristics that may be associated with improved efficacy. Data is presented as standardized mean differences (SMD) or risk ratios (RR) with 95% confidence intervals (CI). For ALI, MSC-EVs markedly reduced lung injury (SMD -4.33, CI -5.73 to -2.92), vascular permeability (SMD -2.43, CI -3.05 to -1.82), and mortality (RR 0.39, CI 0.22 to 0.68). Small EVs were more consistently effective than large EVs whereas no differences were observed between tissue sources, immunocompatibility or isolation techniques. For BPD, alveolarization was improved by MSC-EVs (SMD -1.45, CI -2.08 to -0.82) with small EVs more consistently beneficial then small/large EVs. In PAH, right ventricular systolic pressure (SMD -4.16, CI -5.68 to -2.64) and hypertrophy (SMD -2.80, CI -3.68 to -1.91) were significantly attenuated by EVs. In BPD and PAH, EVs isolated by ultracentrifugation demonstrated therapeutic benefit whereas tangential flow filtration (N = 2) displayed minimal efficacy. Lastly, risk of bias and quality of reporting for experimental design were consistently unclear across all studies. Our findings demonstrate clear potential of MSC-EVs to be developed as therapy for acute and chronic lung diseases. However, greater transparency in research design and direct comparisons of isolation technique and EV subtypes are needed to generate robust evidence to guide clinical translation. Protocol Registration: PROSPERO CRD42020145334.
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Affiliation(s)
- Alvin Tieu
- Department of Cellular and Molecular MedicineUniversity of OttawaOttawaOntarioCanada
- Clinical Epidemiology ProgramBLUEPRINT Translational Research Group, Ottawa Hospital Research InstituteOttawaOntarioCanada
- Regenerative Medicine ProgramOttawa Hospital Research InstituteOttawaOntarioCanada
| | - Kevin Hu
- Clinical Epidemiology ProgramBLUEPRINT Translational Research Group, Ottawa Hospital Research InstituteOttawaOntarioCanada
| | - Catherine Gnyra
- Clinical Epidemiology ProgramBLUEPRINT Translational Research Group, Ottawa Hospital Research InstituteOttawaOntarioCanada
| | - Joshua Montroy
- Clinical Epidemiology ProgramBLUEPRINT Translational Research Group, Ottawa Hospital Research InstituteOttawaOntarioCanada
| | - Dean A. Fergusson
- Clinical Epidemiology ProgramBLUEPRINT Translational Research Group, Ottawa Hospital Research InstituteOttawaOntarioCanada
- Department of MedicineThe Ottawa HospitalOttawaOntarioCanada
| | - David S. Allan
- Clinical Epidemiology ProgramBLUEPRINT Translational Research Group, Ottawa Hospital Research InstituteOttawaOntarioCanada
- Regenerative Medicine ProgramOttawa Hospital Research InstituteOttawaOntarioCanada
- Department of MedicineThe Ottawa HospitalOttawaOntarioCanada
| | - Duncan J. Stewart
- Department of Cellular and Molecular MedicineUniversity of OttawaOttawaOntarioCanada
- Regenerative Medicine ProgramOttawa Hospital Research InstituteOttawaOntarioCanada
- Department of MedicineThe Ottawa HospitalOttawaOntarioCanada
| | - Bernard Thébaud
- Department of Cellular and Molecular MedicineUniversity of OttawaOttawaOntarioCanada
- Regenerative Medicine ProgramOttawa Hospital Research InstituteOttawaOntarioCanada
- Division of NeonatologyDepartment of PediatricsChildren's Hospital of Eastern OntarioOttawaOntarioCanada
| | - Manoj M. Lalu
- Department of Cellular and Molecular MedicineUniversity of OttawaOttawaOntarioCanada
- Clinical Epidemiology ProgramBLUEPRINT Translational Research Group, Ottawa Hospital Research InstituteOttawaOntarioCanada
- Regenerative Medicine ProgramOttawa Hospital Research InstituteOttawaOntarioCanada
- Departments of Anesthesiology and Pain Medicine, The Ottawa HospitalOttawaOntarioCanada
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10
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Ghafouri-Fard S, Niazi V, Hussen BM, Omrani MD, Taheri M, Basiri A. The Emerging Role of Exosomes in the Treatment of Human Disorders With a Special Focus on Mesenchymal Stem Cells-Derived Exosomes. Front Cell Dev Biol 2021; 9:653296. [PMID: 34307345 PMCID: PMC8293617 DOI: 10.3389/fcell.2021.653296] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2021] [Accepted: 06/10/2021] [Indexed: 12/14/2022] Open
Abstract
Extracellular vesicles (EVs) are produced by diverse eukaryotic and prokaryotic cells. They have prominent roles in the modulation of cell-cell communication, inflammation versus immunomodulation, carcinogenic processes, cell proliferation and differentiation, and tissue regeneration. These acellular vesicles are more promising than cellular methods because of the lower risk of tumor formation, autoimmune responses and toxic effects compared with cell therapy. Moreover, the small size and lower complexity of these vesicles compared with cells have made their production and storage easier than cellular methods. Exosomes originated from mesenchymal stem cells has also been introduced as therapeutic option for a number of human diseases. The current review aims at summarization of the role of EVs in the regenerative medicine with a focus on their therapeutic impacts in liver fibrosis, lung disorders, osteoarthritis, colitis, myocardial injury, spinal cord injury and retinal injury.
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Affiliation(s)
- Soudeh Ghafouri-Fard
- Department of Medical Genetics, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Vahid Niazi
- Department of Tissue Engineering and Applied Cell Sciences, School of Advanced Technologies in Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Bashdar Mahmud Hussen
- Department of Pharmacognosy, College of Pharmacy, Hawler Medical University, Erbil, Iraq
| | - Mir Davood Omrani
- Department of Medical Genetics, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Mohammad Taheri
- Skull Base Research Center, Loghman Hakim Hospital, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Abbas Basiri
- Urology and Nephrology Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
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11
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Du T, Ju G, Zhou J, Zhong L, Rong L, Chen W, Zhang X, Zhou R, Ding D, Ji T. Microvesicles derived from human umbilical cord mesenchyme promote M2 macrophage polarization and ameliorate renal fibrosis following partial nephrectomy via hepatocyte growth factor. Hum Cell 2021; 34:1103-1113. [PMID: 33860459 DOI: 10.1007/s13577-021-00525-z] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2020] [Accepted: 03/28/2021] [Indexed: 12/21/2022]
Abstract
The intraoperative ischemia in partial nephrectomy (PN) often leads to postoperative renal function impairment and fibrosis, which can be regulated by macrophage polarization. We have previously demonstrated that microvesicles derived from human Wharton's Jelly mesenchymal stromal cells (hWJMSC-MVs) attenuated renal ischemia-induced renal fibrosis and contained a substantial quantity of hepatocyte growth factor (HGF). Herein, we investigated whether MSC-MVs regulate macrophage polarization and ameliorate renal fibrosis following ischemia-PN via transferring HGF. A rat model of ischemia-PN was established by 45 min of left renal ischemia followed by removal of 1/3 upper left kidney. MSC-MVs were injected through the tail vein immediately after ischemia. Renal injury biomarkers were measured and histologic analysis was performed to analyze renal injury. A co-culture model of THP-1 macrophages and MSC-MVs was utilized. The expression of M1 markers and M2 markers were determined to evaluate macrophage polarization. MSC-MV administration significantly ameliorated renal inflammation, lesions, and fibrosis in ischemia-PN rats, and promoted M2 macrophage polarization both in rat remnant renal tissues and LPS-treated THP-1 cells. These effects of MSC-MVs were compromised when HGF expression was downregulated in MSC-MVs. Collectively, MSC-MVs promote M2 macrophage polarization and attenuate renal fibrosis following ischemia-PN via transferring HGF.
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Affiliation(s)
- Tao Du
- Department of Urology, Zhengzhou University People's Hospital, Zhengzhou, China
- Henan Provincial People's Hospital, No. 7, Weiwu Road, Jinshui District, Zhengzhou, 450003, China
- Henan University People's Hospital, Zhengzhou, China
| | - Guanqun Ju
- Department of Urology, Changzheng Hospital, Naval Medical University, Shanghai, China
| | - Jun Zhou
- Department of Urology, Zhengzhou University People's Hospital, Zhengzhou, China
- Henan Provincial People's Hospital, No. 7, Weiwu Road, Jinshui District, Zhengzhou, 450003, China
- Henan University People's Hospital, Zhengzhou, China
| | - Liang Zhong
- Department of Urology, Shanghai Children Medical Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Lu Rong
- Department of Urology, Zhengzhou University People's Hospital, Zhengzhou, China
- Henan Provincial People's Hospital, No. 7, Weiwu Road, Jinshui District, Zhengzhou, 450003, China
- Henan University People's Hospital, Zhengzhou, China
| | - Wenxia Chen
- Department of Pediatrics, The First Affiliated Hospital of Henan University of Traditional Chinese Medicine, Zhengzhou, China
| | - Xiaoli Zhang
- Department of Urology, Zhengzhou University People's Hospital, Zhengzhou, China
- Henan Provincial People's Hospital, No. 7, Weiwu Road, Jinshui District, Zhengzhou, 450003, China
- Henan University People's Hospital, Zhengzhou, China
| | - Ruijin Zhou
- Department of Urology, Zhengzhou University People's Hospital, Zhengzhou, China
| | - Degang Ding
- Department of Urology, Zhengzhou University People's Hospital, Zhengzhou, China.
- Henan Provincial People's Hospital, No. 7, Weiwu Road, Jinshui District, Zhengzhou, 450003, China.
- Henan University People's Hospital, Zhengzhou, China.
| | - Tongyu Ji
- Department of Urology, Zhengzhou University People's Hospital, Zhengzhou, China.
- Henan Provincial People's Hospital, No. 7, Weiwu Road, Jinshui District, Zhengzhou, 450003, China.
- Henan University People's Hospital, Zhengzhou, China.
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12
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Zheng D, Zhou H, Wang H, Zhu Y, Wu Y, Li Q, Li T, Liu L. Mesenchymal stem cell-derived microvesicles improve intestinal barrier function by restoring mitochondrial dynamic balance in sepsis rats. Stem Cell Res Ther 2021; 12:299. [PMID: 34039427 PMCID: PMC8152336 DOI: 10.1186/s13287-021-02363-0] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2021] [Accepted: 04/29/2021] [Indexed: 12/15/2022] Open
Abstract
BACKGROUND Sepsis is a major cause of death in ICU, and intestinal barrier dysfunction is its important complication, while the treatment is limited. Recently, mesenchymal stem cell-derived microvesicles (MMVs) attract much attention as a strategy of cell-free treatment; whether MMVs are therapeutic in sepsis induced-intestinal barrier dysfunction is obscure. METHODS In this study, cecal ligation and puncture-induced sepsis rats and lipopolysaccharide-stimulated intestinal epithelial cells to investigate the effect of MMVs on intestinal barrier dysfunction. MMVs were harvested from mesenchymal stem cells and were injected into sepsis rats, and the intestinal barrier function was measured. Afterward, MMVs were incubated with intestinal epithelial cells, and the effect of MMVs on mitochondrial dynamic balance was measured. Then the expression of mfn1, mfn2, OPA1, and PGC-1α in MMVs were measured by western blot. By upregulation and downregulation of mfn2 and PGC-1α, the role of MMVs in mitochondrial dynamic balance was investigated. Finally, the role of MMV-carried mitochondria in mitochondrial dynamic balance was investigated. RESULTS MMVs restored the intestinal barrier function by improving mitochondrial dynamic balance and metabolism of mitochondria. Further study revealed that MMVs delivered mfn2 and PGC-1α to intestinal epithelial cells, and promoted mitochondrial fusion and biogenesis, thereby improving mitochondrial dynamic balance. Furthermore, MMVs delivered functional mitochondria to intestinal epithelial cells and enhanced energy metabolism directly. CONCLUSION MMVs can deliver mfn2, PGC-1α, and functional mitochondria to intestinal epithelial cells, synergistically improve mitochondrial dynamic balance of target cells after sepsis, and restore the mitochondrial function and intestinal barrier function. The study illustrated that MMVs might be a promising strategy for the treatment of sepsis.
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Affiliation(s)
- Danyang Zheng
- State Key Laboratory of Trauma, Burns and Combined Injury, Shock and Transfusion Department, Research Institute of Surgery, Daping Hospital, Army Medical University, Daping, Chongqing, 400042, People's Republic of China
| | - Henan Zhou
- State Key Laboratory of Trauma, Burns and Combined Injury, Shock and Transfusion Department, Research Institute of Surgery, Daping Hospital, Army Medical University, Daping, Chongqing, 400042, People's Republic of China
| | - Hongchen Wang
- State Key Laboratory of Trauma, Burns and Combined Injury, Shock and Transfusion Department, Research Institute of Surgery, Daping Hospital, Army Medical University, Daping, Chongqing, 400042, People's Republic of China
| | - Yu Zhu
- State Key Laboratory of Trauma, Burns and Combined Injury, Shock and Transfusion Department, Research Institute of Surgery, Daping Hospital, Army Medical University, Daping, Chongqing, 400042, People's Republic of China
| | - Yue Wu
- State Key Laboratory of Trauma, Burns and Combined Injury, Shock and Transfusion Department, Research Institute of Surgery, Daping Hospital, Army Medical University, Daping, Chongqing, 400042, People's Republic of China
| | - Qinghui Li
- State Key Laboratory of Trauma, Burns and Combined Injury, Shock and Transfusion Department, Research Institute of Surgery, Daping Hospital, Army Medical University, Daping, Chongqing, 400042, People's Republic of China
| | - Tao Li
- State Key Laboratory of Trauma, Burns and Combined Injury, Shock and Transfusion Department, Research Institute of Surgery, Daping Hospital, Army Medical University, Daping, Chongqing, 400042, People's Republic of China.
| | - Liangming Liu
- State Key Laboratory of Trauma, Burns and Combined Injury, Shock and Transfusion Department, Research Institute of Surgery, Daping Hospital, Army Medical University, Daping, Chongqing, 400042, People's Republic of China.
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13
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Wang W, Lei W, Jiang L, Gao S, Hu S, Zhao ZG, Niu CY, Zhao ZA. Therapeutic mechanisms of mesenchymal stem cells in acute respiratory distress syndrome reveal potentials for Covid-19 treatment. J Transl Med 2021; 19:198. [PMID: 33971907 PMCID: PMC8107778 DOI: 10.1186/s12967-021-02862-x] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2021] [Accepted: 04/30/2021] [Indexed: 02/07/2023] Open
Abstract
The mortality rate of critically ill patients with acute respiratory distress syndrome (ARDS) is 30.9% to 46.1%. The emergence of the coronavirus disease 2019 (Covid-19) has become a global issue with raising dire concerns. Patients with severe Covid-19 may progress toward ARDS. Mesenchymal stem cells (MSCs) can be derived from bone marrow, umbilical cord, adipose tissue and so on. The easy accessibility and low immunogenicity enable MSCs for allogeneic administration, and thus they were widely used in animal and clinical studies. Accumulating evidence suggests that mesenchymal stem cell infusion can ameliorate ARDS. However, the underlying mechanisms of MSCs need to be discussed. Recent studies showed MSCs can modulate immune/inflammatory cells, attenuate endoplasmic reticulum stress, and inhibit pulmonary fibrosis. The paracrine cytokines and exosomes may account for these beneficial effects. In this review, we summarize the therapeutic mechanisms of MSCs in ARDS, analyzed the most recent animal experiments and Covid-19 clinical trial results, discussed the adverse effects and prospects in the recent studies, and highlight the potential roles of MSC therapy for Covid-19 patients with ARDS.
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Affiliation(s)
- Wendi Wang
- Institute of Microcirculation, Hebei North University, 11 Diamond South-road, Keji Building, Room 213, Zhangjiakou, 075000, Hebei, China.,Department of Pathophysiology of Basic Medical College, Hebei North University, Zhangjiakou, 075000, Hebei, China.,Hebei Key Laboratory of Critical Disease Mechanism and Intervention, Shijiazhuang, 050017, Hebei, China.,Hebei Key Laboratory of Critical Disease Mechanism and Intervention, Zhangjiakou, 075000, Hebei, China.,Pathophysiology Experimental Teaching Center of Basic Medical College, Hebei North University, Zhangjiakou, 075000, Hebei, China
| | - Wei Lei
- Department of Cardiovascular Surgery of the First Affiliated Hospital & Institute for Cardiovascular Science, State Key Laboratory of Radiation Medicine and Protection, Medical College, Soochow University, Suzhou, 215000, Jiangsu, China
| | - Lina Jiang
- Institute of Microcirculation, Hebei North University, 11 Diamond South-road, Keji Building, Room 213, Zhangjiakou, 075000, Hebei, China.,Hebei Key Laboratory of Critical Disease Mechanism and Intervention, Shijiazhuang, 050017, Hebei, China.,Hebei Key Laboratory of Critical Disease Mechanism and Intervention, Zhangjiakou, 075000, Hebei, China
| | - Siqi Gao
- Institute of Microcirculation, Hebei North University, 11 Diamond South-road, Keji Building, Room 213, Zhangjiakou, 075000, Hebei, China.,Department of Pathophysiology of Basic Medical College, Hebei North University, Zhangjiakou, 075000, Hebei, China.,Hebei Key Laboratory of Critical Disease Mechanism and Intervention, Shijiazhuang, 050017, Hebei, China.,Hebei Key Laboratory of Critical Disease Mechanism and Intervention, Zhangjiakou, 075000, Hebei, China.,Pathophysiology Experimental Teaching Center of Basic Medical College, Hebei North University, Zhangjiakou, 075000, Hebei, China
| | - Shijun Hu
- Department of Cardiovascular Surgery of the First Affiliated Hospital & Institute for Cardiovascular Science, State Key Laboratory of Radiation Medicine and Protection, Medical College, Soochow University, Suzhou, 215000, Jiangsu, China
| | - Zi-Gang Zhao
- Institute of Microcirculation, Hebei North University, 11 Diamond South-road, Keji Building, Room 213, Zhangjiakou, 075000, Hebei, China. .,Hebei Key Laboratory of Critical Disease Mechanism and Intervention, Shijiazhuang, 050017, Hebei, China. .,Hebei Key Laboratory of Critical Disease Mechanism and Intervention, Zhangjiakou, 075000, Hebei, China. .,Pathophysiology Experimental Teaching Center of Basic Medical College, Hebei North University, Zhangjiakou, 075000, Hebei, China.
| | - Chun-Yu Niu
- Hebei Key Laboratory of Critical Disease Mechanism and Intervention, Shijiazhuang, 050017, Hebei, China. .,Hebei Key Laboratory of Critical Disease Mechanism and Intervention, Zhangjiakou, 075000, Hebei, China. .,Basic Medical College, Hebei Medical University, Shijiazhuang, 050017, Hebei, China.
| | - Zhen-Ao Zhao
- Institute of Microcirculation, Hebei North University, 11 Diamond South-road, Keji Building, Room 213, Zhangjiakou, 075000, Hebei, China. .,Department of Pathophysiology of Basic Medical College, Hebei North University, Zhangjiakou, 075000, Hebei, China. .,Hebei Key Laboratory of Critical Disease Mechanism and Intervention, Shijiazhuang, 050017, Hebei, China. .,Hebei Key Laboratory of Critical Disease Mechanism and Intervention, Zhangjiakou, 075000, Hebei, China. .,Pathophysiology Experimental Teaching Center of Basic Medical College, Hebei North University, Zhangjiakou, 075000, Hebei, China.
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14
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Ellison-Hughes GM, Colley L, O'Brien KA, Roberts KA, Agbaedeng TA, Ross MD. The Role of MSC Therapy in Attenuating the Damaging Effects of the Cytokine Storm Induced by COVID-19 on the Heart and Cardiovascular System. Front Cardiovasc Med 2020; 7:602183. [PMID: 33363221 PMCID: PMC7756089 DOI: 10.3389/fcvm.2020.602183] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2020] [Accepted: 11/17/2020] [Indexed: 01/08/2023] Open
Abstract
The global pandemic of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that causes coronavirus disease 2019 (COVID-19) has led to 47 m infected cases and 1. 2 m (2.6%) deaths. A hallmark of more severe cases of SARS-CoV-2 in patients with acute respiratory distress syndrome (ARDS) appears to be a virally-induced over-activation or unregulated response of the immune system, termed a "cytokine storm," featuring elevated levels of pro-inflammatory cytokines such as IL-2, IL-6, IL-7, IL-22, CXCL10, and TNFα. Whilst the lungs are the primary site of infection for SARS-CoV-2, in more severe cases its effects can be detected in multiple organ systems. Indeed, many COVID-19 positive patients develop cardiovascular complications, such as myocardial injury, myocarditis, cardiac arrhythmia, and thromboembolism, which are associated with higher mortality. Drug and cell therapies targeting immunosuppression have been suggested to help combat the cytokine storm. In particular, mesenchymal stromal cells (MSCs), owing to their powerful immunomodulatory ability, have shown promise in early clinical studies to avoid, prevent or attenuate the cytokine storm. In this review, we will discuss the mechanistic underpinnings of the cytokine storm on the cardiovascular system, and how MSCs potentially attenuate the damage caused by the cytokine storm induced by COVID-19. We will also address how MSC transplantation could alleviate the long-term complications seen in some COVID-19 patients, such as improving tissue repair and regeneration.
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Affiliation(s)
- Georgina M. Ellison-Hughes
- Faculty of Life Sciences & Medicine, Centre for Human and Applied Physiological Sciences, School of Basic and Medical Biosciences, King's College London Guy's Campus, London, United Kingdom
| | - Liam Colley
- School of Sport, Health, and Exercise Sciences, Bangor University, Bangor, United Kingdom
| | - Katie A. O'Brien
- Department of Physiology, Development, and Neuroscience, University of Cambridge, Cambridge, United Kingdom
| | - Kirsty A. Roberts
- Research Institute for Sport and Exercise Sciences, Liverpool John Moores University, Liverpool, United Kingdom
| | - Thomas A. Agbaedeng
- Faculty of Health & Medical Sciences, Centre for Heart Rhythm Disorders, School of Medicine, The University of Adelaide, Adelaide, SA, Australia
| | - Mark D. Ross
- School of Applied Sciences, Edinburgh Napier University, Edinburgh, United Kingdom
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15
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Wang F, Fang B, Qiang X, Shao J, Zhou L. The efficacy of mesenchymal stromal cell-derived therapies for acute respiratory distress syndrome-a meta-analysis of preclinical trials. Respir Res 2020; 21:307. [PMID: 33218340 PMCID: PMC7677103 DOI: 10.1186/s12931-020-01574-y] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2020] [Accepted: 11/15/2020] [Indexed: 12/26/2022] Open
Abstract
Background The investigation of mesenchymal stromal cell (MSC)-conditioned medium or extracellular vesicles (exosomes or microvesicles) as a remedy for acute lung injury (ALI) or acute respiratory distress syndrome (ARDS) has become a fast-growing field in recent years. Our purpose was to conduct a meta-analysis to investigate the efficacy of MSC-derived therapies (MDTs) for ALI/ARDS in animal models. Methods A meta-analysis of MDTs for ALI/ARDS in animal trials was performed. PubMed and EMBASE were searched to screen relevant preclinical trials with a predetermined search strategy. Results A total of 17 studies that compared MDT with the ALI control group were included in our study. The pooled result derived from the comparison of the two groups suggested that MDT could significantly reduce the lung injury score (standardized mean difference (SMD) = − 4.02, 95% CI [− 5.28, − 2.23], P < 0.0001) and improve animal survival (OR = − 6.45, 95% CI [2.78, 14.97], P < 0.0001). MDT mitigated the infiltration of neutrophils in alveoli (SMD = − 3.38, 95% CI [− 4.58, − 2.18], P < 0.00001). MDT also reduced the wet-dry weight ratio of the lung (SMD = − 2.34, 95% CI [− 3.42, − 1.26], P < 0.0001) and the total protein in BALF (SMD = − 2.23, 95% CI [− 3.07, − 1.40], P < 0.00001). Furthermore, MDT was found to downregulate proinflammatory mediators such as IL-1, IL-6 and TNF-a and to upregulate anti-inflammatory mediators such as IL-10. Conclusion MDT reduces lung injury and improves survival in animal ARDS models since it can ameliorate lung permeability, decrease inflammatory cell infiltration, downregulate proinflammatory mediators, and upregulate anti-inflammatory mediators. However, more animal studies and human trials are needed for further investigation.
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Affiliation(s)
- Fengyun Wang
- Department of Critical Care Medicine, The First People's Hospital of Foshan, Lingnan Avenue North 81, Shiwan, Chancheng, Foshan, 528000, China
| | - Bin Fang
- Department of Critical Care Medicine, The First People's Hospital of Foshan, Lingnan Avenue North 81, Shiwan, Chancheng, Foshan, 528000, China
| | - Xinhua Qiang
- Department of Critical Care Medicine, The First People's Hospital of Foshan, Lingnan Avenue North 81, Shiwan, Chancheng, Foshan, 528000, China
| | - Jingsong Shao
- Department of Critical Care Medicine, The First People's Hospital of Foshan, Lingnan Avenue North 81, Shiwan, Chancheng, Foshan, 528000, China
| | - Lixin Zhou
- Department of Critical Care Medicine, The First People's Hospital of Foshan, Lingnan Avenue North 81, Shiwan, Chancheng, Foshan, 528000, China.
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16
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Khalaj K, Figueira RL, Antounians L, Lauriti G, Zani A. Systematic review of extracellular vesicle-based treatments for lung injury: are EVs a potential therapy for COVID-19? J Extracell Vesicles 2020; 9:1795365. [PMID: 32944185 PMCID: PMC7481829 DOI: 10.1080/20013078.2020.1795365] [Citation(s) in RCA: 65] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
Severe COVID-19 infection results in bilateral interstitial pneumonia, often leading to
acute respiratory distress syndrome (ARDS) and pulmonary fibrosis in survivors. Most
patients with severe COVID-19 infections who died had developed ARDS. Currently, ARDS is
treated with supportive measures, but regenerative medicine approaches including
extracellular vesicle (EV)-based therapies have shown promise. Herein, we aimed to analyse
whether EV-based therapies could be effective in treating severe pulmonary conditions that
affect COVID-19 patients and to understand their relevance for an eventual therapeutic
application to human patients. Using a defined search strategy, we conducted a systematic
review of the literature and found 39 articles (2014–2020) that reported effects of EVs,
mainly derived from stem cells, in lung injury models (one large animal study, none in
human). EV treatment resulted in: (1) attenuation of inflammation (reduction of
pro-inflammatory cytokines and neutrophil infiltration, M2 macrophage polarization); (2)
regeneration of alveolar epithelium (decreased apoptosis and stimulation of surfactant
production); (3) repair of microvascular permeability (increased endothelial cell junction
proteins); (4) prevention of fibrosis (reduced fibrin production). These effects were
mediated by the release of EV cargo and identified factors including miRs-126, −30b-3p,
−145, −27a-3p, syndecan-1, hepatocyte growth factor and angiopoietin-1. This review
indicates that EV-based therapies hold great potential for COVID-19 related lung injuries
as they target multiple pathways and enhance tissue regeneration. However, before
translating EV therapies into human clinical trials, efforts should be directed at
developing good manufacturing practice solutions for EVs and testing optimal dosage and
administration route in large animal models.
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Affiliation(s)
- Kasra Khalaj
- Developmental and Stem Cell Biology Program, Peter Gilgan Centre for Research and Learning, The Hospital for Sick Children, Toronto, Ontario, Canada.,Division of General and Thoracic Surgery, The Hospital for Sick Children, Toronto, Ontario, Canada
| | - Rebeca Lopes Figueira
- Developmental and Stem Cell Biology Program, Peter Gilgan Centre for Research and Learning, The Hospital for Sick Children, Toronto, Ontario, Canada.,Division of General and Thoracic Surgery, The Hospital for Sick Children, Toronto, Ontario, Canada
| | - Lina Antounians
- Developmental and Stem Cell Biology Program, Peter Gilgan Centre for Research and Learning, The Hospital for Sick Children, Toronto, Ontario, Canada.,Division of General and Thoracic Surgery, The Hospital for Sick Children, Toronto, Ontario, Canada
| | - Giuseppe Lauriti
- Department of Pediatric Surgery, Spirito Santo Hospital, Pescara, Italy.,Department of Medicine and Aging Sciences, G. D'Annunzio University, Chieti-Pescara, Italy
| | - Augusto Zani
- Developmental and Stem Cell Biology Program, Peter Gilgan Centre for Research and Learning, The Hospital for Sick Children, Toronto, Ontario, Canada.,Division of General and Thoracic Surgery, The Hospital for Sick Children, Toronto, Ontario, Canada
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17
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Chen WX, Zhou J, Zhou SS, Zhang YD, Ji TY, Zhang XL, Wang SM, Du T, Ding DG. Microvesicles derived from human Wharton's jelly mesenchymal stem cells enhance autophagy and ameliorate acute lung injury via delivery of miR-100. Stem Cell Res Ther 2020; 11:113. [PMID: 32169098 PMCID: PMC7071666 DOI: 10.1186/s13287-020-01617-7] [Citation(s) in RCA: 38] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2019] [Revised: 02/10/2020] [Accepted: 02/24/2020] [Indexed: 12/16/2022] Open
Abstract
Objectives Microvesicles (MVs) derived from human Wharton’s jelly mesenchymal stem cells (MSC-MVs) were demonstrated to ameliorate acute lung injury (ALI). We have previously found that MSC-MV-transferred hepatocyte growth factor was partly involved in their therapeutic effects. Since MSC-MVs also contained a substantial quantity of miR-100, which plays an important role in lung cancer and injury, we speculated that miR-100 might similarly account for a part of the therapeutic effects of MSC-MVs. Methods MSCs were transfected with miR-100 inhibitor to downregulate miR-100 in MSC-MVs. A rat model of ALI and cell injury in rat type II alveolar epithelial cell line (L2) was induced by bleomycin (BLM). A co-culture model of alveolar epithelial cells and MSC-MVs was utilized to examine the therapeutic role of MSC-MVs and mechanism. Results MSC-MV treatment attenuated BLM-induced apoptosis and inflammation in BLM-treated L2 cells and ameliorated BLM-induced lung apoptosis, inflammation, and fibrosis in BLM-induced ALI rats. The beneficial effect of MSC-MVs was partly eliminated when miR-100 was knocked down in MSCs. Moreover, MSC-MV-transferred miR-100 mediated the therapeutic effect of MSC-MVs in ALI through enhancing autophagy by targeting mTOR. Conclusion MSC-MVs enhance autophagy and ameliorate ALI partially via delivery of miR-100.
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Affiliation(s)
- Wen-Xia Chen
- Department of Pediatrics, The First Affiliated Hospital of Henan University of Traditional Chinese Medicine, Zhengzhou, 450000, Henan, China
| | - Jun Zhou
- Department of Urology, Henan University People's Hospital; Henan Provincial People's Hospital, Zhengzhou, Henan, 450003, China
| | - Sha-Sha Zhou
- Department of Pediatrics, The First Affiliated Hospital of Henan University of Traditional Chinese Medicine, Zhengzhou, 450000, Henan, China
| | - Yu-Dan Zhang
- Department of Pediatrics, The First Affiliated Hospital of Henan University of Traditional Chinese Medicine, Zhengzhou, 450000, Henan, China
| | - Tong-Yu Ji
- Department of Urology, Henan Provincial People's Hospital, Zhengzhou University People's Hospital, Zhengzhou, 450003, Henan, China
| | - Xiao-Li Zhang
- Department of Urology, Henan Provincial People's Hospital, Zhengzhou University People's Hospital, Zhengzhou, 450003, Henan, China
| | - Shu-Min Wang
- Department of Pediatrics, The First Affiliated Hospital of Henan University of Traditional Chinese Medicine, Zhengzhou, 450000, Henan, China.
| | - Tao Du
- Department of Urology, Henan University People's Hospital; Henan Provincial People's Hospital, Zhengzhou, Henan, 450003, China. .,Department of Urology, Henan Provincial People's Hospital, Zhengzhou University People's Hospital, Zhengzhou, 450003, Henan, China.
| | - De-Gang Ding
- Department of Urology, Henan University People's Hospital; Henan Provincial People's Hospital, Zhengzhou, Henan, 450003, China.,Department of Urology, Henan Provincial People's Hospital, Zhengzhou University People's Hospital, Zhengzhou, 450003, Henan, China
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18
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Rockel JS, Rabani R, Viswanathan S. Anti-fibrotic mechanisms of exogenously-expanded mesenchymal stromal cells for fibrotic diseases. Semin Cell Dev Biol 2019; 101:87-103. [PMID: 31757583 DOI: 10.1016/j.semcdb.2019.10.014] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2019] [Revised: 10/11/2019] [Accepted: 10/30/2019] [Indexed: 12/17/2022]
Abstract
Most chronic diseases involving inflammation have a fibrotic component that involves remodeling and excess accumulation of extracellular matrix components. Left unchecked, fibrosis leads to organ failure and death. Mesenchymal stromal cells (MSCs) are emerging as a potent cell-based therapy for a wide spectrum of fibrotic conditions due to their immunomodulatory, anti-inflammatory and anti-fibrotic properties. This review provides an overview of known mechanisms by which MSCs mediate their anti-fibrotic actions and in relation to animal models of pulmonary, liver, renal and cardiac fibrosis. Recent MSC clinical trials results in liver, lung, skin, kidney and hearts are discussed and next steps for future MSC-based therapies including pre-activated or genetically-modified cells, or extracellular vesicles are also considered.
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Affiliation(s)
- Jason S Rockel
- Arthritis Program, University Health Network, Toronto, ON, Canada; Division of Genetics and Development, Krembil Research Institute, University Health Network, Toronto, ON, Canada.
| | - Razieh Rabani
- Arthritis Program, University Health Network, Toronto, ON, Canada; Division of Genetics and Development, Krembil Research Institute, University Health Network, Toronto, ON, Canada
| | - Sowmya Viswanathan
- Arthritis Program, University Health Network, Toronto, ON, Canada; Division of Genetics and Development, Krembil Research Institute, University Health Network, Toronto, ON, Canada; Institute of Biomaterials and Biomedical Engineering, University of Toronto, Toronto, Canada; Division of Hematology, Department of Medicine, University of Toronto, Toronto, Canada
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19
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Isolation and characterization of microvesicles from mesenchymal stem cells. Methods 2019; 177:50-57. [PMID: 31669353 DOI: 10.1016/j.ymeth.2019.10.010] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2019] [Revised: 10/22/2019] [Accepted: 10/23/2019] [Indexed: 12/17/2022] Open
Abstract
Mesenchymal stem or stromal cells are currently under clinical investigation for multiple diseases. While their mechanism of action is still not fully elucidated, vesicles secreted by MSCs are believed to recapitulate their therapeutic potentials to some extent. Microvesicles (MVs), also called as microparticles or ectosome, are among secreted vesicles that could transfer cytoplasmic cargo, including RNA and proteins, from emitting (source) cells to recipient cells. Given the importance of MVs, we here attempted to establish a method to isolate and characterize MVs secreted from unmodified human bone marrow derived MSCs (referred to as native MSCs, and their microvesicles as Native-MVs) and IFNγ stimulated MSCs (referred to as IFNγ-MSCs, and their microvesicles as IFNγ-MVs). We first describe an ultracentrifugation technique to isolate MVs from the conditioned cell culture media of MSCs. Next, we describe characterization and quality control steps to analyze the protein and RNA content of MVs. Finally, we examined the potential of MVs to exert immunomodulatory effects through induction of regulatory T cells (Tregs). Secretory vesicles from MSCs are promising alternatives for cell therapy with applications in drug delivery, regenerative medicine, and immunotherapy.
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