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Rolandsson Enes S, Dzneladze I, Hampton TH, Neff SL, Asarian L, Barua J, Tertel T, Giebel B, Pereyra N, McKenna DH, Hu P, Acton E, Ashare A, Liu KD, Krasnodembskaya AD, English K, Stanton BA, Rocco PRM, Matthay MA, Dos Santos CC, Weiss DJ. Acute respiratory distress vs healthy lung environments differently affect mesenchymal stromal cell extracellular vesicle miRNAs. Cytotherapy 2025; 27:581-596. [PMID: 39945694 DOI: 10.1016/j.jcyt.2025.01.006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2024] [Revised: 01/14/2025] [Accepted: 01/15/2025] [Indexed: 05/24/2025]
Abstract
The acute respiratory distress syndrome (ARDS) inflammatory environment alters mesenchymal stromal cell (MSC) gene and protein expression but effects on microRNA (miRNA) content of MSC-extracellular vesicle (EVs) remain unknown. To assess this, sequencing analysis of EV-miRNAs prepared from human bone marrow-derived MSCs (hMSCs) exposed ex vivo to bronchoalveolar lavage fluid (BALF) from ARDS patients or healthy volunteers (HV) identified a number of differentially expressed miRNAs. Discriminant, differential expression, and functional enrichment analyses identified 14 miRNAs significantly changed following ARDS versus HV BALF exposure. Network analysis showed 4 (miR-760, miR-3175, miR-885-3p, and miR-766-3p) of the 14 EV-miRNAs formed a regulatory "hub", suggesting co-targeting of specific gene pathways. In silico prediction identified a number of pathways important in lung injury. Two miRNAs involved in regulation of the cystic fibrosis transmembrane conductance regulator (CFTR), miRNA-145-5p and miRNA-138-5p, were also significantly increased in ARDS BALF-exposed hMSCs EVs. Functionally, EVs from hMSCs exposed to either ARDS or HV BALF had differential effects on CFTR Cl- secretion by cultured primary human bronchial epithelial cells, an effect predicted to reduce mucociliary clearance. The potential clinical impact of these finding highlights the need for further studies assessing the role of hMSC-EV miRNAs in regulating lung inflammation and mucociliary clearance.
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Affiliation(s)
- Sara Rolandsson Enes
- Department of Medicine, Larner College of Medicine, University of Vermont, Burlington, Vermont, USA; Department of Experimental Medical Science, Faculty of Medicine, Lund University, Lund, Sweden.
| | - Irakli Dzneladze
- Interdepartmental Division of Critical Care, Department of Medicine and the Keenan Center for Biomedical Research, St. Michael's Hospital, University of Toronto, Toronto, Canada
| | - Thomas H Hampton
- Department of Microbiology and Immunology, Geisel School of Medicine at Dartmouth, Hanover, New Hampshire, USA
| | - Samuel L Neff
- Department of Microbiology and Immunology, Geisel School of Medicine at Dartmouth, Hanover, New Hampshire, USA
| | - Lori Asarian
- Department of Medicine, Larner College of Medicine, University of Vermont, Burlington, Vermont, USA
| | - Jayita Barua
- Department of Medicine, Larner College of Medicine, University of Vermont, Burlington, Vermont, USA
| | - Tobias Tertel
- Institute of Transfusion Medicine, University Hospital Essen, University of Duisburg-Essen, Essen Germany
| | - Bernd Giebel
- Institute of Transfusion Medicine, University Hospital Essen, University of Duisburg-Essen, Essen Germany
| | - Nicolas Pereyra
- Department of Biochemistry and Molecular Biology, The University of British Columbia, Canada, The University of British Columbia Centre for Blood Research, Vancouver, Canada
| | - David H McKenna
- Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, USA
| | - Pingzhao Hu
- Department of Biochemistry and Medical Genetics, University of Manitoba, Winnipeg, Canada
| | - Erica Acton
- Interdepartmental Division of Critical Care, Department of Medicine and the Keenan Center for Biomedical Research, St. Michael's Hospital, University of Toronto, Toronto, Canada
| | - Alix Ashare
- Department of Microbiology and Immunology, Geisel School of Medicine at Dartmouth, Hanover, New Hampshire, USA; Section of Pulmonary and Critical Care Medicine, Dartmouth-Hitchcock Medical Center, Lebanon, New Hampshire, USA
| | - Kathleen D Liu
- Departments of Medicine and Anesthesiology and the Cardiovascular Research Institute, University of California San Francisco
| | - Anna D Krasnodembskaya
- Wellcome-Wolfson Institute for Experimental Medicine, School of Medicine, Dentistry, and Biomedical Sciences, Queens University, Belfast, UK
| | - Karen English
- Cellular Immunology Laboratory, Biology Department, Kathleen Lonsdale Institute for Human Health Research, Maynooth University, Maynooth, Co. Kildare, Ireland
| | - Bruce A Stanton
- Department of Microbiology and Immunology, Geisel School of Medicine at Dartmouth, Hanover, New Hampshire, USA
| | - Patricia R M Rocco
- Laboratory of Pulmonary Investigation, Carlos Chagas Filho Institute of Biophysics, Federal University of Rio de Janeiro; National Institute of Science and Technology for Regenerative Medicine, Rio de Janeiro, Brazil
| | - Michael A Matthay
- Departments of Medicine and Anesthesiology and the Cardiovascular Research Institute, University of California San Francisco
| | - Claudia C Dos Santos
- Interdepartmental Division of Critical Care, Department of Medicine and the Keenan Center for Biomedical Research, St. Michael's Hospital, University of Toronto, Toronto, Canada
| | - Daniel J Weiss
- Department of Medicine, Larner College of Medicine, University of Vermont, Burlington, Vermont, USA
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Warren AJ, Liu L, O'Toole DP, Laffey JG, Masterson CH. The impact of the inflammatory pulmonary microenvironment on the behavior and function of mesenchymal stromal cells. Expert Rev Respir Med 2025:1-12. [PMID: 40223328 DOI: 10.1080/17476348.2025.2491715] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2024] [Revised: 03/28/2025] [Accepted: 04/07/2025] [Indexed: 04/15/2025]
Abstract
INTRODUCTION Acute respiratory distress syndrome is characterized by the dysregulation and activation of several inflammatory pathways which lead to widespread inflammation in the lungs. Presently, direct therapy is unavailable and the use of mesenchymal stromal cells as a direct therapy has been proposed, as early-phase studies have shown promise. AREAS COVERED MSCs exert various therapeutic effects on the inflammatory microenvironment, such as anti-microbial effects, restoration of the alveolar-capillary barrier, and exuding various anti-inflammatory effects. However, to exert these effects MSCs need to be submitted to specific external stimuli which can affect their immunomodulation, survival, migration and metabolic state. This review references several articles found through targeted searches in PubMed [Accessed between November 2024 and March 2025], for key terms such as 'mesenchymal stromal cells', 'inflammatory microenvironment', anti-inflammatory', 'metabolism', and 'immunomodulation'. EXPERT OPINION The advancement of MSCs therapy in the treatment of ARDS has not progressed as effectively as one might have anticipated. Several clinical findings have established patient subgroups based on inflammatory cytokine profiles and severity of ARDS. This variation in patients may influence the clinical efficacy of MSCs and instead of concluding that MSCs therapy is not worth pursuing, more research is needed to develop an appropriate therapy.
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Affiliation(s)
- Abigail Jm Warren
- Anaesthesia, School of Medicine, College of Medicine, Nursing and Health Sciences, and CÚRAM Centre for Research in Medical Devices, University of Galway, Galway, Ireland
| | - Lanzhi Liu
- Physiology, School of Medicine, College of Medicine, Nursing and Health Sciences, and CÚRAM Centre for Research in Medical Devices, University of Galway, Galway, Ireland
| | - Daniel P O'Toole
- Physiology, School of Medicine, College of Medicine, Nursing and Health Sciences, and CÚRAM Centre for Research in Medical Devices, University of Galway, Galway, Ireland
| | - John G Laffey
- Anaesthesia, School of Medicine, College of Medicine, Nursing and Health Sciences, and CÚRAM Centre for Research in Medical Devices, University of Galway, Galway, Ireland
- Department of Anaesthesia and Intensive Care Medicine, Galway University Hospitals, Saolta University Healthcare System, Galway, Ireland
| | - Claire H Masterson
- Physiology, School of Medicine, College of Medicine, Nursing and Health Sciences, and CÚRAM Centre for Research in Medical Devices, University of Galway, Galway, Ireland
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Edström D, Niroomand A, Stenlo M, Broberg E, Hirdman G, Ghaidan H, Hyllén S, Pierre L, Olm F, Lindstedt S. Amniotic fluid-derived mesenchymal stem cells reduce inflammation and improve lung function following transplantation in a porcine model. J Heart Lung Transplant 2024; 43:2018-2030. [PMID: 39182800 DOI: 10.1016/j.healun.2024.08.014] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2023] [Revised: 08/03/2024] [Accepted: 08/13/2024] [Indexed: 08/27/2024] Open
Abstract
BACKGROUND Lung transplantation is hindered by low donor lung utilization rates. Infectious complications are reasons to decline donor grafts due to fear of post-transplant primary graft dysfunction. Mesenchymal stem cells are a promising therapy currently investigated in treating lung injury. Full-term amniotic fluid-derived lung-specific mesenchymal stem cell treatment may regenerate damaged lungs. These cells have previously demonstrated inflammatory mediation in other respiratory diseases, and we hypothesized that treatment would improve donor lung quality and postoperative outcomes. METHODS In a transplantation model, donor pigs were stratified to either the treated or the nontreated group. Acute respiratory distress syndrome was induced in donor pigs and harvested lungs were placed on ex vivo lung perfusion (EVLP) before transplantation. Treatment consisted of 3 doses of 2 × 106 cells/kg: one during EVLP and 2 after transplantation. Donors and recipients were assessed on clinically relevant parameters and recipients were followed for 3 days before evaluation for primary graft dysfunction (PGD). RESULTS Repeated injection of the cell treatment showed reductions in inflammation seen through lowered immune cell counts, reduced histology signs of inflammation, and decreased cytokines in the plasma and bronchoalveolar lavage fluid. Treated recipients showed improved pulmonary function, including increased PaO2/FiO2 ratios and reduced incidence of PGD. CONCLUSIONS Repeated injection of lung-specific cell treatment during EVLP and post transplant was associated with improved function of previously damaged lungs. Cell treatment may be considered as a potential therapy to increase the number of lungs available for transplantation and the improvement of postoperative outcomes.
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Affiliation(s)
- Dag Edström
- Wallenberg Center for Molecular Medicine, Lund University, Lund, Sweden; Department of Clinical Sciences, Lund University, Lund, Sweden; Lund Stem Cell Center, Lund University, Lund, Sweden; Department of Cardiothoracic Anesthesia and Intensive Care, Skåne University Hospital, Lund, Sweden
| | - Anna Niroomand
- Wallenberg Center for Molecular Medicine, Lund University, Lund, Sweden; Department of Clinical Sciences, Lund University, Lund, Sweden; Lund Stem Cell Center, Lund University, Lund, Sweden; Department of Cardiothoracic Surgery, NYU Grossman School of Medicine, New York, New York
| | - Martin Stenlo
- Wallenberg Center for Molecular Medicine, Lund University, Lund, Sweden; Department of Clinical Sciences, Lund University, Lund, Sweden; Lund Stem Cell Center, Lund University, Lund, Sweden; Department of Cardiothoracic Anesthesia and Intensive Care, Skåne University Hospital, Lund, Sweden
| | - Ellen Broberg
- Wallenberg Center for Molecular Medicine, Lund University, Lund, Sweden; Department of Clinical Sciences, Lund University, Lund, Sweden; Lund Stem Cell Center, Lund University, Lund, Sweden; Department of Cardiothoracic Anesthesia and Intensive Care, Skåne University Hospital, Lund, Sweden
| | - Gabriel Hirdman
- Wallenberg Center for Molecular Medicine, Lund University, Lund, Sweden; Department of Clinical Sciences, Lund University, Lund, Sweden; Lund Stem Cell Center, Lund University, Lund, Sweden
| | - Haider Ghaidan
- Wallenberg Center for Molecular Medicine, Lund University, Lund, Sweden; Department of Clinical Sciences, Lund University, Lund, Sweden; Lund Stem Cell Center, Lund University, Lund, Sweden; Department of Cardiothoracic Surgery and Transplantation, Skåne University Hospital, Lund, Sweden
| | - Snejana Hyllén
- Wallenberg Center for Molecular Medicine, Lund University, Lund, Sweden; Department of Clinical Sciences, Lund University, Lund, Sweden; Lund Stem Cell Center, Lund University, Lund, Sweden; Department of Cardiothoracic Anesthesia and Intensive Care, Skåne University Hospital, Lund, Sweden
| | - Leif Pierre
- Wallenberg Center for Molecular Medicine, Lund University, Lund, Sweden; Department of Clinical Sciences, Lund University, Lund, Sweden; Lund Stem Cell Center, Lund University, Lund, Sweden; Department of Cardiothoracic Surgery and Transplantation, Skåne University Hospital, Lund, Sweden
| | - Franziska Olm
- Wallenberg Center for Molecular Medicine, Lund University, Lund, Sweden; Department of Clinical Sciences, Lund University, Lund, Sweden; Lund Stem Cell Center, Lund University, Lund, Sweden
| | - Sandra Lindstedt
- Wallenberg Center for Molecular Medicine, Lund University, Lund, Sweden; Department of Clinical Sciences, Lund University, Lund, Sweden; Lund Stem Cell Center, Lund University, Lund, Sweden; Department of Cardiothoracic Surgery and Transplantation, Skåne University Hospital, Lund, Sweden.
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Marquez-Curtis LA, Elliott JAW. Mesenchymal stromal cells derived from various tissues: Biological, clinical and cryopreservation aspects: Update from 2015 review. Cryobiology 2024; 115:104856. [PMID: 38340887 DOI: 10.1016/j.cryobiol.2024.104856] [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: 11/28/2023] [Revised: 01/26/2024] [Accepted: 01/30/2024] [Indexed: 02/12/2024]
Abstract
Mesenchymal stromal cells (MSCs) have become one of the most investigated and applied cells for cellular therapy and regenerative medicine. In this update of our review published in 2015, we show that studies continue to abound regarding the characterization of MSCs to distinguish them from other similar cell types, the discovery of new tissue sources of MSCs, and the confirmation of their properties and functions that render them suitable as a therapeutic. Because cryopreservation is widely recognized as the only technology that would enable the on-demand availability of MSCs, here we show that although the traditional method of cryopreserving cells by slow cooling in the presence of 10% dimethyl sulfoxide (Me2SO) continues to be used by many, several novel MSC cryopreservation approaches have emerged. As in our previous review, we conclude from these recent reports that viable and functional MSCs from diverse tissues can be recovered after cryopreservation using a variety of cryoprotectants, freezing protocols, storage temperatures, and periods of storage. We also show that for logistical reasons there are now more studies devoted to the cryopreservation of tissues from which MSCs are derived. A new topic included in this review covers the application in COVID-19 of MSCs arising from their immunomodulatory and antiviral properties. Due to the inherent heterogeneity in MSC populations from different sources there is still no standardized procedure for their isolation, identification, functional characterization, cryopreservation, and route of administration, and not likely to be a "one-size-fits-all" approach in their applications in cell-based therapy and regenerative medicine.
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Affiliation(s)
- Leah A Marquez-Curtis
- Department of Chemical and Materials Engineering, University of Alberta, Edmonton, AB, Canada, T6G 1H9; Department of Laboratory Medicine and Pathology, University of Alberta, Edmonton, AB, Canada, T6G 1C9
| | - Janet A W Elliott
- Department of Chemical and Materials Engineering, University of Alberta, Edmonton, AB, Canada, T6G 1H9; Department of Laboratory Medicine and Pathology, University of Alberta, Edmonton, AB, Canada, T6G 1C9.
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Aouabdi S, Aboalola D, Zakari S, Alwafi S, Nedjadi T, Alsiary R. Protective potential of mesenchymal stem cells against COVID-19 during pregnancy. Future Sci OA 2024; 10:FSO924. [PMID: 38836262 PMCID: PMC11149780 DOI: 10.2144/fsoa-2023-0179] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2023] [Accepted: 10/17/2023] [Indexed: 06/06/2024] Open
Abstract
SARS-CoV-2 causes COVID-19. COVID-19 has led to severe clinical illnesses and an unprecedented death toll. The virus induces immune inflammatory responses specifically cytokine storm in lungs. Several published reports indicated that pregnant females are less likely to develop severe symptoms compared with non-pregnant. Putative protective role of maternal blood circulating fetal mesenchymal stem cells (MSCs) has emerged and have been put forward as an explanation to alleviated symptoms. MSCs with immune-modulatory, anti-inflammatory and anti-viral roles, hold great potential for the treatment of COVID-19. MSCs could be an alternative to treat infections resulting from the SARS-CoV-2 and potential future outbreaks. This review focuses on the MSCs putative protective roles against COVID-19 in pregnant females.
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Affiliation(s)
- Sihem Aouabdi
- King Abdullah International Medical Research Center, Jeddah, 21423, Saudi Arabia
- King Saud Bin Abdulaziz University for Health Sciences, Jeddah, 21423, Saudi Arabia
| | - Doaa Aboalola
- King Abdullah International Medical Research Center, Jeddah, 21423, Saudi Arabia
- King Saud Bin Abdulaziz University for Health Sciences, Jeddah, 21423, Saudi Arabia
| | - Samer Zakari
- King Abdullah International Medical Research Center, Jeddah, 21423, Saudi Arabia
- King Saud Bin Abdulaziz University for Health Sciences, Jeddah, 21423, Saudi Arabia
| | - Suliman Alwafi
- King Abdullah International Medical Research Center, Jeddah, 21423, Saudi Arabia
- King Saud Bin Abdulaziz University for Health Sciences, Jeddah, 21423, Saudi Arabia
| | - Taoufik Nedjadi
- King Abdullah International Medical Research Center, Jeddah, 21423, Saudi Arabia
- King Saud Bin Abdulaziz University for Health Sciences, Jeddah, 21423, Saudi Arabia
| | - Rawiah Alsiary
- King Abdullah International Medical Research Center, Jeddah, 21423, Saudi Arabia
- King Saud Bin Abdulaziz University for Health Sciences, Jeddah, 21423, Saudi Arabia
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6
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Zhang DW, Lu JL, Dong BY, Fang MY, Xiong X, Qin XJ, Fan XM. Gut microbiota and its metabolic products in acute respiratory distress syndrome. Front Immunol 2024; 15:1330021. [PMID: 38433840 PMCID: PMC10904571 DOI: 10.3389/fimmu.2024.1330021] [Citation(s) in RCA: 4] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2023] [Accepted: 01/30/2024] [Indexed: 03/05/2024] Open
Abstract
The prevalence rate of acute respiratory distress syndrome (ARDS) is estimated at approximately 10% in critically ill patients worldwide, with the mortality rate ranging from 17% to 39%. Currently, ARDS mortality is usually higher in patients with COVID-19, giving another challenge for ARDS treatment. However, the treatment efficacy for ARDS is far from satisfactory. The relationship between the gut microbiota and ARDS has been substantiated by relevant scientific studies. ARDS not only changes the distribution of gut microbiota, but also influences intestinal mucosal barrier through the alteration of gut microbiota. The modulation of gut microbiota can impact the onset and progression of ARDS by triggering dysfunctions in inflammatory response and immune cells, oxidative stress, cell apoptosis, autophagy, pyroptosis, and ferroptosis mechanisms. Meanwhile, ARDS may also influence the distribution of metabolic products of gut microbiota. In this review, we focus on the impact of ARDS on gut microbiota and how the alteration of gut microbiota further influences the immune function, cellular functions and related signaling pathways during ARDS. The roles of gut microbiota-derived metabolites in the development and occurrence of ARDS are also discussed.
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Affiliation(s)
- Dong-Wei Zhang
- Department of Respiratory and Critical Care Medicine, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan, China
- Inflammation & Allergic Diseases Research Unit, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan, China
- Department of Respiratory and Critical Care Medicine, Liuzhou People’s Hospital, Guangxi Medical University, Liuzhou, Guangxi, China
- Key Laboratory of Diagnosis, Treatment and Research of Asthma and Chronic Obstructive Pulmonary Disease, Liuzhou, Guangxi, China
| | - Jia-Li Lu
- Department of Respiratory and Critical Care Medicine, Liuzhou People’s Hospital, Guangxi Medical University, Liuzhou, Guangxi, China
- Key Laboratory of Diagnosis, Treatment and Research of Asthma and Chronic Obstructive Pulmonary Disease, Liuzhou, Guangxi, China
| | - Bi-Ying Dong
- Department of Respiratory and Critical Care Medicine, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan, China
- Inflammation & Allergic Diseases Research Unit, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan, China
- Department of Respiratory and Critical Care Medicine, Liuzhou People’s Hospital, Guangxi Medical University, Liuzhou, Guangxi, China
- Key Laboratory of Diagnosis, Treatment and Research of Asthma and Chronic Obstructive Pulmonary Disease, Liuzhou, Guangxi, China
| | - Meng-Ying Fang
- Department of Respiratory and Critical Care Medicine, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan, China
- Inflammation & Allergic Diseases Research Unit, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan, China
| | - Xia Xiong
- Department of Dermatology, The Affiliated Hospital, Southwest Medical University, Luzhou, Sichuan, China
| | - Xue-Jun Qin
- Department of Respiratory and Critical Care Medicine, Liuzhou People’s Hospital, Guangxi Medical University, Liuzhou, Guangxi, China
- Key Laboratory of Diagnosis, Treatment and Research of Asthma and Chronic Obstructive Pulmonary Disease, Liuzhou, Guangxi, China
| | - Xian-Ming Fan
- Department of Respiratory and Critical Care Medicine, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan, China
- Inflammation & Allergic Diseases Research Unit, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan, China
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Gonzaga A, Andreu E, Hernández-Blasco LM, Meseguer R, Al-Akioui-Sanz K, Soria-Juan B, Sanjuan-Gimenez JC, Ferreras C, Tejedo JR, Lopez-Lluch G, Goterris R, Maciá L, Sempere-Ortells JM, Hmadcha A, Borobia A, Vicario JL, Bonora A, Aguilar-Gallardo C, Poveda JL, Arbona C, Alenda C, Tarín F, Marco FM, Merino E, Jaime F, Ferreres J, Figueira JC, Cañada-Illana C, Querol S, Guerreiro M, Eguizabal C, Martín-Quirós A, Robles-Marhuenda Á, Pérez-Martínez A, Solano C, Soria B. Rationale for combined therapies in severe-to-critical COVID-19 patients. Front Immunol 2023; 14:1232472. [PMID: 37767093 PMCID: PMC10520558 DOI: 10.3389/fimmu.2023.1232472] [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: 05/31/2023] [Accepted: 08/22/2023] [Indexed: 09/29/2023] Open
Abstract
An unprecedented global social and economic impact as well as a significant number of fatalities have been brought on by the coronavirus disease 2019 (COVID-19), produced by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Acute SARS-CoV-2 infection can, in certain situations, cause immunological abnormalities, leading to an anomalous innate and adaptive immune response. While most patients only experience mild symptoms and recover without the need for mechanical ventilation, a substantial percentage of those who are affected develop severe respiratory illness, which can be fatal. The absence of effective therapies when disease progresses to a very severe condition coupled with the incomplete understanding of COVID-19's pathogenesis triggers the need to develop innovative therapeutic approaches for patients at high risk of mortality. As a result, we investigate the potential contribution of promising combinatorial cell therapy to prevent death in critical patients.
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Affiliation(s)
- Aitor Gonzaga
- Alicante Institute for Health and Biomedical Research (ISABIAL), Alicante, Spain
- Institute of Bioengineering, Miguel Hernández University, Elche, Spain
| | - Etelvina Andreu
- Alicante Institute for Health and Biomedical Research (ISABIAL), Alicante, Spain
- Applied Physics Department, Miguel Hernández University, Elche, Spain
| | | | - Rut Meseguer
- Alicante Institute for Health and Biomedical Research (ISABIAL), Alicante, Spain
- Clinic University Hospital, Fundación para la Investigación del Hospital Clínico de la Comunidad Valenciana (INCLIVA) Health Research Institute, Valencia, Spain
| | - Karima Al-Akioui-Sanz
- Alicante Institute for Health and Biomedical Research (ISABIAL), Alicante, Spain
- Hospital La Paz Institute for Health Research, IdiPAZ, University Hospital La Paz, Madrid, Spain
| | - Bárbara Soria-Juan
- Réseau Hospitalier Neuchâtelois, Hôpital Pourtalès, Neuchâtel, Switzerland
| | | | - Cristina Ferreras
- Hospital La Paz Institute for Health Research, IdiPAZ, University Hospital La Paz, Madrid, Spain
| | - Juan R. Tejedo
- Department of Molecular Biology and Biochemical Engineering, University Pablo de Olavide, Seville, Spain
- Biomedical Research Network for Diabetes and Related Metabolic Diseases-Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM) of the Carlos III Health Institute (ISCIII), Madrid, Spain
| | - Guillermo Lopez-Lluch
- University Pablo de Olavide, Centro Andaluz de Biología del Desarrollo - Consejo Superior de Investigaciones Científicas (CABD-CSIC), Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Sevilla, Spain
| | - Rosa Goterris
- Clinic University Hospital, Fundación para la Investigación del Hospital Clínico de la Comunidad Valenciana (INCLIVA) Health Research Institute, Valencia, Spain
| | - Loreto Maciá
- Nursing Department, University of Alicante, Alicante, Spain
| | - Jose M. Sempere-Ortells
- Alicante Institute for Health and Biomedical Research (ISABIAL), Alicante, Spain
- Biotechnology Department, University of Alicante, Alicante, Spain
| | - Abdelkrim Hmadcha
- Department of Molecular Biology and Biochemical Engineering, University Pablo de Olavide, Seville, Spain
- Biosanitary Research Institute (IIB-VIU), Valencian International University (VIU), Valencia, Spain
| | - Alberto Borobia
- Clinical Pharmacology Department, La Paz University Hospital, School of Medicine, Universidad Autónoma de Madrid, IdiPAz, Madrid, Spain
| | - Jose L. Vicario
- Transfusion Center of the Autonomous Community of Madrid, Madrid, Spain
| | - Ana Bonora
- Health Research Institute Hospital La Fe, Valencia, Spain
| | | | - Jose L. Poveda
- Health Research Institute Hospital La Fe, Valencia, Spain
| | - Cristina Arbona
- Valencian Community Blood Transfusion Center, Valencia, Spain
| | - Cristina Alenda
- Alicante Institute for Health and Biomedical Research (ISABIAL), Alicante, Spain
| | - Fabian Tarín
- Alicante Institute for Health and Biomedical Research (ISABIAL), Alicante, Spain
| | - Francisco M. Marco
- Alicante Institute for Health and Biomedical Research (ISABIAL), Alicante, Spain
- Immunology Department, Dr. Balmis General University Hospital, Alicante, Spain
| | - Esperanza Merino
- Alicante Institute for Health and Biomedical Research (ISABIAL), Alicante, Spain
- Department of Clinical Medicine, Miguel Hernández University, Elche, Spain
- Infectious Diseases Unit, Dr. Balmis General University Hospital, Alicante, Spain
| | - Francisco Jaime
- Alicante Institute for Health and Biomedical Research (ISABIAL), Alicante, Spain
| | - José Ferreres
- Intensive Care Service, Hospital Clinico Universitario, Fundación para la Investigación del Hospital Clínico de la Comunidad Valenciana (INCLIVA), Valencia, Spain
| | | | | | | | - Manuel Guerreiro
- Department of Hematology, Hospital Universitario y Politécnico La Fe, Valencia, Spain
| | - Cristina Eguizabal
- Research Unit, Basque Center for Blood Transfusion and Human Tissues, Galdakao, Spain
- Cell Therapy, Stem Cells and Tissues Group, Biocruces Bizkaia Health Research Institute, Barakaldo, Spain
| | | | | | - Antonio Pérez-Martínez
- Hospital La Paz Institute for Health Research, IdiPAZ, University Hospital La Paz, Madrid, Spain
- Department of Pediatrics, Faculty of Medicine, Universidad Autónoma de Madrid, Madrid, Spain
| | - Carlos Solano
- Hematology Service, Hospital Clínico Universitario, Fundación para la Investigación del Hospital Clínico de la Comunidad Valenciana (INCLIVA), Valencia, Spain
| | - Bernat Soria
- Alicante Institute for Health and Biomedical Research (ISABIAL), Alicante, Spain
- Institute of Bioengineering, Miguel Hernández University, Elche, Spain
- Biomedical Research Network for Diabetes and Related Metabolic Diseases-Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM) of the Carlos III Health Institute (ISCIII), Madrid, Spain
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Samanipour R, Tabatabaee S, delyanee M, Tavakoli A. The promising approach of MSCs therapy for COVID-19 treatment. Cell Tissue Bank 2023; 24:597-612. [PMID: 36526819 PMCID: PMC9757632 DOI: 10.1007/s10561-022-10060-2] [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: 10/30/2021] [Accepted: 12/04/2022] [Indexed: 12/23/2022]
Abstract
Several ongoing investigations have been founded on the development of an optimized therapeutic strategy for the COVID-19 virus as an undeniable acute challenge for human life. Cell-based therapy and particularly, mesenchymal stem cells (MSCs) therapy has obtained desired outcomes in decreasing the mortality rate of severe acute respiratory syndrome coronavirus 2 (SARS-COV-2), mainly owing to its immunoregulatory impact that prevents the overactivation of the immune system. Also, these cells with their multipotent nature, are capable of repairing the damaged tissue of the lung which leads to reducing the probability of acute respiratory distress syndrome (ARDS). Although this cell-based method is not quite cost-effective for developing countries, regarding its promising results in order to treat SARS-COV-2, more economical evaluation as well as clinical trials should be performed for improving this therapeutic approach. Here in this article, the functional mechanism of MSCs therapy for the treatment of COVID-19 and the clinical trials based on this method will be reviewed. Moreover, its economic efficiency will be discussed.
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Affiliation(s)
- Reza Samanipour
- Department of Tissue Engineering and Applied Sciences, School of Advanced Technologies in Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Sara Tabatabaee
- Department of Bio-Computing, Faculty of Interdisciplinary Sciences and Technologies, Tarbiat Modares University, Tehran, Iran
| | - Mahsa delyanee
- Biomedical Engineering Department, Amirkabir University of Technology, Tehran, Iran
| | - Amirhossein Tavakoli
- Iranian Tissue Bank and Research Center, Tehran University of Medical Sciences, Tehran, Iran
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9
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Zanier ER, Pischiutta F, Rulli E, Vargiolu A, Elli F, Gritti P, Gaipa G, Belotti D, Basso G, Zoerle T, Stocchetti N, Citerio G. MesenchymAl stromal cells for Traumatic bRain Injury (MATRIx): a study protocol for a multicenter, double-blind, randomised, placebo-controlled phase II trial. Intensive Care Med Exp 2023; 11:56. [PMID: 37620640 PMCID: PMC10449745 DOI: 10.1186/s40635-023-00535-1] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2023] [Accepted: 07/07/2023] [Indexed: 08/26/2023] Open
Abstract
BACKGROUND Traumatic brain injury (TBI) is a significant cause of death and disability, with no effective neuroprotective drugs currently available for its treatment. Mesenchymal stromal cell (MSC)-based therapy shows promise as MSCs release various soluble factors that can enhance the injury microenvironment through processes, such as immunomodulation, neuroprotection, and brain repair. Preclinical studies across different TBI models and severities have demonstrated that MSCs can improve functional and structural outcomes. Moreover, clinical evidence supports the safety of third-party donor bank-stored MSCs in adult subjects. Building on this preclinical and clinical data, we present the protocol for an academic, investigator-initiated, multicenter, double-blind, randomised, placebo-controlled, adaptive phase II dose-finding study aiming to evaluate the safety and efficacy of intravenous administration of allogeneic bone marrow-derived MSCs to severe TBI patients within 48 h of injury. METHODS/DESIGN The study will be conducted in two steps. Step 1 will enrol 42 patients, randomised in a 1:1:1 ratio to receive 80 million MSCs, 160 million MSCs or a placebo to establish safety and identify the most promising dose. Step 2 will enrol an additional 36 patients, randomised in a 1:1 ratio to receive the selected dose of MSCs or placebo. The activity of MSCs will be assessed by quantifying the plasmatic levels of neurofilament light (NfL) at 14 days as a biomarker of neuronal damage. It could be a significant breakthrough if the study demonstrates the safety and efficacy of MSC-based therapy for severe TBI patients. The results of this trial could inform the design of a phase III clinical trial aimed at establishing the efficacy of the first neurorestorative therapy for TBI. DISCUSSION Overall, the MATRIx trial is a critical step towards developing an effective treatment for TBI, which could significantly improve the lives of millions worldwide affected by this debilitating condition. Trial Registration EudraCT: 2022-000680-49.
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Affiliation(s)
- Elisa R Zanier
- Department of Acute Brain and Cardiovascular Injury, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Milan, Italy
| | - Francesca Pischiutta
- Department of Acute Brain and Cardiovascular Injury, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Milan, Italy
| | - Eliana Rulli
- Department of Clinical Oncology, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Milan, Italy
| | - Alessia Vargiolu
- School of Medicine and Surgery, University of Milano-Bicocca, Milan, Italy
| | - Francesca Elli
- Neurological Intensive Care Unit, Department of Neurosciences, Fondazione IRCCS San Gerardo dei Tintori, Monza, Italy
| | - Paolo Gritti
- Department of Anesthesia, Emergency and Critical Care Medicine, ASST Ospedale Papa Giovanni XXIII, Bergamo, Italy
| | - Giuseppe Gaipa
- M. Tettamanti Research Center, Fondazione IRCCS San Gerardo dei Tintori, Monza, Italy
| | - Daniela Belotti
- M. Tettamanti Research Center, Fondazione IRCCS San Gerardo dei Tintori, Monza, Italy
| | - Gianpaolo Basso
- School of Medicine and Surgery, University of Milano-Bicocca, Milan, Italy
- Department of Neurosciences, Neuroradiology, Fondazione IRCCS San Gerardo dei Tintori, Monza, Italy
| | - Tommaso Zoerle
- Neuroscience Intensive Care Unit, Department of Anaesthesia and Critical Care, Fondazione IRCCS Ca' Granda-Ospedale Maggiore Policlinico, Milan, Italy
- Department of Pathophysiology and Transplants, University of Milan, Milan, Italy
| | - Nino Stocchetti
- Neuroscience Intensive Care Unit, Department of Anaesthesia and Critical Care, Fondazione IRCCS Ca' Granda-Ospedale Maggiore Policlinico, Milan, Italy
- Department of Pathophysiology and Transplants, University of Milan, Milan, Italy
| | - Giuseppe Citerio
- School of Medicine and Surgery, University of Milano-Bicocca, Milan, Italy.
- Neurological Intensive Care Unit, Department of Neurosciences, Fondazione IRCCS San Gerardo dei Tintori, Monza, Italy.
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10
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Perez JA, Parcero Valdes JJ, Corral Moreno R, Gomez Cuevas LI, Lopez JJ, Ichim T, McGreevy K, Lin F, Kesari S, Datta S. Intravenous Administration of Umbilical Cord-Derived Mesenchymal Stem Cells (UC-MSC) for Acute Respiratory Distress Syndrome Due to COVID-19 Infection. Cureus 2023; 15:e44110. [PMID: 37638263 PMCID: PMC10452932 DOI: 10.7759/cureus.44110] [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] [Accepted: 08/25/2023] [Indexed: 08/29/2023] Open
Abstract
The COVID-19 pandemic has posed significant therapeutic challenges in addressing acute respiratory distress syndrome (ARDS). This serious illness has caused numerous fatalities worldwide and has had profound health and economic impacts. Previous studies have shown that mesenchymal stem cells (MSCs) can suppress ARDS. In this case series, we report on the treatment of nine patients with a single intravenous dose of 100 million hypoxic cultured umbilical cord-derived MSCs (UC-MSCs). Following the intravenous administration of UC-MSCs, obtained from the lining of the umbilical cord, longitudinal laboratory analysis revealed a sustained decrease in inflammatory markers and stabilized pulmonary function in eight out of nine patients. UC-MSCs possess immunomodulatory and anti-inflammatory properties, enabling them to attenuate the cytokine storm and potentially aid in lung repair. Importantly, no adverse events associated with the treatment were observed. These findings collectively suggest that a cell-based approach significantly enhances the survival rate of ARDS induced by SARS-CoV-2 and offers a promising treatment option in both preclinical and clinical settings.
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Affiliation(s)
- Jesus A Perez
- Medicine, Instituto de Medicina Regenerativa SA de CV, Tijuana, MEX
| | | | | | | | - Jose J Lopez
- Neurology, Instituto de Medicina Regenerativa SA de CV, Tijuana, MEX
| | - Thomas Ichim
- Immunology, CureScience Institute, San Diego, USA
| | - Kristen McGreevy
- Clinical Sciences, Pacific Neuroscience Institute, Santa Monica, USA
| | - Feng Lin
- Research and Development, CureScience Institute, San Diego, USA
| | - Santosh Kesari
- Translational Neurosciences, Pacific Neuroscience Institute, Santa Monica, USA
| | - Souvik Datta
- Clinical Research, Rhenix Lifesciences, Hyderabad, IND
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11
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Couto PS, Al-Arawe N, Filgueiras IS, Fonseca DLM, Hinterseher I, Catar RA, Chinnadurai R, Bersenev A, Cabral-Marques O, Moll G, Verter F. Systematic review and meta-analysis of cell therapy for COVID-19: global clinical trial landscape, published safety/efficacy outcomes, cell product manufacturing and clinical delivery. Front Immunol 2023; 14:1200180. [PMID: 37415976 PMCID: PMC10321603 DOI: 10.3389/fimmu.2023.1200180] [Citation(s) in RCA: 15] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2023] [Accepted: 05/24/2023] [Indexed: 07/08/2023] Open
Abstract
During the pandemic of severe respiratory distress syndrome coronavirus 2 (SARS-CoV2), many novel therapeutic modalities to treat Coronavirus 2019 induced disease (COVID-19) were explored. This study summarizes 195 clinical trials of advanced cell therapies targeting COVID-19 that were registered over the two years between January 2020 to December 2021. In addition, this work also analyzed the cell manufacturing and clinical delivery experience of 26 trials that published their outcomes by July 2022. Our demographic analysis found the highest number of cell therapy trials for COVID-19 was in United States, China, and Iran (N=53, 43, and 19, respectively), with the highest number per capita in Israel, Spain, Iran, Australia, and Sweden (N=0.641, 0.232, 0,223, 0.194, and 0.192 trials per million inhabitants). The leading cell types were multipotent mesenchymal stromal/stem cells (MSCs), natural killer (NK) cells, and mononuclear cells (MNCs), accounting for 72%, 9%, and 6% of the studies, respectively. There were 24 published clinical trials that reported on infusions of MSCs. A pooled analysis of these MSC studies found that MSCs provide a relative risk reduction for all-cause COVID-19 mortality of RR=0.63 (95% CI 0.46 to 0.85). This result corroborates previously published smaller meta-analyses, which suggested that MSC therapy demonstrated a clinical benefit for COVID-19 patients. The sources of the MSCs used in these studies and their manufacturing and clinical delivery methods were remarkably heterogeneous, with some predominance of perinatal tissue-derived products. Our results highlight the important role that cell therapy products may play as an adjunct therapy in the management of COVID-19 and its related complications, as well as the importance of controlling key manufacturing parameters to ensure comparability between studies. Thus, we support ongoing calls for a global registry of clinical studies with MSC products that could better link cell product manufacturing and delivery methods to clinical outcomes. Although advanced cell therapies may provide an important adjunct treatment for patients affected by COVID-19 in the near future, preventing pathology through vaccination still remains the best protection to date. We conducted a systematic review and meta-analysis of advanced cell therapy clinical trials as potential novel treatment for COVID-19 (resulting from SARS-CoV-2 coronavirus infection), including analysis of the global clinical trial landscape, published safety/efficacy outcomes (RR/OR), and details on cell product manufacturing and clinical delivery. This study had a 2-year observation interval from start of January 2020 to end of December 2021, including a follow-up period until end of July to identify published outcomes, which covers the most vivid period of clinical trial activity, and is also the longest observation period studied until today. In total, we identified 195 registered advanced cell therapy studies for COVID-19, employing 204 individual cell products. Leading registered trial activity was attributed to the USA, China, and Iran. Through the end of July 2022, 26 clinical trials were published, with 24 out of 26 articles employing intravenous infusions (IV) of mesenchymal stromal/stem cell (MSC) products. Most of the published trials were attributed to China and Iran. The cumulative results from the 24 published studies employing infusions of MSCs indicated an improved survival (RR=0.63 with 95% Confidence Interval 0.46 to 0.85). Our study is the most comprehensive systematic review and meta-analysis on cell therapy trials for COVID-19 conducted to date, clearly identifying the USA, China, and Iran as leading advanced cell therapy trial countries for COVID-19, with further strong contributions from Israel, Spain, Australia and Sweden. Although advanced cell therapies may provide an important adjunct treatment for patients affected by COVID-19 in the future, preventing pathology through vaccination remains the best protection.
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Affiliation(s)
- Pedro S. Couto
- Department of Biochemical Engineering, Advanced Centre for Biochemical Engineering, University College London, London, United Kingdom
- CellTrials.org and Parent’s Guide to Cord Blood Foundation, a non-profit organization headquartered in Brookeville, Brookeville, MD, United States
| | - Nada Al-Arawe
- Department of Nephrology and Internal Intensive Care Medicine, Charité Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, Berlin Institute of Health (BIH), Berlin, Germany
- Vascular Surgery Clinic, Charité Universitätsmedizin Berlin, Berlin, Germany
| | - Igor S. Filgueiras
- Department of Immunology, Institute of Biomedical Sciences, University of São Paulo (USP), São Paulo, SP, Brazil
| | - Dennyson L. M. Fonseca
- Interunit Postgraduate Program on Bioinformatics, Institute of Mathematics and Statistics (IME), University of São Paulo (USP), São Paulo, SP, Brazil
| | - Irene Hinterseher
- Vascular Surgery Clinic, Charité Universitätsmedizin Berlin, Berlin, Germany
- Department of Vascular Surgery, Universitätsklinikum Ruppin-Brandenburg, Medizinische Hochschule Brandenburg Theodor Fontane, Neuruppin, Germany
- Fakultät der Gesundheitswissenschaften Brandenburg, Gemeinsame Fakultät der Universität Potsdam, der Medizinischen Hochschule Brandenburg Theodor Fontane, und der Brandenburg Technischen Universität (BTU) Cottbus-Senftenberg, Potsdam, Germany
| | - Rusan A. Catar
- Department of Nephrology and Internal Intensive Care Medicine, Charité Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, Berlin Institute of Health (BIH), Berlin, Germany
| | - Raghavan Chinnadurai
- Department of Biomedical Sciences, Mercer University School of Medicine, Savannah, GA, United States
| | - Alexey Bersenev
- Advanced Cell Therapy (ACT) Laboratory, Yale School of Medicine, New Haven, CT, United States
| | - Otávio Cabral-Marques
- Department of Immunology, Institute of Biomedical Sciences, University of São Paulo (USP), São Paulo, SP, Brazil
- Interunit Postgraduate Program on Bioinformatics, Institute of Mathematics and Statistics (IME), University of São Paulo (USP), São Paulo, SP, Brazil
- Department of Clinical and Toxicological Analyses, School of Pharmaceutical Sciences, University of São Paulo (USP), São Paulo, SP, Brazil
- Department of Pharmacy and Postgraduate Program of Health and Science, Federal University of Rio Grande do Norte, Natal, Brazil
- Department of Medicine, Division of Molecular Medicine, University of São Paulo School of Medicine, São Paulo, Brazil
- Laboratory of Medical Investigation 29, University of São Paulo School of Medicine, São Paulo, Brazil
| | - Guido Moll
- Department of Nephrology and Internal Intensive Care Medicine, Charité Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, Berlin Institute of Health (BIH), Berlin, Germany
- Berlin Institute of Health (BIH) Center for Regenerative Therapies (BCRT), Charité - Universitätsmedizin Berlin, Berlin, Germany
| | - Frances Verter
- CellTrials.org and Parent’s Guide to Cord Blood Foundation, a non-profit organization headquartered in Brookeville, Brookeville, MD, United States
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12
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Mattoli S, Schmidt M. Investigational Use of Mesenchymal Stem/Stromal Cells and Their Secretome as Add-On Therapy in Severe Respiratory Virus Infections: Challenges and Perspectives. Adv Ther 2023; 40:2626-2692. [PMID: 37069355 PMCID: PMC10109238 DOI: 10.1007/s12325-023-02507-z] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2022] [Accepted: 03/24/2023] [Indexed: 04/19/2023]
Abstract
Serious manifestations of respiratory virus infections such as influenza and coronavirus disease 2019 (COVID-19) are associated with a dysregulated immune response and systemic inflammation. Treating the immunological/inflammatory dysfunction with glucocorticoids, Janus kinase inhibitors, and monoclonal antibodies against the interleukin-6 receptor has significantly reduced the risk of respiratory failure and death in hospitalized patients with severe COVID-19, but the proportion of those requiring invasive mechanical ventilation (IMV) and dying because of respiratory failure remains elevated. Treatment of severe influenza-associated pneumonia and acute respiratory distress syndrome (ARDS) with available immunomodulators and anti-inflammatory compounds is still not recommended. New therapies are therefore needed to reduce the use of IMV and the risk of death in hospitalized patients with rapidly increasing oxygen demand and systemic inflammation who do not respond to the current standard of care. This paper provides a critical assessment of the published clinical trials that have tested the investigational use of intravenously administered allogeneic mesenchymal stem/stromal cells (MSCs) and MSC-derived secretome with putative immunomodulatory/antiinflammatory/regenerative properties as add-on therapy to improve the outcome of these patients. Increased survival rates are reported in 5 of 12 placebo-controlled or open-label comparative trials involving patients with severe and critical COVID-19 and in the only study concerning patients with influenza-associated ARDS. Results are encouraging but inconclusive for the following reasons: small number of patients tested in each trial; differences in concomitant treatments and respiratory support; imbalances between study arms; differences in MSC source, MSC-derived product, dosing and starting time of the investigational therapy; insufficient/inappropriate reporting of clinical data. Solutions are proposed for improving the clinical development plan, with the aim of facilitating regulatory approval of the MSC-based investigational therapy for life-threatening respiratory virus infections in the future. Major issues are the absence of a biomarker predicting responsiveness to MSCs and MSC-derived secretome and the lack of pharmacoeconomic evaluations.
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Affiliation(s)
- Sabrina Mattoli
- Center of Expertise in Research and Innovation of the International Network for the Advancement of Viable and Applicable Innovations in Life Sciences (InAvail), InAvail at Rosental Nexxt, 4058 Basel, Switzerland
- Avail Biomedical Research Institute, 80539 Munich, Germany
| | - Matthias Schmidt
- Avail Biomedical Research Institute, 80539 Munich, Germany
- Discovery and Translational Research Center, 80539 Munich, Germany
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13
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Liu Q, Ma F, Zhong Y, Wang G, Hu L, Zhang Y, Xie J. Efficacy and safety of human umbilical cord-derived mesenchymal stem cells for COVID-19 pneumonia: a meta-analysis of randomized controlled trials. Stem Cell Res Ther 2023; 14:118. [PMID: 37143167 PMCID: PMC10159228 DOI: 10.1186/s13287-023-03286-8] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2022] [Accepted: 03/16/2023] [Indexed: 05/06/2023] Open
Abstract
BACKGROUND Elevated levels of inflammatory factors are associated with poor prognosis in coronavirus disease-19 (COVID-19). However, mesenchymal stem cells (MSCs) have immunomodulatory functions. Accordingly, this meta-analysis aimed to determine the efficacy and safety of MSC-based therapy in patients with COVID-19 pneumonia. METHODS Online global databases were used to find relevant studies. Two independent researchers then selected and evaluated the studies for suitability while the Cochrane risk of bias tool determined the quality of all articles and Cochran's Q test and I2 index assessed the degree of heterogeneity in the principal studies. Statistical analysis was performed using Review Manager software, and the effect of each study on the overall estimate was evaluated by sensitivity analysis. RESULTS Seven studies were included in the meta-analysis, and all MSCs used in the trials were acquired from the umbilical cord. The results of these studies (n = 328) indicated that patients with COVID-19 pneumonia who received MSCs had a 0.58 risk of death compared with controls (95% CI = 0.38, 0.87; P = 0.53; I2 = 0%). In terms of inflammatory biomarkers, MSCs reduced the levels of C-reactive protein (n = 88; MD = - 32.49; 95% CI = - 48.43, - 16.56; P = 0.46; I2 = 0%) and interferon-gamma (n = 44; SMD = - 1.23; 95% CI = - 1.89, - 0.57; P = 0.37; I2 = 0%) in severe COVID-19 patients but had no significant effect on interleukin-6 (n = 185; MD = - 0.75; 95% CI = - 7.76, 6.27; P = 0.57; I2 = 0%). A summary of the data revealed no significant differences in adverse events (n = 287) or serious adverse events (n = 229) between the MSC and control groups. CONCLUSIONS Infusion of umbilical cord-derived MSCs is an effective strategy for treating patients with COVID-19 pneumonia, with no noticeable adverse effects.
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Affiliation(s)
- Qinxue Liu
- Department of Anesthesiology, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, No.3 East Qingchun Road, Jianggan District, Hangzhou, 310016, China
| | - Fengjie Ma
- Department of Anesthesiology, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, No.3 East Qingchun Road, Jianggan District, Hangzhou, 310016, China
| | - Yizhi Zhong
- Department of Anesthesiology, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, No.3 East Qingchun Road, Jianggan District, Hangzhou, 310016, China
| | - Gaojian Wang
- Department of Anesthesiology, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, No.3 East Qingchun Road, Jianggan District, Hangzhou, 310016, China
| | - Li Hu
- Department of Anesthesiology, Second Affiliated Hospital of Jiaxing University, No.1518 North Huancheng Road, Nanhu District, Jiaxing, 314000, China
| | - Yaping Zhang
- Department of Anesthesiology, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, No.3 East Qingchun Road, Jianggan District, Hangzhou, 310016, China
| | - Junran Xie
- Department of Anesthesiology, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, No.3 East Qingchun Road, Jianggan District, Hangzhou, 310016, China.
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14
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Lian J, Zhu X, Du J, Huang B, Zhao F, Ma C, Guo R, Zhang Y, Ji L, Yahaya BH, Lin J. Extracellular vesicle-transmitted miR-671-5p alleviates lung inflammation and injury by regulating the AAK1/NF-κB axis. Mol Ther 2023; 31:1365-1382. [PMID: 36733250 PMCID: PMC10188640 DOI: 10.1016/j.ymthe.2023.01.025] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2022] [Revised: 01/08/2023] [Accepted: 01/29/2023] [Indexed: 02/04/2023] Open
Abstract
Mesenchymal stem cells regulate remote intercellular signaling communication via their secreted extracellular vesicles. Here, we report that menstrual blood-derived stem cells alleviate acute lung inflammation and injury via their extracellular vesicle-transmitted miR-671-5p. Disruption of this abundantly expressed miR-671-5p dramatically reduced the ameliorative effect of extracellular vesicles released by menstrual blood-derived stem cells on lipopolysaccharide (LPS)-induced pulmonary inflammatory injury. Mechanistically, miR-671-5p directly targets the kinase AAK1 for post-transcriptional degradation. AAK1 is found to positively regulate the activation of nuclear factor κB (NF-κB) signaling by controlling the stability of the inhibitory protein IκBα. This study identifies a potential molecular basis of how extracellular vesicles derived from mesenchymal stem cells improve pulmonary inflammatory injury and highlights the functional importance of the miR-671-5p/AAK1 axis in the progression of pulmonary inflammatory diseases. More importantly, this study provides a promising cell-based approach for the treatment of pulmonary inflammatory disorders through an extracellular vesicle-dependent pathway.
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Affiliation(s)
- Jie Lian
- Henan Joint International Research Laboratory of Stem Cell Medicine, School of Medical Engineering, Xinxiang Medical University, Xinxiang 453003, China; Lung Stem Cells and Gene Therapy Group, Department of Biomedical Sciences, Advanced Medical and Dental Institute (AMDI), Universiti Sains Malaysia, SAINS@Bertam, 13200 Kepala Batas, Penang, Malaysia; Stem Cells and Biotherapy Engineering Research Center of Henan, National Joint Engineering Laboratory of Stem Cells and Biotherapy, School of Life Science and Technology, Xinxiang Medical University, Xinxiang 453003, China
| | - Xinxing Zhu
- Henan Joint International Research Laboratory of Stem Cell Medicine, School of Medical Engineering, Xinxiang Medical University, Xinxiang 453003, China.
| | - Jiang Du
- Henan Joint International Research Laboratory of Stem Cell Medicine, School of Medical Engineering, Xinxiang Medical University, Xinxiang 453003, China
| | - Beijia Huang
- Henan Joint International Research Laboratory of Stem Cell Medicine, School of Medical Engineering, Xinxiang Medical University, Xinxiang 453003, China
| | - Fengting Zhao
- Henan Joint International Research Laboratory of Stem Cell Medicine, School of Medical Engineering, Xinxiang Medical University, Xinxiang 453003, China
| | - Chunya Ma
- Henan Joint International Research Laboratory of Stem Cell Medicine, School of Medical Engineering, Xinxiang Medical University, Xinxiang 453003, China
| | - Rui Guo
- Henan Joint International Research Laboratory of Stem Cell Medicine, School of Medical Engineering, Xinxiang Medical University, Xinxiang 453003, China
| | - Yangxia Zhang
- Henan Joint International Research Laboratory of Stem Cell Medicine, School of Medical Engineering, Xinxiang Medical University, Xinxiang 453003, China
| | - Longkai Ji
- Henan Joint International Research Laboratory of Stem Cell Medicine, School of Medical Engineering, Xinxiang Medical University, Xinxiang 453003, China
| | - Badrul Hisham Yahaya
- Lung Stem Cells and Gene Therapy Group, Department of Biomedical Sciences, Advanced Medical and Dental Institute (AMDI), Universiti Sains Malaysia, SAINS@Bertam, 13200 Kepala Batas, Penang, Malaysia.
| | - Juntang Lin
- Henan Joint International Research Laboratory of Stem Cell Medicine, School of Medical Engineering, Xinxiang Medical University, Xinxiang 453003, China; Stem Cells and Biotherapy Engineering Research Center of Henan, National Joint Engineering Laboratory of Stem Cells and Biotherapy, School of Life Science and Technology, Xinxiang Medical University, Xinxiang 453003, China.
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15
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Weiss DJ. What is the need and why is it time for innovative models for understanding lung repair and regeneration? Front Pharmacol 2023; 14:1130074. [PMID: 36860303 PMCID: PMC9968746 DOI: 10.3389/fphar.2023.1130074] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2022] [Accepted: 01/23/2023] [Indexed: 02/15/2023] Open
Abstract
Advances in tissue engineering continue at a rapid pace and have provided novel methodologies and insights into normal cell and tissue homeostasis, disease pathogenesis, and new potential therapeutic strategies. The evolution of new techniques has particularly invigorated the field and span a range from novel organ and organoid technologies to increasingly sophisticated imaging modalities. This is particularly relevant for the field of lung biology and diseases as many lung diseases, including chronic obstructive pulmonary disease (COPD) and idiopathic fibrosis (IPF), among others, remain incurable with significant morbidity and mortality. Advances in lung regenerative medicine and engineering also offer new potential avenues for critical illnesses such as the acute respiratory distress syndrome (ARDS) which also continue to have significant morbidity and mortality. In this review, an overview of lung regenerative medicine with focus on current status of both structural and functional repair will be presented. This will serve as a platform for surveying innovative models and techniques for study, highlighting the need and timeliness for these approaches.
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16
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Li Y, Wei Z, Ma X, Xu J, Zhao X, Cao Q, Di G. Efficacy and Safety of Mesenchymal Stromal Cells Therapy for COVID-19 Infection: A Systematic Review and Meta-analysis. Curr Stem Cell Res Ther 2023; 18:143-152. [PMID: 34872483 DOI: 10.2174/1574888x16666211206145839] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2021] [Revised: 08/30/2021] [Accepted: 09/14/2021] [Indexed: 11/22/2022]
Abstract
BACKGROUND Coronavirus disease 2019 (COVID-19) is an infectious respiratory disease prevalent worldwide with a high mortality rate, and there is currently no specific medicine to treat patients. OBJECTIVE We aimed to assess the safety and efficacy of stem cell therapy for COVID-19 by providing references for subsequent clinical treatments and trials. METHOD We systematically searched PubMed, Embase, Cochrane, and Web of Science, using the following keywords: "stem cell" or "stromal cell" and "COVID-19." Controlled clinical trials published in English until 24th August 2021 were included. We followed the PRISMA guidelines and used Cochrane Collaboration's tool for assessing the risk of bias. We analysed the data using a fixed-effect model. RESULTS We identified 1779 studies, out of which eight were eligible and included in this study. Eight relevant studies consisted of 156 patients treated with stem cells and 144 controls (300 individuals in total). There were no SAEs associated with stem cell therapy in all six studies, and no significant differences in AEs (p = 0.09, I2 = 40%, OR = 0.53, 95% CI: 0.26 to 1.09) between the experimental group and control group were observed. Moreover, the meta-analysis found that stem cell therapy effectively reduced the high mortality rate of COVID-19 (14/156 vs. 43/144; p<0.0001, I2 = 0%, OR=0.18, 95% CI: 0.08 to 0.41). CONCLUSION This study suggests that MSCs therapy for COVID-19 has shown some promising results in safety and efficacy. It effectively reduces the high mortality rate of COVID-19 and does not increase the incidence of adverse events.
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Affiliation(s)
- Yaxin Li
- School of Basic Medicine, Qingdao University, Qingdao, China
| | - Ziyang Wei
- School of Basic Medicine, Qingdao University, Qingdao, China
| | - Xinyu Ma
- School of Basic Medicine, Qingdao University, Qingdao, China
| | - Jing Xu
- School of Basic Medicine, Qingdao University, Qingdao, China
| | - Xia Zhao
- Department of Hematology, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Qilong Cao
- Qingdao Haier Biotech Co. Ltd., Qingdao, China
| | - Guohu Di
- School of Basic Medicine, Qingdao University, Qingdao, China
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Sharun K, Tiwari R, Yatoo MI, Natesan S, Megawati D, Singh KP, Michalak I, Dhama K. A comprehensive review on pharmacologic agents, immunotherapies and supportive therapeutics for COVID-19. NARRA J 2022; 2:e92. [PMID: 38449903 PMCID: PMC10914132 DOI: 10.52225/narra.v2i3.92] [Citation(s) in RCA: 27] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/10/2022] [Accepted: 12/06/2022] [Indexed: 03/08/2024]
Abstract
The emergence of coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has affected many countries throughout the world. As urgency is a necessity, most efforts have focused on identifying small molecule drugs that can be repurposed for use as anti-SARS-CoV-2 agents. Although several drug candidates have been identified using in silico method and in vitro studies, most of these drugs require the support of in vivo data before they can be considered for clinical trials. Several drugs are considered promising therapeutic agents for COVID-19. In addition to the direct-acting antiviral drugs, supportive therapies including traditional Chinese medicine, immunotherapies, immunomodulators, and nutritional therapy could contribute a major role in treating COVID-19 patients. Some of these drugs have already been included in the treatment guidelines, recommendations, and standard operating procedures. In this article, we comprehensively review the approved and potential therapeutic drugs, immune cells-based therapies, immunomodulatory agents/drugs, herbs and plant metabolites, nutritional and dietary for COVID-19.
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Affiliation(s)
- Khan Sharun
- Division of Surgery, ICAR-Indian Veterinary Research Institute, Izatnagar, India
| | - Ruchi Tiwari
- Department of Veterinary Microbiology and Immunology, College of Veterinary Sciences, UP Pandit Deen Dayal Upadhayay Pashu Chikitsa Vigyan Vishwavidyalay Evum Go-Anusandhan Sansthan (DUVASU), Mathura, India
| | - Mohd I. Yatoo
- Division of Veterinary Clinical Complex, Faculty of Veterinary Sciences and Animal Husbandry, Shuhama, Alusteng Srinagar, Sher-E-Kashmir University of Agricultural Sciences and Technology of Kashmir, Shalimar, Jammu and Kashmir, India
| | - Senthilkumar Natesan
- Department of Infectious Diseases, Indian Institute of Public Health Gandhinagar, Opp to Airforce station HQ, Gandhinagar, India
| | - Dewi Megawati
- Department of Microbiology and Parasitology, Faculty of Medicine and Health Sciences, Warmadewa University, Denpasar, Indonesia
- Department of Medical Microbiology and Immunology, University of California, Davis, California, USA
| | - Karam P. Singh
- Division of Pathology, ICAR-Indian Veterinary Research Institute, Izatnagar, India
| | - Izabela Michalak
- Faculty of Chemistry, Department of Advanced Material Technologies, Wrocław University of Science and Technology, Wrocław, Poland
| | - Kuldeep Dhama
- Division of Pathology, ICAR-Indian Veterinary Research Institute, Izatnagar, India
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18
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Cao JX, You J, Wu LH, Luo K, Wang ZX. Clinical efficacy analysis of mesenchymal stem cell therapy in patients with COVID-19: A systematic review. World J Clin Cases 2022; 10:9714-9726. [PMID: 36186213 PMCID: PMC9516915 DOI: 10.12998/wjcc.v10.i27.9714] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/14/2022] [Revised: 06/26/2022] [Accepted: 08/21/2022] [Indexed: 02/05/2023] Open
Abstract
BACKGROUND Currently, ongoing trials of mesenchymal stem cells (MSC) therapies for coronavirus disease 2019 (COVID-19) have been reported.
AIM In this study, we investigated whether MSCs have therapeutic efficacy in novel COVID-19 patients.
METHODS Search terms included stem cell, MSC, umbilical cord blood, novel coronavirus, severe acute respiratory syndrome coronavirus-2 and COVID-19, applied to PubMed, the Cochrane Controlled Trials Register, EMBASE and Web of Science.
RESULTS A total of 13 eligible clinical trials met our inclusion criteria with a total of 548 patients. The analysis showed no significant decrease in C-reactive protein (CRP) levels after stem cell therapy (P = 0.11). A reduction of D-dimer levels was also not observed in patients after stem cell administration (P = 0.82). Furthermore, interleukin 6 (IL-6) demonstrated no decrease after stem cell therapy (P = 0.45). Finally, we investigated the overall survival (OS) rate after stem cell therapy in COVID-19 patients. There was a significant improvement in OS after stem cell therapy; the OS of enrolled patients who received stem cell therapy was 90.3%, whereas that of the control group was 79.8% (P = 0.02).
CONCLUSION Overall, our analysis suggests that while MSC therapy for COVID-19 patients does not significantly decrease inflammatory markers such as CRP, D-dimer and IL-6, OS is improved.
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Affiliation(s)
- Jun-Xia Cao
- Biotherapy Center, The Seventh Medical Center of People's Liberation Army General Hospital, Beijing 100700, China
| | - Jia You
- Biotherapy Center, The Seventh Medical Center of People's Liberation Army General Hospital, Beijing 100700, China
| | - Li-Hua Wu
- Biotherapy Center, The Seventh Medical Center of People's Liberation Army General Hospital, Beijing 100700, China
| | - Kai Luo
- Biotherapy Center, The Seventh Medical Center of People's Liberation Army General Hospital, Beijing 100700, China
| | - Zheng-Xu Wang
- Biotherapy Center, The Seventh Medical Center of People's Liberation Army General Hospital, Beijing 100700, China
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19
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Battaglini D, Cruz F, Robba C, Pelosi P, Rocco PRM. Failed clinical trials on COVID-19 acute respiratory distress syndrome in hospitalized patients: common oversights and streamlining the development of clinically effective therapeutics. Expert Opin Investig Drugs 2022; 31:995-1015. [PMID: 36047644 DOI: 10.1080/13543784.2022.2120801] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/18/2023]
Abstract
INTRODUCTION The coronavirus disease 2019 (COVID-19) pandemic has put a strain on global healthcare systems. Despite admirable efforts to develop rapidly new pharmacotherapies, supportive treatments remain the standard of care. Multiple clinical trials have failed due to design issues, biased patient enrollment, small sample sizes, inadequate control groups, and lack of long-term outcomes monitoring. AREAS COVERED This narrative review depicts the current situation around failed and success COVID-19 clinical trials and recommendations in hospitalized patients with COVID-19, oversights and streamlining of clinically effective therapeutics. PubMed, EBSCO, Cochrane Library, and WHO and NIH guidelines were searched for relevant literature up to 5 August 2022. EXPERT OPINION The WHO, NIH, and IDSA have issued recommendations to better clarify which drugs should be used during the different phases of the disease. Given the biases and high heterogeneity of published studies, interpretation of the current literature is difficult. Future clinical trials should be designed to standardize clinical approaches, with appropriate organization, patient selection, addition of control groups, and careful identification of disease phase to reduce heterogeneity and bias and should rely on the integration of scientific societies to promote a consensus on interpretation of the data and recommendations for optimal COVID-19 therapies.
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Affiliation(s)
- Denise Battaglini
- Dipartimento di Anestesia e Rianimazione, Policlinico San Martino, IRCCS per l'Oncologia e le Neuroscienze, Genoa, Italy
| | - Fernanda Cruz
- Laboratory of Pulmonary Investigation, Carlos Chagas Filho Institute of Biophysics, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil
| | - Chiara Robba
- Policlinico San Martino, IRCCS per l'Oncologia e Neuroscienze, Dipartimento di Scienze Chirurgiche e Diagnostiche Integrate, Università degli Studi di Genova, Genoa, Italy
| | - Paolo Pelosi
- Dipartimento di Anestesia e Rianimazione, Policlinico San Martino, IRCCS per l'Oncologia e le Neuroscienze, Genoa, Italy.,Policlinico San Martino, IRCCS per l'Oncologia e Neuroscienze, Dipartimento di Scienze Chirurgiche e Diagnostiche Integrate, Università degli Studi di Genova, Genoa, Italy
| | - Patricia R M Rocco
- Laboratory of Pulmonary Investigation, Carlos Chagas Filho Institute of Biophysics, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil.,COVID-19 Virus Network from Ministry of Science, Technology, and Innovation, Brazilian Council for Scientific and Technological Development, and Foundation Carlos Chagas Filho Research Support of the State of Rio de Janeiro, Rio de Janeiro, Brazil
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20
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Gentile P. Hair Loss and Telogen Effluvium Related to COVID-19: The Potential Implication of Adipose-Derived Mesenchymal Stem Cells and Platelet-Rich Plasma as Regenerative Strategies. Int J Mol Sci 2022; 23:9116. [PMID: 36012383 PMCID: PMC9409133 DOI: 10.3390/ijms23169116] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2022] [Revised: 08/09/2022] [Accepted: 08/12/2022] [Indexed: 11/16/2022] Open
Abstract
The diffusion of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) inducing coronavirus disease 2019 (COVID-19) has increased the incidence of several dermatological disorders, including hair loss (HL). This article aims to review the literature regarding the incidence of HL and telogen effluvium (TE) in COVID-19 patients and critically appraise the available evidence regarding the role of regenerative strategies like Platelet-Rich Plasma (PRP) and Human Follicle Stem Cells (HFSCs). A literature review regarding the correlation of HL and TE in COVID-19 patients analyzing the biomolecular pathway involved and the role of regenerative strategies was performed using PubMed, MEDLINE, Embase, PreMEDLINE, Scopus, and the Cochrane databases. Observational studies revealed an escalated incidence of pattern HL and TE in COVID-19 patients. Psychological stress, systemic inflammation, and oxidative stress are potential culprits. Proinflammatory cytokines and stress hormones negatively affect the normal metabolism of proteoglycans. Reduced anagenic expression of proteoglycans is a potential mediating mechanism that connects HL to COVID-19. Currently, only one study has been published on PRP against HL in COVID-19 patients. Further controlled trials are required to confirm PRP and HFSCs efficacy in COVID-19 patients.
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Affiliation(s)
- Pietro Gentile
- Plastic and Reconstructive Surgery, Department of Surgical Science, "Tor Vergata" University, 00133 Rome, Italy
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21
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Wiercinska E, Bönig H. Zelltherapie in den Zeiten von SARS-CoV-2. TRANSFUSIONSMEDIZIN 2022. [DOI: 10.1055/a-1720-7975] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/15/2022]
Abstract
ZusammenfassungEin breites Spektrum von Disruptionen, aber auch blitzschnelle Innovationen, hat
die SARS-CoV-2 Pandemie gebracht. Dieser Übersichtsartikel betrachtet
die Pandemie aus der Warte der Zelltherapie; konkret werden vier Aspekte
untersucht: Wie unterscheiden sich die Risiken von Zelltherapie-Patienten mit
SARS-CoV-2 Infektion und COVID von denen der Allgemeinbevölkerung? Sind
Empfänger von Zelltherapien, hier speziell autologe und allogene
Stammzelltransplantationsempfänger sowie Empfänger von
CAR-T-Zell-Präparaten, klinisch relevant durch SARS-CoV-2 Vakzine
immunisierbar? Welche Auswirkungen hat die Pandemie mit Spenderausfallrisiko und
Zusammenbruch von Supply Chains auf die Versorgung mit Zelltherapeutika? Gibt es
Zelltherapeutika, die bei schwerem COVID therapeutisch nutzbringend eingesetzt
werden können? In aller Kürze, das erwartete massiv
erhöhte Risiko von Zelltherapie-Patienten, im Infektionsfall einen
schweren Verlauf zu erleiden oder zu sterben, wurde bestätigt. Die
Vakzine induziert jedoch bei vielen dieser Patienten humorale und
zelluläre Immunität, wenn auch weniger zuverlässig als
bei Gesunden. Dank kreativer Lösungen gelang es, die Versorgung mit
Zelltherapeutika im Wesentlichen uneingeschränkt aufrecht zu erhalten.
SARS-CoV-2-spezifische T-Zell-Präparate für den adoptiven
Immuntransfer wurden entwickelt, eine therapeutische Konstellation diese
anzuwenden ergab sich jedoch nicht. Therapiestudien mit mesenchymalen
Stromazellen beim schweren COVID laufen weltweit; die Frage der Wirksamkeit
bleibt zurzeit offen, bei jedoch substanziellem Optimismus in der Szene. Einige
der Erkenntnisse und Innovationen aus der SARS-CoV-2-Pandemie können
möglicherweise verallgemeinert werden und so auf die Zeit nach ihrem
Ende langfristig nachwirken.
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Affiliation(s)
- Eliza Wiercinska
- DRK-Blutspendedienst Baden-Württemberg-Hessen, Institut
Frankfurt, Frankfurt a.M
| | - Halvard Bönig
- DRK-Blutspendedienst Baden-Württemberg-Hessen, Institut
Frankfurt, Frankfurt a.M
- Goethe Universität, Institut für Transfusionsmedizin
und Immunhämatologie, Frankfurt a.M
- University of Washington, Seattle, WA
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22
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Pu D, Zhai X, Zhou Y, Xie Y, Tang L, Yin L, Liu H, Li L. A narrative review of COVID-19-related acute respiratory distress syndrome (CARDS): "typical" or "atypical" ARDS? ANNALS OF TRANSLATIONAL MEDICINE 2022; 10:908. [PMID: 36111011 PMCID: PMC9469157 DOI: 10.21037/atm-22-3717] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/14/2022] [Accepted: 08/08/2022] [Indexed: 11/06/2022]
Abstract
Background and Objective The coronavirus disease of 2019 (COVID-19) is highly infectious and mainly involves the respiratory system, with some patients rapidly progress to acute respiratory distress syndrome (ARDS), which is the leading cause of death in COVID-19 patients. Hence, fully understanding the features of COVID-19-related ARDS (CARDS) and early management of this disease would improve the prognosis and reduce the mortality of severe COVID-19. With the development of recent studies which have focused on CARDS, whether CARDS is "typical" or "atypical" ARDS has become a hotly debated topic. Methods We searched for relevant literature from 1999 to 2021 published in PubMed by using the following keywords and their combinations: "COVID-19", "CARDS", "ARDS", "pathophysiological mechanism", "clinical manifestations", "prognosis", and "clinical trials". Then, we analyzed, compared and highlighted the differences between classic ARDS and CARDS from all of the aspects above. Key Content and Findings Classical ARDS commonly occurs within 1 week after a predisposing cause, yet the median time from symptoms onset to CARDS is longer than that of classical ARDS, manifesting within a period of 9.0-12.0 days. Although the lung mechanics exhibited in CARDS grossly match those of classical ARDS, there are some atypical manifestations of CARDS: the severity of hypoxemia seemed not to be proportional to injury of lung mechanics and an increase of thrombogenic processes. Meanwhile, some patients' symptoms do not correspond with the extent of the organic injury: a chest computed tomography (CT) will reveal the severe and diffuse lung injuries, yet the clinical presentations of patients can be mild. Conclusions Despite the differences between the CARDS and ARDS, in addition to the treatment of antivirals, clinicians should continue to follow the accepted evidence-based framework for managing all ARDS cases, including CARDS.
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Affiliation(s)
- Dan Pu
- Lung Cancer Center, West China Hospital, Sichuan University, Chengdu, China
| | - Xiaoqian Zhai
- Lung Cancer Center, West China Hospital, Sichuan University, Chengdu, China
| | - Yuwen Zhou
- Department of Biotherapy, Cancer Center, West China Hospital, Sichuan University, Chengdu, China
| | - Yao Xie
- Department of Dermatology, West China Hospital, Sichuan University, Chengdu, China
| | - Liansha Tang
- Department of Biotherapy, Cancer Center, West China Hospital, Sichuan University, Chengdu, China
| | - Liyuan Yin
- Lung Cancer Center, West China Hospital, Sichuan University, Chengdu, China
| | - Hangtian Liu
- Data Science and Big Data Technology, Chengdu University of Information Technology, Chengdu, China
| | - Lu Li
- Lung Cancer Center, West China Hospital, Sichuan University, Chengdu, China
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23
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Weiss DJ, Filiano A, Galipeau J, Khoury M, Krampera M, Lalu M, Blanc KL, Nolta J, Phinney DG, Rocco PR, Shi Y, Tarte K, Viswanathan S, Martin I. An ISCT MSC Committee Editorial on overcoming limitations in clinical trials of mesenchymal stromal cell therapy for COVID-19: Time for a global registry. Cytotherapy 2022; 24:1071-1073. [PMID: 36028438 PMCID: PMC9339970 DOI: 10.1016/j.jcyt.2022.07.010] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2022] [Accepted: 07/27/2022] [Indexed: 12/23/2022]
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24
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Immunomodulation of Mesenchymal Stem Cells in Acute Lung Injury: From Preclinical Animal Models to Treatment of Severe COVID-19. Int J Mol Sci 2022; 23:ijms23158196. [PMID: 35897770 PMCID: PMC9331939 DOI: 10.3390/ijms23158196] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2022] [Accepted: 07/23/2022] [Indexed: 02/01/2023] Open
Abstract
The coronavirus disease 2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has been a major public health challenge worldwide. Owing to the emergence of novel viral variants, the risks of reinfections and vaccine breakthrough infections has increased considerably despite a mass of vaccination. The formation of cytokine storm, which subsequently leads to acute respiratory distress syndrome, is the major cause of mortality in patients with COVID-19. Based on results of preclinical animal models and clinical trials of acute lung injury and acute respiratory distress syndrome, the immunomodulatory, tissue repair, and antiviral properties of MSCs highlight their potential to treat COVID-19. This review article summarizes the potential mechanisms and outcomes of MSC therapy in COVID-19, along with the pathogenesis of the SARS-CoV-2 infection. The properties of MSCs and lessons from preclinical animal models of acute lung injury are mentioned ahead. Important issues related to the use of MSCs in COVID-19 are discussed finally.
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25
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Qu W, Wang Z, Engelberg-Cook E, Yan D, Siddik AB, Bu G, Allickson JG, Kubrova E, Caplan AI, Hare JM, Ricordi C, Pepine CJ, Kurtzberg J, Pascual JM, Mallea JM, Rodriguez RL, Nayfeh T, Saadi S, Durvasula RV, Richards EM, March K, Sanfilippo FP. Efficacy and Safety of MSC Cell Therapies for Hospitalized Patients with COVID-19: A Systematic Review and Meta-Analysis. Stem Cells Transl Med 2022; 11:688-703. [PMID: 35640138 PMCID: PMC9299515 DOI: 10.1093/stcltm/szac032] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2021] [Accepted: 03/09/2022] [Indexed: 08/10/2023] Open
Abstract
MSC (a.k.a. mesenchymal stem cell or medicinal signaling cell) cell therapies show promise in decreasing mortality in acute respiratory distress syndrome (ARDS) and suggest benefits in treatment of COVID-19-related ARDS. We performed a meta-analysis of published trials assessing the efficacy and adverse events (AE) rates of MSC cell therapy in individuals hospitalized for COVID-19. Systematic searches were performed in multiple databases through November 3, 2021. Reports in all languages, including randomized clinical trials (RCTs), non-randomized interventional trials, and uncontrolled trials, were included. Random effects model was used to pool outcomes from RCTs and non-randomized interventional trials. Outcome measures included all-cause mortality, serious adverse events (SAEs), AEs, pulmonary function, laboratory, and imaging findings. A total of 736 patients were identified from 34 studies, which included 5 RCTs (n = 235), 7 non-randomized interventional trials (n = 370), and 22 uncontrolled comparative trials (n = 131). Patients aged on average 59.4 years and 32.2% were women. When compared with the control group, MSC cell therapy was associated with a reduction in all-cause mortality (RR = 0.54, 95% CI: 0.35-0.85, I 2 = 0.0%), reduction in SAEs (IRR = 0.36, 95% CI: 0.14-0.90, I 2 = 0.0%) and no significant difference in AE rate. A sub-group with pulmonary function studies suggested improvement in patients receiving MSC. These findings support the potential for MSC cell therapy to decrease all-cause mortality, reduce SAEs, and improve pulmonary function compared with conventional care. Large-scale double-blinded, well-powered RCTs should be conducted to further explore these results.
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Affiliation(s)
- Wenchun Qu
- Corresponding co-authors: Wenchun Qu, MD, PhD, Department of Pain Medicine, Mayo Clinic Florida, 4500 San Pablo Road, Jacksonville, FL 32224.
| | - Zhen Wang
- Evidence-Based Practice Center, Mayo Clinic, Rochester, MN, USA
- Robert D. and Patricia E. Kern Center for the Science of Health Care Delivery, Mayo Clinic, Rochester, MN, USA
| | | | - Dan Yan
- Department of Pain Medicine, Mayo Clinic, Jacksonville, FL, USA
| | | | - Guojun Bu
- Center for Regenerative Medicine, Mayo Clinic, Jacksonville, FL, USA
- Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA
| | | | - Eva Kubrova
- Department of Physical Medicine and Rehabilitation, Mayo Clinic, Rochester, MN, USA
| | - Arnold I Caplan
- Skeletal Research Center, Biology Department, Case Western Reserve University, Cleveland, OH, USA
| | - Joshua M Hare
- Interdisciplinary Stem Cell Institute and Cardiology Division, Department of Medicine, University of Miami, Miller School of Medicine, Miami, FL, USA
| | - Camillo Ricordi
- Department of Surgery, Diabetes Research Institute and Cell Transplant Center, University of Miami Miller School of Medicine, Miami, FL, USA
| | - Carl J Pepine
- Division of Cardiovascular Medicine, and Center for Regenerative Medicine, University of Florida, Gainesville, FL, USA
| | - Joanne Kurtzberg
- Marcus Center for Cellular Cures, Duke University School of Medicine, Durham, NC, USA
| | - Jorge M Pascual
- Division of Pulmonary, Allergy and Sleep Medicine, Department of Medicine, Mayo Clinic, Jacksonville, FL, USA
| | - Jorge M Mallea
- Division of Pulmonary, Allergy and Sleep Medicine, Department of Medicine, Mayo Clinic, Jacksonville, FL, USA
| | | | - Tarek Nayfeh
- Evidence-Based Practice Center, Mayo Clinic, Rochester, MN, USA
- Robert D. and Patricia E. Kern Center for the Science of Health Care Delivery, Mayo Clinic, Rochester, MN, USA
| | - Samer Saadi
- Evidence-Based Practice Center, Mayo Clinic, Rochester, MN, USA
- Robert D. and Patricia E. Kern Center for the Science of Health Care Delivery, Mayo Clinic, Rochester, MN, USA
| | | | - Elaine M Richards
- Department of Physiology and Functional Genomics, Center of Regenerative Medicine, University of Florida, Gainesville, FL, USA
| | - Keith March
- Division of Cardiovascular Medicine, and Center for Regenerative Medicine, University of Florida, Gainesville, FL, USA
| | - Fred P Sanfilippo
- Fred P. Sanfilippo, MD, PhD, Pathology and Laboratory Medicine, School of Medicine, Emory University, 1518 Clifton Road, 730GCR, Atlanta, GA 30322, USA.
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26
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Wang J, Luo F, Suo Y, Zheng Y, Chen K, You D, Liu Y. Safety, efficacy and biomarkers analysis of mesenchymal stromal cells therapy in ARDS: a systematic review and meta-analysis based on phase I and II RCTs. Stem Cell Res Ther 2022; 13:275. [PMID: 35752865 PMCID: PMC9233855 DOI: 10.1186/s13287-022-02956-3] [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: 04/05/2022] [Accepted: 06/08/2022] [Indexed: 11/11/2022] Open
Abstract
Background Mesenchymal stromal cells (MSCs) therapy for acute respiratory distress syndrome (ARDS) is an emerging treatment, but most of the current trials of MSCs stay in the animal experimental stage, and the safety and efficacy of MSCs in clinical application are not clear. We aimed to analyze the safety, efficacy and biomarkers of mesenchymal stromal cells in the treatment of ARDS. Methods For this systematic review and meta-analysis, we searched PubMed, Embase, Cochrane Central Register of Controlled Trials, Web of science, CNKI, VIP and Wan Fang data, studies published between database inception and Mar 17, 2022. All randomized controlled trials (RCT) of stem cell interventions for ARDS were included, without language or date restrictions. We did separate meta-analyses for mortality, subjects with adverse events (AEs) and subjects with serious adverse events (SAEs). Since the trials data are dichotomous outcomes, the odds ratio (OR) is adopted for meta-analysis. The quality of the evidence was assessed with the Cochrane risk of bias tool. Findings In total, 5 trials involving 171 patients with ARDS were included in this meta-analysis. A total of 99 individuals were randomly assigned to receive MSCs treatment, and 72 were randomly assigned to receive placebo treatment. Treatment with MSCs appeared to increase the occurrence of adverse events, but this result was not statistically significant (OR, 1.58; 95%CI, 0.64–3.91; P = 0.32). The occurrence of serious adverse events was lower in the MSCs group than in the placebo group (OR, 0.57; 95%CI, 0.14–2.32; P = 0.43); there seems to be no significant difference between the two groups in terms of 28 days mortality (OR, 0.93; 95%CI, 0.45–1.89); oxygenation index and biomarkers showed a tendency to improve in treatment, but there was a lack of more statistically significant clinical evidence to support them. Interpretation Based on the current clinical trials, MSCs intervention has some safety for ARDS patients, but its effectiveness and predictive value of airspace biomarkers need to be determined by more large-scale, standard randomized controlled trials. Supplementary Information The online version contains supplementary material available at 10.1186/s13287-022-02956-3.
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Affiliation(s)
- Jianbao Wang
- Department of Respiratory and Critical Care Medicine, Fujian Respiratory Medical Center, The Second Affiliated Hospital of Fujian Medical University, Quanzhou City, Fujian Province, China
| | - Fenbin Luo
- Department of Respiratory and Critical Care Medicine, Fujian Respiratory Medical Center, The Second Affiliated Hospital of Fujian Medical University, Quanzhou City, Fujian Province, China
| | - Ye Suo
- Department of Respiratory and Critical Care Medicine, Fujian Respiratory Medical Center, The Second Affiliated Hospital of Fujian Medical University, Quanzhou City, Fujian Province, China
| | - Yuxin Zheng
- Department of Respiratory and Critical Care Medicine, Fujian Respiratory Medical Center, The Second Affiliated Hospital of Fujian Medical University, Quanzhou City, Fujian Province, China
| | - Kaikai Chen
- Department of Respiratory and Critical Care Medicine, Fujian Respiratory Medical Center, The Second Affiliated Hospital of Fujian Medical University, Quanzhou City, Fujian Province, China
| | - Deyuan You
- Department of Respiratory and Critical Care Medicine, Fujian Respiratory Medical Center, The Second Affiliated Hospital of Fujian Medical University, Quanzhou City, Fujian Province, China
| | - Yuqi Liu
- Department of Respiratory and Critical Care Medicine, Fujian Respiratory Medical Center, The Second Affiliated Hospital of Fujian Medical University, Quanzhou City, Fujian Province, China.
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27
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Zhang M, Yan X, Shi M, Li R, Pi Z, Ren X, Wang Y, Yan S, Wang Y, Jin Y, Wang X. Safety and efficiency of stem cell therapy for COVID-19: a systematic review and meta-analysis. Glob Health Res Policy 2022; 7:19. [PMID: 35733229 PMCID: PMC9217728 DOI: 10.1186/s41256-022-00251-5] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2022] [Accepted: 05/31/2022] [Indexed: 11/13/2022] Open
Abstract
Background With the COVID-19 pandemic continuing, various treatments have become widely practiced. Stem cells have a wide range of applications in the treatment of lung diseases and have therefore been experimentally used to treat patients with COVID-19, but whether the expanded use of stem cells is safe and reliable still lacks enough evidence. To address this issue, we systematically reviewed the safety and efficiency of stem cell therapy in COVID-19 cases. Methods We searched PubMed, Embase, Web of Science, The Cochrane Library, CNKI, WanFang, VIP and SinoMed up to January 18, 2022. The included studies were assessed using the Risk-of-bias tool 1.0 and MINORS instrument. The adverse events, mortality, length of hospital day and laboratory parameters were analyzed by meta-analysis. We adhered to PRISMA reporting guideline. Results We have included 17 studies meeting the inclusion data. There were no significant differences in AEs (OR = 0·39, 95% CI = 0·12 to 1·33, P = 0·13, I2 = 58%) and SAEs (OR = 0·21, 95% CI = 0·04 to 1·03, P = 0·05, I2 = 0%) between stem cell therapy group and control group. The analysis showed that stem cell treatment could significantly reduce the mortality rate(OR = 0·24, 95% CI = 0·13 to 0·45, P < 0·01, I2 = 0%), but was not able to cause changes in length of hospital stay or most laboratory parameters. Conclusions The present study shows that stem cell therapy for COVID-19 has a remarkable effect on efficiency without increasing risks of adverse events and length of hospital stay. It is potentially necessary to establish the criteria for COVID-19 for stem cell therapy. Supplementary Information The online version contains supplementary material available at 10.1186/s41256-022-00251-5.
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Affiliation(s)
- Minghe Zhang
- Center for Evidence-Based and Translational Medicine, Zhongnan Hospital of Wuhan University, Wuhan, 430071, China.,Department of Hepatobiliary and Pancreatic Surgery, Zhongnan Hospital of Wuhan University, Wuhan, 430071, China
| | - Xinchun Yan
- Center for Evidence-Based and Translational Medicine, Zhongnan Hospital of Wuhan University, Wuhan, 430071, China
| | - Minghui Shi
- Center for Evidence-Based and Translational Medicine, Zhongnan Hospital of Wuhan University, Wuhan, 430071, China.,Department of Anesthesiology, Zhongnan Hospital of Wuhan University, Wuhan, 430071, China
| | - Ruihang Li
- Center for Evidence-Based and Translational Medicine, Zhongnan Hospital of Wuhan University, Wuhan, 430071, China
| | - Ziwei Pi
- Center for Evidence-Based and Translational Medicine, Zhongnan Hospital of Wuhan University, Wuhan, 430071, China.,Department of Neurosurgery, Zhongnan Hospital of Wuhan University, Wuhan, 430071, China
| | - Xiangying Ren
- Center for Evidence-Based and Translational Medicine, Zhongnan Hospital of Wuhan University, Wuhan, 430071, China
| | - Yongbo Wang
- Center for Evidence-Based and Translational Medicine, Zhongnan Hospital of Wuhan University, Wuhan, 430071, China
| | - Siyu Yan
- Center for Evidence-Based and Translational Medicine, Zhongnan Hospital of Wuhan University, Wuhan, 430071, China
| | - Yunyun Wang
- Center for Evidence-Based and Translational Medicine, Zhongnan Hospital of Wuhan University, Wuhan, 430071, China
| | - Yinghui Jin
- Center for Evidence-Based and Translational Medicine, Zhongnan Hospital of Wuhan University, Wuhan, 430071, China
| | - Xinghuan Wang
- Center for Evidence-Based and Translational Medicine, Zhongnan Hospital of Wuhan University, Wuhan, 430071, China. .,Department of Urology, Zhongnan Hospital of Wuhan University, Wuhan, 430071, China.
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Arias M, Oliveros H, Lechtig S, Bustos RH. Biologics in COVID-19 So Far: Systematic Review. Pharmaceuticals (Basel) 2022; 15:ph15070783. [PMID: 35890081 PMCID: PMC9321859 DOI: 10.3390/ph15070783] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2022] [Revised: 06/07/2022] [Accepted: 06/10/2022] [Indexed: 12/17/2022] Open
Abstract
This systematic review aimed to reevaluate the available evidence of the use of biologics as treatment candidates for the treatment of severe and advanced COVID-19 disease; what are the rationale for their use, which are the most studied, and what kind of efficacy measures are described? A search through Cochrane, Embase, Pubmed, Medline, medrxiv.org, and Google scholar was performed on the use of biologic interventions in COVID-19/SARS-CoV-2 infection, viral pneumonia, and sepsis, until 11 January 2022. Throughout the research, we identified 4821 records, of which 90 were selected for qualitative analysis. Amongst the results, we identified five popular targets of use: IL6 and IL1 inhibitors, interferons, mesenchymal stem cells treatment, and anti-spike antibodies. None of them offered conclusive evidence of their efficacy with consistency and statistical significance except for some studies with anti-spike antibodies; however, Il6 and IL1 inhibitors as well as interferons show encouraging data in terms of increased survival and favorable clinical course that require further studies with better methodology standardization.
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Affiliation(s)
- Milton Arias
- Department of Clinical Pharmacology, Evidence-Based Therapeutics Group, Faculty of Medicine, Universidad de La Sabana and Clínica Universidad de La Sabana, Autopista Norte de Bogotá, Chía 140013, Colombia; (M.A.); (S.L.)
| | - Henry Oliveros
- Department of Epidemiology, Health Research Group, Faculty of Medicine, Universidad de La Sabana, Campus del Puente del Común, Km. 7, Autopista Norte de Bogotá, Chía 140013, Colombia;
| | - Sharon Lechtig
- Department of Clinical Pharmacology, Evidence-Based Therapeutics Group, Faculty of Medicine, Universidad de La Sabana and Clínica Universidad de La Sabana, Autopista Norte de Bogotá, Chía 140013, Colombia; (M.A.); (S.L.)
| | - Rosa-Helena Bustos
- Department of Clinical Pharmacology, Evidence-Based Therapeutics Group, Faculty of Medicine, Universidad de La Sabana and Clínica Universidad de La Sabana, Autopista Norte de Bogotá, Chía 140013, Colombia; (M.A.); (S.L.)
- Correspondence: ; Tel.: +57-1608615555
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Kirkham AM, Monaghan M, Bailey AJ, Shorr R, Lalu MM, Fergusson DA, Allan DS. Mesenchymal stem/stromal cell-based therapies for COVID-19: First iteration of a living systematic review and meta-analysis: MSCs and COVID-19. Cytotherapy 2022; 24:639-649. [PMID: 35219584 PMCID: PMC8802614 DOI: 10.1016/j.jcyt.2021.12.001] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2021] [Revised: 11/22/2021] [Accepted: 12/09/2021] [Indexed: 01/27/2023]
Abstract
BACKGROUND Mesenchymal stem/stromal cells (MSCs) and their secreted products are a promising therapy for COVID-19 given their immunomodulatory and tissue repair capabilities. Many small studies were launched at the onset of the pandemic, and repeated meta-analysis is critical to obtain timely and sufficient statistical power to determine efficacy. METHODS AND FINDINGS All English-language published studies identified in our systematic search (up to February 3, 2021) examining the use of MSC-derived products to treat patients with COVID-19 were identified. Risk of bias (RoB) was assessed for all studies. Nine studies were identified (189 patients), four of which were controlled (93 patients). Three of the controlled studies reported on mortality (primary analysis) and were pooled through random-effects meta-analysis. MSCs decreased the risk of death at study endpoint compared with controls (risk ratio, 0.18; 95% confidence interval [CI], 0.04 to 0.74; P = .02; I2 = 0%), although follow-up differed. Among secondary outcomes, interleukin-6 levels were most commonly reported and were decreased compared with controls (standardized mean difference, -0.69; 95% CI, -1.15 to -0.22; P = .004; I2 = 0%) (n = 3 studies). Other outcomes were not reported consistently, and pooled estimates of effect were not performed. Substantial heterogeneity was observed between studies in terms of study design. Adherence to published ISCT criteria for MSC characterization was low. In two of nine studies, RoB analysis revealed a low to moderate risk of bias in controlled studies, and uncontrolled case series were of good (3 studies) or fair (2 studies) quality. CONCLUSION Use of MSCs to treat COVID-19 appears promising; however, few studies were identified, and potential risk of bias was detected in all studies. More controlled studies that report uniform clinical outcomes and use MSC products that meet standard ISCT criteria should be performed. Future iterations of our systematic search should refine estimates of efficacy and clarify potential adverse effects.
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Affiliation(s)
- Aidan M. Kirkham
- Departments of Biochemistry, Microbiology & Immunology, University of Ottawa, Ottawa, ON, Canada,Clinical Epidemiology, Ottawa Hospital Research Institute, Ottawa, ON, Canada
| | - Madeline Monaghan
- Clinical Epidemiology, Ottawa Hospital Research Institute, Ottawa, ON, Canada
| | - Adrian J.M. Bailey
- Clinical Epidemiology, Ottawa Hospital Research Institute, Ottawa, ON, Canada
| | - Risa Shorr
- Medical Information and Learning Services, The Ottawa Hospital, Ottawa, ON, Canada
| | - Manoj M. Lalu
- Cellular and Molecular Medicine, University of Ottawa, Ottawa, ON, Canada,Anesthesiology and Pain Medicine, University of Ottawa, Ottawa, ON, Canada,Clinical Epidemiology, Ottawa Hospital Research Institute, Ottawa, ON, Canada,Regenerative Medicine, Ottawa Hospital Research Institute, Ottawa, ON, Canada,Departments Anesthesia, The Ottawa Hospital, Ottawa, ON, Canada
| | - Dean A. Fergusson
- Medicine, University of Ottawa, Ottawa, ON, Canada,Epidemiology and Public Health, Faculty of Medicine, University of Ottawa, Ottawa, ON, Canada,Clinical Epidemiology, Ottawa Hospital Research Institute, Ottawa, ON, Canada,Medicine, The Ottawa Hospital, Ottawa, ON, Canada
| | - David S. Allan
- Departments of Biochemistry, Microbiology & Immunology, University of Ottawa, Ottawa, ON, Canada,Medicine, University of Ottawa, Ottawa, ON, Canada,Clinical Epidemiology, Ottawa Hospital Research Institute, Ottawa, ON, Canada,Regenerative Medicine, Ottawa Hospital Research Institute, Ottawa, ON, Canada,Medicine, The Ottawa Hospital, Ottawa, ON, Canada,Corresponding Author: Dr. David Allan, Ottawa Hospital Research Institute, 501 Smyth Rd, Box 704 Ottawa ON K1H 8L6, Canada, Fax +1 613-737-8861
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ACE2 overexpressing mesenchymal stem cells alleviates COVID-19 lung injury by inhibiting pyroptosis. iScience 2022; 25:104046. [PMID: 35287354 PMCID: PMC8907105 DOI: 10.1016/j.isci.2022.104046] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2021] [Revised: 02/07/2022] [Accepted: 03/08/2022] [Indexed: 02/07/2023] Open
Abstract
Mesenchymal stem cells (MSCs) have shown some efficacy in the COVID-19 treatment. We proposed that exogenous supplementation of ACE2 via MSCs (ACE2-MSCs) might have better therapeutic effects. We constructed SARS-CoV-2 spike glycoprotein stably transfected AT-II and Beas-2B cells and used SARS-CoV-2 spike pseudovirus to infect hACE2 transgenic mice. The results showed that spike glycoprotein transfection triggers the release of apoptotic bodies and formation of membrane pores in pyroptosis. Inflammatory factors and pyroptosis factors were highly upregulated by spike glycoprotein transfection. SARS-CoV-2 spike pseudovirus worsened lung injury and increased the main factors of cytokine storm and pyroptosis. Compared to using MSCs or rh-ACE2 alone, the administration of ACE2-MSCs could significantly reduce these factors better and alleviate lung injury in vivo and in vitro, which might be because of the increased activities of secretory ACE2. Our proposal is a promising therapeutic solution for preclinical or clinical research.
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31
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Efficacy and safety of mesenchymal stem cells in the treatment of systemic sclerosis: a systematic review and meta-analysis. Stem Cell Res Ther 2022; 13:118. [PMID: 35313985 PMCID: PMC8935249 DOI: 10.1186/s13287-022-02786-3] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2021] [Accepted: 02/17/2022] [Indexed: 11/28/2022] Open
Abstract
Background Systemic sclerosis (SSc) is an autoimmune disease with high morbidity and mortality characterized by fibrosis of the skin and internal organs. Some studies have investigated the use of stem cells to treat SSc. Herein, a systematic review and meta-analysis was conducted to determine the efficacy and safety of mesenchymal stem cells (MSCs) in the treatment of SSc. Methods PubMed, Embase, Cochrane Library, Web of Science, OVID, China National Knowledge Infrastructure and Wanfang databases were searched up to February 1, 2021. Literature screening, data extraction and quality assessment were conducted independently by two researchers in according to the inclusion and exclusion criteria. The discrepancies were resolved by a third researcher. Results A total of 9 studies encompassing 133 SSc patients were included in the study. Compared to the baseline after treatment with MSCs: 1. The modified Rodnan skin score (mRSS) was significantly reduced in patients with SSc (P < 0.00001). 2. MSCs decreased the number of digital ulcer, mouth handicap scale, and visual analog scale of hand pain in SSc patients (P = 0.0007 and P = 0.03, respectively). 3. No statistical differences were detected in Raynaud's condition score and Cochin hand function scale score at 6 months of MSCs therapy (P = 0.5 and P = 0.62). 4. After 12 months of follow-up, MSCs improve carbon monoxide diffusing capacity and forced vital capacity of SSc patients (P < 0.05). 5. Overall, MSCs application was safe; a few cases exhibited swelling at the injection site, diarrhea and arthralgia, which had self-recovery, and no severe adverse events occurred in the included trials. Conclusions MSC therapy improves the degree of skin thickening, lung function, and mouth opening and relieves finger ulcers and pain in patients with SSc without severe adverse events. Thus, MSCs or MSCs combined with plasma and traditional medicine might be an effective and promising treatment of SSc patients. PROSPERO registration number: CRD42020200350
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Kebria MM, Milan PB, Peyravian N, Kiani J, Khatibi S, Mozafari M. Stem cell therapy for COVID-19 pneumonia. MOLECULAR BIOMEDICINE 2022; 3:6. [PMID: 35174448 PMCID: PMC8850486 DOI: 10.1186/s43556-021-00067-8] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2021] [Accepted: 12/22/2021] [Indexed: 12/11/2022] Open
Abstract
Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) virus is a highly contagious microorganism, and despite substantial investigation, no progress has been achieved in treating post-COVID complications. However, the virus has made various mutations and has spread around the world. Researchers have tried different treatments to reduce the side effects of the COVID-19 symptoms. One of the most common and effective treatments now used is steroid therapy to reduce the complications of this disease. Long-term steroid therapy for chronic inflammation following COVID-19 is harmful and increases the risk of secondary infection, and effective treatment remains challenging owing to fibrosis and severe inflammation and infection. Sometimes our immune system can severely damage ourselves in disease. In the past, many researchers have conducted various studies on the immunomodulatory properties of stem cells. This property of stem cells led them to modulate the immune system of autoimmune diseases like diabetes, multiple sclerosis, and Parkinson's. Because of their immunomodulatory properties, stem cell-based therapy employing mesenchymal or hematopoietic stem cells may be a viable alternative treatment option in some patients. By priming the immune system and providing cytokines, chemokines, and growth factors, stem cells can be employed to build a long-term regenerative and protective response. This review addresses the latest trends and rapid progress in stem cell treatment for Acute Respiratory Distress Syndrome (ARDS) following COVID-19.
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Affiliation(s)
- Maziar Malekzadeh Kebria
- Cellular and Molecular Research Centre, Iran University of Medical Sciences, Tehran, Iran
- Department of Tissue Engineering and Regenerative Medicine, Faculty of Advanced Technologies in Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Peiman Brouki Milan
- Cellular and Molecular Research Centre, Iran University of Medical Sciences, Tehran, Iran
- Department of Tissue Engineering and Regenerative Medicine, Faculty of Advanced Technologies in Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Noshad Peyravian
- Cellular and Molecular Research Centre, Iran University of Medical Sciences, Tehran, Iran
- Department of Tissue Engineering and Regenerative Medicine, Faculty of Advanced Technologies in Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Jafar Kiani
- Oncopathology Research Center, Iran University of Medical Sciences, Tehran, Iran
- Present Address: Department of Molecular Medicine, Faculty of Advanced Technologies in Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Soheil Khatibi
- Babol University of Medical Sciences, Infection Diseases Centre, Mazandaran, Iran
| | - Masoud Mozafari
- Department of Tissue Engineering and Regenerative Medicine, Faculty of Advanced Technologies in Medicine, Iran University of Medical Sciences, Tehran, Iran
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Karakaş N, Üçüncüoğlu S, Uludağ D, Karaoğlan BS, Shah K, Öztürk G. Mesenchymal Stem Cell-Based COVID-19 Therapy: Bioengineering Perspectives. Cells 2022; 11:465. [PMID: 35159275 PMCID: PMC8834073 DOI: 10.3390/cells11030465] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2021] [Revised: 12/18/2021] [Accepted: 12/22/2021] [Indexed: 02/06/2023] Open
Abstract
The novel pathogenic severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes coronavirus disease 2019 (COVID-19). Mesenchymal stem cells (MSCs) are currently utilized in clinics for pulmonary inflammatory diseases, including acute respiratory distress syndrome and acute lung injury. Given that MSCs offer a promising treatment against COVID-19, they are being used against COVID-19 in more than 70 clinical trials with promising findings. Genetically engineered MSCs offer promising therapeutic options in pulmonary diseases. However, their potential has not been explored yet. In this review, we provide perspectives on the functionally modified MSCs that can be developed and harnessed for COVID-19 therapy. Options to manage the SARS-CoV-2 infection and its variants using various bioengineering tools to increase the therapeutic efficacy of MSCs are highlighted.
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Affiliation(s)
- Nihal Karakaş
- Department of Medical Biology, School of Medicine, İstanbul Medipol University, İstanbul 34810, Turkey
- Regenerative and Restorative Medicine Research Center (REMER), Institute for Health Sciences and Technologies (SABITA), İstanbul Medipol University, İstanbul 34810, Turkey; (S.Ü.); (D.U.); (B.S.K.); (G.Ö.)
| | - Süleyman Üçüncüoğlu
- Regenerative and Restorative Medicine Research Center (REMER), Institute for Health Sciences and Technologies (SABITA), İstanbul Medipol University, İstanbul 34810, Turkey; (S.Ü.); (D.U.); (B.S.K.); (G.Ö.)
- Department of Biophysics, International School of Medicine, İstanbul Medipol University, İstanbul 34810, Turkey
| | - Damla Uludağ
- Regenerative and Restorative Medicine Research Center (REMER), Institute for Health Sciences and Technologies (SABITA), İstanbul Medipol University, İstanbul 34810, Turkey; (S.Ü.); (D.U.); (B.S.K.); (G.Ö.)
- Graduate School for Health Sciences, Medical Biology and Genetics Program, İstanbul Medipol University, İstanbul 34810, Turkey
| | - Birnur Sinem Karaoğlan
- Regenerative and Restorative Medicine Research Center (REMER), Institute for Health Sciences and Technologies (SABITA), İstanbul Medipol University, İstanbul 34810, Turkey; (S.Ü.); (D.U.); (B.S.K.); (G.Ö.)
| | - Khalid Shah
- Center for Stem Cell and Translational Immunotherapies, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02114, USA;
| | - Gürkan Öztürk
- Regenerative and Restorative Medicine Research Center (REMER), Institute for Health Sciences and Technologies (SABITA), İstanbul Medipol University, İstanbul 34810, Turkey; (S.Ü.); (D.U.); (B.S.K.); (G.Ö.)
- Department of Physiology, International School of Medicine, İstanbul Medipol University, İstanbul 34810, Turkey
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Wang Z, Li H, Fang J, Wang X, Dai S, Cao W, Guo Y, Li Z, Zhu H. Comparative Analysis of the Therapeutic Effects of Amniotic Membrane and Umbilical Cord Derived Mesenchymal Stem Cells for the Treatment of Type 2 Diabetes. Stem Cell Rev Rep 2022; 18:1193-1206. [PMID: 35015214 PMCID: PMC8749914 DOI: 10.1007/s12015-021-10320-w] [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] [Accepted: 12/16/2021] [Indexed: 11/09/2022]
Abstract
Type 2 diabetes mellitus (T2DM), one of the most common carbohydrate metabolism disorders, is characterized by chronic hyperglycemia and insulin resistance (IR), and has become an urgent global health challenge. Mesenchymal stem cells (MSCs) originating from perinatal tissues such as umbilical cord (UC) and amniotic membrane (AM) serve as ideal candidates for the treatment of T2DM due to their great advantages in terms of abundant source, proliferation capacity, immunomodulation and plasticity for insulin-producing cell differentiation. However, the optimally perinatal MSC source to treat T2DM remains elusive. This study aims to compare the therapeutic efficacy of MSCs derived from AM and UC (AMMSCs and UCMSCs) of the same donor in the alleviation of T2DM symptoms and explore the underlying mechanisms. Our results showed that AMMSCs and UCMSCs displayed indistinguishable immunophenotype and multi-lineage differentiation potential, but UCMSCs had a much higher expansion capacity than AMMSCs. Moreover, we uncovered that single-dose intravenous injection of either AMMSCs or UCMSCs could comparably reduce hyperglycemia and improve IR in T2DM db/db mice. Mechanistic investigations revealed that either AMMSC or UCMSC infusion could greatly improve glycolipid metabolism in the liver of db/db mice, which was evidenced by decreased liver to body weight ratio, reduced lipid accumulation, upregulated glycogen synthesis, and increased Akt phosphorylation. Taken together, these data indicate that the same donor-derived AMMSCs and UCMSCs possessed comparable effects and shared a similar hepatoprotective mechanism on the alleviation of T2DM symptoms.
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Affiliation(s)
- Zhifeng Wang
- Sinoneural Cell Engineering Group Holdings Co., Ltd, Shanghai, 201100, China. .,Translational Medical Center for Stem Cell Therapy and Institute for Regenerative Medicine, Shanghai East Hospital, Shanghai Key Laboratory of Signaling and Disease Research, Frontier Science Center for Stem Cell Research, School of Life Sciences and Technology, Tongji University, Shanghai, 200092, China.
| | - Haisen Li
- Sinoneural Cell Engineering Group Holdings Co., Ltd, Shanghai, 201100, China
| | - Jingmeng Fang
- Sinoneural Cell Engineering Group Holdings Co., Ltd, Shanghai, 201100, China
| | - Xiaoyu Wang
- Sinoneural Cell Engineering Group Holdings Co., Ltd, Shanghai, 201100, China
| | - Shuhang Dai
- Sinoneural Cell Engineering Group Holdings Co., Ltd, Shanghai, 201100, China
| | - Wei Cao
- Sinoneural Cell Engineering Group Holdings Co., Ltd, Shanghai, 201100, China
| | - Yinhong Guo
- Sinoneural Cell Engineering Group Holdings Co., Ltd, Shanghai, 201100, China
| | - Zhe Li
- Sinoneural Cell Engineering Group Holdings Co., Ltd, Shanghai, 201100, China
| | - Hao Zhu
- Sinoneural Cell Engineering Group Holdings Co., Ltd, Shanghai, 201100, China.
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Bagno LL, Salerno AG, Balkan W, Hare JM. Mechanism of Action of Mesenchymal Stem Cells (MSCs): impact of delivery method. Expert Opin Biol Ther 2021; 22:449-463. [PMID: 34882517 DOI: 10.1080/14712598.2022.2016695] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/19/2022]
Abstract
INTRODUCTION Mesenchymal stromal cells (MSCs; AKA mesenchymal stem cells) stimulate healing and reduce inflammation. Promising therapeutic responses are seen in many late-phase clinical trials, but others have not satisfied their primary endpoints, making translation of MSCs into clinical practice difficult. These inconsistencies may be related to the route of MSC delivery, lack of product optimization, or varying background therapies received in clinical trials over time. AREAS COVERED Here we discuss the different routes of MSC delivery, highlighting the proposed mechanism(s) of therapeutic action as well as potential safety concerns. PubMed search criteria used: MSC plus: local administration; routes of administration; delivery methods; mechanism of action; therapy in different diseases. EXPERT OPINION Direct injection of MSCs using a controlled local delivery approach appears to have benefits in certain disease states, but further studies are required to make definitive conclusions regarding the superiority of one delivery method over another.
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Affiliation(s)
- Luiza L Bagno
- Interdisciplinary Stem Cell Institute, University of Miami Miller School of Medicine, Miami, FL, USA
| | - Alessandro G Salerno
- Interdisciplinary Stem Cell Institute, University of Miami Miller School of Medicine, Miami, FL, USA
| | - Wayne Balkan
- Interdisciplinary Stem Cell Institute, University of Miami Miller School of Medicine, Miami, FL, USA.,Department of Medicine, University of Miami Miller School of Medicine, Miami
| | - Joshua M Hare
- Interdisciplinary Stem Cell Institute, University of Miami Miller School of Medicine, Miami, FL, USA.,Department of Medicine, University of Miami Miller School of Medicine, Miami
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Mesenchymal Stem Cells Versus Covid-19. Can They Win the Battle? SERBIAN JOURNAL OF EXPERIMENTAL AND CLINICAL RESEARCH 2021. [DOI: 10.2478/sjecr-2021-0024] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
Abstract
Mesenchymal stem cells (MSCs) are multipotent stem cells with numerous features potentially useful in various pathologies. It has been shown that MSCs have regenerative potential due to modulation of immune system response, inflammation diminishing, trans differentiation into various types of cells, proangiogenetic and anti fibrotic influence. Besides all of these traits, MSCs posses anti viral capacity and have been further employed in clinical trails since last year. Here, we revised immunomodulatory, biological and antiviral traits of MSCs, but also pathogenesis of Covid-19 and it’s impact on immune system. Conspicuously, there is a growing number of studies examining effect of MSCs in patients suffering from Covid-19 pneumonia and ARDS. Since MSCs are in theory capable of healing lung injury and inflammation, here we discuss hypothesis, pros and cons of MSCs treatment in Covid-19 patients. Finally, we debate if MSCs based therapy can be promising tool for Covid-19 lung pathologies.
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Arabpour E, Khoshdel S, Tabatabaie N, Akhgarzad A, Zangiabadian M, Nasiri MJ. Stem Cells Therapy for COVID-19: A Systematic Review and Meta-Analysis. Front Med (Lausanne) 2021; 8:737590. [PMID: 34912818 PMCID: PMC8666565 DOI: 10.3389/fmed.2021.737590] [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: 07/07/2021] [Accepted: 10/22/2021] [Indexed: 12/19/2022] Open
Abstract
Introduction: Vaccination seems to be a good solution for preventing and controlling coronavirus disease (COVID-19) pandemic, but still there are some challenges in COVID-19 vaccination. Investigating new therapeutic options for COVID-19 is necessary. The current study aimed to evaluate the safety and efficacy of stem cells in treating patients with COVID-19. Methods: We reviewed the relevant scientific literature published up to April 1, 2021. The pooled risk ratio (RR) with 95% CI was assessed using a fixed or random-effect model. We considered P < 0.05 as statistically significant for publication bias. Data were analyzed by Comprehensive Meta-Analysis software, Version 2.0 (Biostat, Englewood, NJ). Results: After reviewing 1,262 records, we identified 10 studies that met the inclusion criteria. The analysis showed that stem cell therapy could significantly reduce the mortality rate (RR 0.471, 95% CI: 0.270-0.821) and morbidity (RR 0.788, 95% CI: 0.626-0.992) in patients with COVID-19; compared with the control group. Conclusions: The present study suggests that stem cell therapy has a remarkable effect on reducing mortality and morbidity of patients with COVID-19. Further large-scale studies are needed to approve these results. Defining a protocol for stem cell therapy in patients with COVID-19 can lead to achieving the best clinical outcomes.
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Affiliation(s)
- Erfan Arabpour
- Student Research Committee, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Sina Khoshdel
- Student Research Committee, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Negin Tabatabaie
- Student Research Committee, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Ali Akhgarzad
- Student Research Committee, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Moein Zangiabadian
- Student Research Committee, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Mohammad Javad Nasiri
- Department of Microbiology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
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Becerra J, Duran I. Inflammation, a common mechanism in frailty and COVID-19, and stem cells as a therapeutic approach. Stem Cells Transl Med 2021; 10:1482-1490. [PMID: 34164948 PMCID: PMC8550702 DOI: 10.1002/sctm.21-0074] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2021] [Revised: 05/12/2021] [Accepted: 06/06/2021] [Indexed: 12/15/2022] Open
Abstract
As our life expectancy increases, specific medical conditions appear, and new challenges are met in terms of global health. Frailty has become a medical and scientific concept to define pathologies where inflammation, depressed immune system, cellular senescence, and molecular aging converge. But more importantly, frailty is the ultimate cause of death that limits our life span and deteriorates health in an increasing proportion of the world population. The difficulty of tackling this problem is the combination of factors that influence frailty appearance, such as stem cells exhaustion, inflammation, loss of regeneration capability, and impaired immunomodulation. To date, multiple research fields have found mechanisms participating in this health condition, but to make progress, science will need to investigate frailty with an interdisciplinary approach. This article summarizes the current efforts to understand frailty from their processes mediated by inflammation, aging, and stem cells to provide a new perspective that unifies the efforts in producing advanced therapies against medical conditions in the context of frailty. We believe this approach against frailty is particularly relevant to COVID-19, since people in a state of frailty die more frequently due to the hyperinflammatory process associated with this infection.
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Affiliation(s)
- José Becerra
- Department of Cell Biology, Genetics, and PhysiologyFaculty of Sciences, University of Málaga, IBIMAMálagaSpain
- Networking Biomedical Research Center in Bioengineering, Biomaterials, and Nanomedicine (CIBER‐BBN)Andalusian Centre for Nanomedicine and Biotechnology‐BIONANDMálagaSpain
| | - Ivan Duran
- Department of Cell Biology, Genetics, and PhysiologyFaculty of Sciences, University of Málaga, IBIMAMálagaSpain
- Networking Biomedical Research Center in Bioengineering, Biomaterials, and Nanomedicine (CIBER‐BBN)Andalusian Centre for Nanomedicine and Biotechnology‐BIONANDMálagaSpain
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Sadeghi B, Roshandel E, Pirsalehi A, Kazemi S, Sankanian G, Majidi M, Salimi M, Aghdami N, Sadrosadat H, Samadi Kochaksaraei S, Alaeddini F, Ringden O, Hajifathali A. Conquering the cytokine storm in COVID-19-induced ARDS using placenta-derived decidua stromal cells. J Cell Mol Med 2021; 25:10554-10564. [PMID: 34632708 PMCID: PMC8581334 DOI: 10.1111/jcmm.16986] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2021] [Revised: 09/23/2021] [Accepted: 09/24/2021] [Indexed: 01/08/2023] Open
Abstract
Acute respiratory distress syndrome (ARDS) is the most common cause of death in COVID‐19 patients. The cytokine storm is the main driver of the severity and magnitude of ARDS. Placenta‐derived decidua stromal cells (DSCs) have a stronger immunosuppressive effect than other sources of mesenchymal stromal cells. Safety and efficacy study included 10 patients with a median age of 50 (range 14–68) years with COVID‐19‐induced ARDS. DSCs were administered 1–2 times at a dose of 1 × 106/kg. End points were safety and efficacy by survival, oxygenation and effects on levels of cytokines. Oxygenation levels increased from a median of 80.5% (range 69–88) to 95% (range 78–99) (p = 0.012), and pulmonary infiltrates disappeared in all patients. Levels of IL‐6 decreased from a median of 69.3 (range 35.0–253.4) to 11 (range 4.0–38.3) pg/ml (p = 0.018), and CRP decreased from 69 (range 5–169) to 6 (range 2–31) mg/ml (p = 0.028). Two patients died, one of a myocardial infarction and the other of multiple organ failure, diagnosed before the DSC therapy. The other patients recovered and left the intensive care unit (ICU) within a median of 6 (range 3–12) days. DSC therapy is safe and capable of improving oxygenation, decreasing inflammatory cytokine level and clearing pulmonary infiltrates in patients with COVID‐19.
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Affiliation(s)
- Behnam Sadeghi
- Translational Cell Therapy Research (TCR), Department of Clinical Science, Intervention and Technology, CLINTEC, Karolinska Institutet, Huddinge, Sweden
| | - Elham Roshandel
- Hematopoietic Stem Cell Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Ali Pirsalehi
- Department of Internal Medicine, School of Medicine, Taleghani Hospital, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Sepide Kazemi
- Translational Cell Therapy Research (TCR), Department of Clinical Science, Intervention and Technology, CLINTEC, Karolinska Institutet, Huddinge, Sweden.,Advanced Therapy Medicinal Product (ATMP), Breast Cancer Research Center, Motamed Cancer Institute, ACECR, Tehran, Iran
| | - Ghazaleh Sankanian
- Hematopoietic Stem Cell Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Mohammad Majidi
- Department of Tissue Engineering & Regenerative Medicine, Faculty of Advanced Technologies in Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Maryam Salimi
- Hematopoietic Stem Cell Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Nasser Aghdami
- Department of Regenerative Medicine, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran.,Department of Infectious Diseases and Tropical Medicines, Tehran University of Medical Sciences, Tehran, Iran
| | - Hoda Sadrosadat
- Advanced Therapy Medicinal Product (ATMP), Breast Cancer Research Center, Motamed Cancer Institute, ACECR, Tehran, Iran
| | - Sarvenaz Samadi Kochaksaraei
- Translational Cell Therapy Research (TCR), Department of Clinical Science, Intervention and Technology, CLINTEC, Karolinska Institutet, Huddinge, Sweden.,Advanced Therapy Medicinal Product (ATMP), Breast Cancer Research Center, Motamed Cancer Institute, ACECR, Tehran, Iran
| | - Farshid Alaeddini
- Research Center for Health Management in Mass Gathering, Red Crescent Society of the Islamic Republic of Iran, Tehran, Iran
| | - Olle Ringden
- Translational Cell Therapy Research (TCR), Department of Clinical Science, Intervention and Technology, CLINTEC, Karolinska Institutet, Huddinge, Sweden
| | - Abbas Hajifathali
- Hematopoietic Stem Cell Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
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Wang J, Shi P, Chen D, Wang S, Wang P, Feng X, Zhang L. Research Status of the Safety and Efficacy of Mesenchymal Stem Cells in the Treatment of COVID-19-Related Pneumonia: A Systematic Review and Meta-Analysis. Stem Cells Dev 2021; 30:947-969. [PMID: 34416823 DOI: 10.1089/scd.2021.0179] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022] Open
Abstract
Mesenchymal stem cell (MSC) therapy is considered one of the most promising treatments in the context of the coronavirus disease 2019 (COVID-19) pandemic. However, the safety and effectiveness of MSCs in the treatment of COVID-19-associated pneumonia patients need to be systematically reviewed and analyzed. Two independent researchers searched for relevant studies published between October 2019 and April 2021 in the PubMed, Embase, Cochrane Library, WAN FANG, and CNKI databases. All relevant randomized controlled trials, clinically controlled studies, retrospective studies, case reports, letters (with valid data), and case series were included in this meta-analysis. A fixed-effects model and 95% confidence interval (CI) were used to analyze the results. A total of 22 studies involving 371 patients were included in the present study. Allogeneic MSCs from umbilical cord, adipose tissue, menstrual blood, placental tissue, Wharton's jelly, or unreported sources were administered in 247 participants. Combined results revealed that MSC therapy significantly reduced the incidence of adverse events [AEs; odds ratio (OR) = 0.43, 95% CI = 0.22-0.84, P = 0.01] and mortality (OR = 0.17, 95% CI = 0.06-0.49, P < 0.01), and the difference compared with control group was statistically significant. No serious MSC treatment-related AEs were reported. Lung function, radiographic outcomes, and inflammation- and immunity-related biomarker levels all showed improving trends. Therefore, MSC therapy is an effective and safe method for the treatment of COVID-19-associated pneumonia and shows advantages in reducing AEs and mortality. However, a standard and effective MSC treatment program must be developed.
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Affiliation(s)
- Junwu Wang
- Department of Orthopedics, Clinical Medical College of Yangzhou University, Yangzhou, China
| | - Pengzhi Shi
- Graduate School of Dalian Medical University, Dalian, China
| | - Dong Chen
- Department of Orthopedics, Clinical Medical College of Yangzhou University, Yangzhou, China
| | - Shuguang Wang
- Graduate School of Dalian Medical University, Dalian, China
| | - Pingchuan Wang
- Department of Orthopedics, Clinical Medical College of Yangzhou University, Yangzhou, China
| | - Xinmin Feng
- Department of Orthopedics, Clinical Medical College of Yangzhou University, Yangzhou, China
| | - Liang Zhang
- Department of Orthopedics, Clinical Medical College of Yangzhou University, Yangzhou, China
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Qiao Q, Liu X, Yang T, Cui K, Kong L, Yang C, Zhang Z. Nanomedicine for acute respiratory distress syndrome: The latest application, targeting strategy, and rational design. Acta Pharm Sin B 2021; 11:3060-3091. [PMID: 33977080 PMCID: PMC8102084 DOI: 10.1016/j.apsb.2021.04.023] [Citation(s) in RCA: 103] [Impact Index Per Article: 25.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2021] [Revised: 03/22/2021] [Accepted: 04/06/2021] [Indexed: 01/08/2023] Open
Abstract
Acute respiratory distress syndrome (ARDS) is characterized by the severe inflammation and destruction of the lung air-blood barrier, leading to irreversible and substantial respiratory function damage. Patients with coronavirus disease 2019 (COVID-19) have been encountered with a high risk of ARDS, underscoring the urgency for exploiting effective therapy. However, proper medications for ARDS are still lacking due to poor pharmacokinetics, non-specific side effects, inability to surmount pulmonary barrier, and inadequate management of heterogeneity. The increased lung permeability in the pathological environment of ARDS may contribute to nanoparticle-mediated passive targeting delivery. Nanomedicine has demonstrated unique advantages in solving the dilemma of ARDS drug therapy, which can address the shortcomings and limitations of traditional anti-inflammatory or antioxidant drug treatment. Through passive, active, or physicochemical targeting, nanocarriers can interact with lung epithelium/endothelium and inflammatory cells to reverse abnormal changes and restore homeostasis of the pulmonary environment, thereby showing good therapeutic activity and reduced toxicity. This article reviews the latest applications of nanomedicine in pre-clinical ARDS therapy, highlights the strategies for targeted treatment of lung inflammation, presents the innovative drug delivery systems, and provides inspiration for strengthening the therapeutic effect of nanomedicine-based treatment.
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Key Words
- ACE2, angiotensin-converting enzyme 2
- AEC II, alveolar type II epithelial cells
- AM, alveolar macrophages
- ARDS, acute respiratory distress syndrome
- Acute lung injury
- Acute respiratory distress syndrome
- Anti-inflammatory therapy
- BALF, bronchoalveolar lavage fluid
- BSA, bovine serum albumin
- CD, cyclodextrin
- CLP, cecal ligation and perforation
- COVID-19
- COVID-19, coronavirus disease 2019
- DOPE, phosphatidylethanolamine
- DOTAP, 1-diolefin-3-trimethylaminopropane
- DOX, doxorubicin
- DPPC, dipalmitoylphosphatidylcholine
- Drug delivery
- ECM, extracellular matrix
- ELVIS, extravasation through leaky vasculature and subsequent inflammatory cell-mediated sequestration
- EPCs, endothelial progenitor cells
- EPR, enhanced permeability and retention
- EVs, extracellular vesicles
- EphA2, ephrin type-A receptor 2
- Esbp, E-selectin-binding peptide
- FcgR, Fcγ receptor
- GNP, peptide-gold nanoparticle
- H2O2, hydrogen peroxide
- HO-1, heme oxygenase-1
- ICAM-1, intercellular adhesion molecule-1
- IKK, IκB kinase
- IL, interleukin
- LPS, lipopolysaccharide
- MERS, Middle East respiratory syndrome
- MPMVECs, mouse pulmonary microvascular endothelial cells
- MPO, myeloperoxidase
- MSC, mesenchymal stem cells
- NAC, N-acetylcysteine
- NE, neutrophil elastase
- NETs, neutrophil extracellular traps
- NF-κB, nuclear factor-κB
- Nanomedicine
- PC, phosphatidylcholine
- PCB, poly(carboxybetaine)
- PDA, polydopamine
- PDE4, phosphodiesterase 4
- PECAM-1, platelet-endothelial cell adhesion molecule
- PEG, poly(ethylene glycol)
- PEI, polyetherimide
- PEVs, platelet-derived extracellular vesicles
- PLGA, poly(lactic-co-glycolic acid)
- PS-PEG, poly(styrene-b-ethylene glycol)
- Pathophysiologic feature
- RBC, red blood cells
- RBD, receptor-binding domains
- ROS, reactive oxygen species
- S1PLyase, sphingosine-1-phosphate lyase
- SARS, severe acute respiratory syndrome
- SARS-CoV-2, severe acute respiratory syndrome coronavirus 2
- SDC1, syndecan-1
- SORT, selective organ targeting
- SP, surfactant protein
- Se, selenium
- Siglec, sialic acid-binding immunoglobulin-like lectin
- TLR, toll-like receptor
- TNF-α, tumor necrosis factor-α
- TPP, triphenylphosphonium cation
- Targeting strategy
- YSA, YSAYPDSVPMMS
- cRGD, cyclic arginine glycine-d-aspartic acid
- iNOS, inducible nitric oxide synthase
- rSPANb, anti-rat SP-A nanobody
- scFv, single chain variable fragments
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Affiliation(s)
- Qi Qiao
- Tongji School of Pharmacy, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Xiong Liu
- Tongji School of Pharmacy, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Ting Yang
- Tongji School of Pharmacy, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Kexin Cui
- Tongji School of Pharmacy, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Li Kong
- Tongji School of Pharmacy, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Conglian Yang
- Tongji School of Pharmacy, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Zhiping Zhang
- Tongji School of Pharmacy, Huazhong University of Science and Technology, Wuhan 430030, China
- National Engineering Research Center for Nanomedicine, Huazhong University of Science and Technology, Wuhan 430030, China
- Hubei Engineering Research Center for Novel Drug Delivery System, Huazhong University of Science and Technology, Wuhan 430030, China
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Swaminathan M, Kopyt N, Atta MG, Radhakrishnan J, Umanath K, Nguyen S, O'Rourke B, Allen A, Vaninov N, Tilles A, LaPointe E, Blair A, Gemmiti C, Miller B, Parekkadan B, Barcia RN. Pharmacological effects of ex vivo mesenchymal stem cell immunotherapy in patients with acute kidney injury and underlying systemic inflammation. Stem Cells Transl Med 2021; 10:1588-1601. [PMID: 34581517 PMCID: PMC8641088 DOI: 10.1002/sctm.21-0043] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2021] [Revised: 06/07/2021] [Accepted: 06/30/2021] [Indexed: 01/20/2023] Open
Abstract
Mesenchymal stem cells (MSCs) have natural immunoregulatory functions that have been explored for medicinal use as a cell therapy with limited success. A phase Ib study was conducted to evaluate the safety and immunoregulatory mechanism of action of MSCs using a novel ex vivo product (SBI-101) to preserve cell activity in patients with severe acute kidney injury. Pharmacological data demonstrated MSC-secreted factor activity that was associated with anti-inflammatory signatures in the molecular and cellular profiling of patient blood. Systems biology analysis captured multicompartment effects consistent with immune reprogramming and kidney tissue repair. Although the study was not powered for clinical efficacy, these results are supportive of the therapeutic hypothesis, namely, that treatment with SBI-101 elicits an immunotherapeutic response that triggers an accelerated phenotypic switch from tissue injury to tissue repair. Ex vivo administration of MSCs, with increased power of testing, is a potential new biological delivery paradigm that assures sustained MSC activity and immunomodulation.
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Affiliation(s)
- Madhav Swaminathan
- Department of Anesthesiology, Duke University School of Medicine, Duke University, Durham, North Carolina, USA
| | - Nelson Kopyt
- Nephrology Section, Department of Medicine, Lehigh Valley Health Network, Allentown, Pennsylvania, USA
| | - Mohamed G Atta
- Department of Medicine, Division of Nephrology, Johns Hopkins School of Medicine, Baltimore, Maryland, USA
| | - Jai Radhakrishnan
- Columbia University Medical Center, Division of Nephrology, NY Presbyterian Hospital/Columbia, New York, New York, USA
| | - Kausik Umanath
- Division of Nephrology and Hypertension, Henry Ford Hospital, Detroit, Michigan, USA.,Division of Nephrology and Hypertension, Wayne State University, Detroit, Michigan, USA
| | - Sunny Nguyen
- Sentien Biotechnologies, Lexington, Massachusetts, USA
| | | | - Ashley Allen
- Sentien Biotechnologies, Lexington, Massachusetts, USA
| | | | - Arno Tilles
- Sentien Biotechnologies, Lexington, Massachusetts, USA
| | | | - Andrew Blair
- Sentien Biotechnologies, Lexington, Massachusetts, USA
| | - Chris Gemmiti
- Sentien Biotechnologies, Lexington, Massachusetts, USA
| | - Brian Miller
- Sentien Biotechnologies, Lexington, Massachusetts, USA
| | - Biju Parekkadan
- Sentien Biotechnologies, Lexington, Massachusetts, USA.,Department of Surgery, Center for Surgery, Innovation, and Bioengineering, Massachusetts General Hospital, Harvard Medical School and Shriners Hospitals for Children, Boston, Massachusetts, USA.,Harvard Stem Cell Institute, Cambridge, Massachusetts, USA.,Department of Biomedical Engineering, Rutgers University, Piscataway, New Jersey, USA
| | - Rita N Barcia
- Sentien Biotechnologies, Lexington, Massachusetts, USA
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Rasouli M, Vakilian F, Ranjbari J. Therapeutic and protective potential of mesenchymal stem cells, pharmaceutical agents and current vaccines against covid-19. Curr Stem Cell Res Ther 2021; 17:166-185. [PMID: 33349221 DOI: 10.2174/1574888x16666201221151853] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2021] [Revised: 07/07/2021] [Accepted: 07/19/2021] [Indexed: 11/22/2022]
Abstract
It has been almost 18 months since the first outbreak of COVID-19 disease was reported in Wuhan, China. This unexpected devastating phenomenon, raised a great deal of concerns and anxiety among people around the world and imposed a huge economic burden on the nations' health care systems. Accordingly, clinical scientists, pharmacologists and physicians worldwide felt an urgent demand for a safe, effective therapeutic agent, treatment strategy or vaccine in order to prevent or cure the recently-emerged disease. Initially, due to lack of specific pharmacological agents and approved vaccines to combat the COVID-19, the disease control in the confirmed cases was limited to supportive care. Accordingly, repositioning or repurposing current drugs and examining their possible therapeutic efficacy received a great deal of attention. Despite revealing promising results in some clinical trials, the overall results are conflicting. For this reason, there is an urgent to seek and investigate other potential therapeutics. Mesenchymal stem cells (MSC) representing immunomodulatory and regenerative capacity to treat both curable and intractable diseases, have been investigated in COVID-19 clinical trials carried out in different parts of the world. Nevertheless, up to now, none of MSC-based approaches has been approved in controlling COVID-19 infection. Thanks to the fact that the final solution for defeating the pandemic is developing a safe, effective vaccine, enormous efforts and clinical research have been carried out. In this review, we will concisely discuss the safety and efficacy of the most relevant pharmacological agents, MSC-based approaches and candidate vaccines for treating and preventing COVID-19 infection.
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Affiliation(s)
- Mehdi Rasouli
- Department of Tissue Engineering and Applied Cell Sciences, School of Advanced Technologies in Medicine, Shahid Beheshti University of Medical Sciences, Tehran. Iran
| | | | - Javad Ranjbari
- Department of Medical Biotechnology, School of Advanced Technologies in Medicine, Shahid Beheshti University of Medical Sciences, Tehran. Iran
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Zhang LS, Yu Y, Yu H, Han ZC. Therapeutic prospects of mesenchymal stem/stromal cells in COVID-19 associated pulmonary diseases: From bench to bedside. World J Stem Cells 2021; 13:1058-1071. [PMID: 34567425 PMCID: PMC8422925 DOI: 10.4252/wjsc.v13.i8.1058] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/08/2021] [Revised: 03/10/2021] [Accepted: 04/21/2021] [Indexed: 02/06/2023] Open
Abstract
The ongoing outbreak of coronavirus disease 2019 (COVID-19) caused by the novel severe acute respiratory syndrome coronavirus 2 has become a sudden public emergency of international concern and seriously threatens millions of people’s life health. Two current studies have indicated a favorable role for mesenchymal stem/stromal cells (MSCs) in clinical remission of COVID-19 associated pulmonary diseases, yet the systematical elaboration of the therapeutics and underlying mechanism is far from satisfaction. In the present review, we summarize the therapeutic potential of MSCs in COVID-19 associated pulmonary diseases such as pneumonia induced acute lung injury, acute respiratory distress syndrome, and pulmonary fibrosis. Furthermore, we review the underlying mechanism of MSCs including direct- and trans-differentiation, autocrine and paracrine anti-inflammatory effects, homing, and neovascularization, as well as constitutive microenvironment. Finally, we discuss the prospects and supervision of MSC-based cytotherapy for COVID-19 management before large-scale application in clinical practice. Collectively, this review supplies overwhelming new references for understanding the landscapes of MSCs in the remission of COVID-19 associated pulmonary diseases.
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Affiliation(s)
- Lei-Sheng Zhang
- Qianfoshan Hospital & The First Affiliated Hospital, Shandong First Medical University, Jinan 250014, Shandong Province, China
- State Key Laboratory of Experimental Hematology & National Clinical Research Center for Blood Disease, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin 300020, China
- School of Medicine, Nankai University, Tianjin 300071, China
- Precision Medicine Division, Health-Biotech (Tianjin) Stem Cell Research Institute Co., Ltd., Tianjin 301700, China
| | - Yi Yu
- State Key Laboratory of Experimental Hematology & National Clinical Research Center for Blood Disease, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin 300020, China
- The First Affiliated Hospital, Zhejiang University, Hangzhou 310003, Zhejiang Province, China
| | - Hao Yu
- School of Medicine, Nankai University, Tianjin 300071, China
- Cell Products of National Engineering Center & National Stem Cell Engineering Research Center, Tianjin IMCELL Stem Cell and Gene Technology Co., Ltd., Tianjin 300457, China
| | - Zhong-Chao Han
- State Key Laboratory of Experimental Hematology & National Clinical Research Center for Blood Disease, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin 300020, China
- Precision Medicine Division, Health-Biotech (Tianjin) Stem Cell Research Institute Co., Ltd., Tianjin 301700, China
- Cell Products of National Engineering Center & National Stem Cell Engineering Research Center, Tianjin IMCELL Stem Cell and Gene Technology Co., Ltd., Tianjin 300457, China
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45
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O Ercelen N, Pekkoc-Uyanik KC, Alpaydin N, Gulay GR, Simsek M. Clinical experience on umbilical cord mesenchymal stem cell treatment in 210 severe and critical COVID-19 cases in Turkey. Stem Cell Rev Rep 2021; 17:1917-1925. [PMID: 34319510 PMCID: PMC8317476 DOI: 10.1007/s12015-021-10214-x] [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] [Accepted: 06/24/2021] [Indexed: 12/17/2022]
Abstract
Objective Treatment for COVID-19 is still urgent need for the critically ill and severe cases. UC-MSC administration has a therapeutic benefit for severe COVID-19 patients even in the recovery period. In this paper, we aimed to present our clinical experience with UC-MSC treatment in severe and critical severe COVID-19 patients. Methods In this study we evaluated the clinical outcome of severe/critically severe 210 COVID-19 patients treated with UC-MSCs, 1–2 × 106 per kilogram to 210 patients from 15/10/2020 until 25/04/2021. Results Out of 99 critically severe intubated patients we have observed good clinical progress/discharged from ICU in 52 (52.5%) patients. Where as 86 (77.5%) of 111 severe unintubated patients discharged from ICU. Intubated 47 (47.5%) patients and unintubated 25 (22.5%) patients pass away. Significantly higher survival was observed in patients who underwent UC-MSCs before intubation (OR = 1.475, 95% CI = 1.193–1.824 p < 0.001). It was observed that the SaO2 parameter tended to improve after UC-MSC therapy compared to all groups. But SaO2 parameter between intubated and unintubated groups was not statistically significant (p > 0.05), while in discharged cases SaO2 parameter was statistically significant (p = 0.01). Besides, there was a statistically significant relation with intubation status, age (OR = 3.868, 95% CI = 0.574–7.152 p = 0.02) and weigh (OR = 6.768, 95% CI = 3.423–10.112 p < 0.001) thus presented an elevated risk for COVID-19. The linear regression analysis confirmed that the high weight was associated with the risk of intubation in COVID-19 (p = 0.001). Conclusions According to our results and from recent studies, UC-MSC treatment is safe with high potential to be used as an added therapeutic treatment for severe COVID-19 patients. Our experience showed that UC-MSC therapy may restore oxygenation and downregulate cytokine storm in patients hospitalized with severe COVID-19. We advice wider randomised studies to discover the detailed therapeutic pathophysiology of the MSCs on COVID-19 patients. Graphical abstract MSCs transplantation improves the damaging effects of the cytokine storm through immunomodulation and improving tissue and organ repair. Severe patients who were unintubated were in the Phase I, while critical patients who were intubated were in the Phase II. The figure is created via biorender application, (BioRender.com).
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Affiliation(s)
- Nesrin O Ercelen
- Department of Medical Genetics, Faculty of Medicine, Haliç University, İstanbul, Turkey.
| | | | | | | | - Murat Simsek
- Geneis, Genetic System Solutions, İstanbul, Turkey
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da Silva KN, Gobatto ALN, Costa-Ferro ZSM, Cavalcante BRR, Caria ACI, de Aragão França LS, Nonaka CKV, de Macêdo Lima F, Lopes-Pacheco M, Rocco PRM, de Freitas Souza BS. Is there a place for mesenchymal stromal cell-based therapies in the therapeutic armamentarium against COVID-19? Stem Cell Res Ther 2021; 12:425. [PMID: 34315546 PMCID: PMC8314259 DOI: 10.1186/s13287-021-02502-7] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2021] [Accepted: 07/04/2021] [Indexed: 02/07/2023] Open
Abstract
The COVID-19 pandemic, caused by the rapid global spread of the novel coronavirus (SARS-CoV-2), has caused healthcare systems to collapse and led to hundreds of thousands of deaths. The clinical spectrum of COVID-19 is not only limited to local pneumonia but also represents multiple organ involvement, with potential for systemic complications. One year after the pandemic, pathophysiological knowledge has evolved, and many therapeutic advances have occurred, but mortality rates are still elevated in severe/critical COVID-19 cases. Mesenchymal stromal cells (MSCs) can exert immunomodulatory, antiviral, and pro-regenerative paracrine/endocrine actions and are therefore promising candidates for MSC-based therapies. In this review, we discuss the rationale for MSC-based therapies based on currently available preclinical and clinical evidence of safety, potential efficacy, and mechanisms of action. Finally, we present a critical analysis of the risks, limitations, challenges, and opportunities that place MSC-based products as a therapeutic strategy that may complement the current arsenal against COVID-19 and reduce the pandemic's unmet medical needs.
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Affiliation(s)
- Kátia Nunes da Silva
- Goncalo Moniz Institute, Oswaldo Cruz Foundation (FIOCRUZ), Rua Waldemar Falcão, 121, Candeal, Salvador, Bahia, 40296-710, Brazil
- D'Or Institute for Research and Education (IDOR), Salvador, Brazil
- Center for Biotechnology and Cell Therapy, São Rafael Hospital, Salvador, Brazil
| | | | - Zaquer Suzana Munhoz Costa-Ferro
- D'Or Institute for Research and Education (IDOR), Salvador, Brazil
- Center for Biotechnology and Cell Therapy, São Rafael Hospital, Salvador, Brazil
| | - Bruno Raphael Ribeiro Cavalcante
- Goncalo Moniz Institute, Oswaldo Cruz Foundation (FIOCRUZ), Rua Waldemar Falcão, 121, Candeal, Salvador, Bahia, 40296-710, Brazil
| | - Alex Cleber Improta Caria
- Graduate Program in Medicine and Health, Faculty of Medicine, Federal University of Bahia, Salvador, Brazil
| | - Luciana Souza de Aragão França
- D'Or Institute for Research and Education (IDOR), Salvador, Brazil
- Center for Biotechnology and Cell Therapy, São Rafael Hospital, Salvador, Brazil
| | - Carolina Kymie Vasques Nonaka
- D'Or Institute for Research and Education (IDOR), Salvador, Brazil
- Center for Biotechnology and Cell Therapy, São Rafael Hospital, Salvador, Brazil
| | | | - Miquéias Lopes-Pacheco
- Laboratory of Pulmonary Investigation, Carlos Chagas Filho Institute of Biophysics, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil
| | - Patricia Rieken Macêdo Rocco
- Laboratory of Pulmonary Investigation, Carlos Chagas Filho Institute of Biophysics, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil
- National Institute of Science and Technology for Regenerative Medicine, Rio de Janeiro, Rio de Janeiro, Brazil
- COVID-19 Virus Network, Ministry of Science and Technology, and Innovation, Rio de Janeiro, Brazil
| | - Bruno Solano de Freitas Souza
- Goncalo Moniz Institute, Oswaldo Cruz Foundation (FIOCRUZ), Rua Waldemar Falcão, 121, Candeal, Salvador, Bahia, 40296-710, Brazil.
- D'Or Institute for Research and Education (IDOR), Salvador, Brazil.
- Center for Biotechnology and Cell Therapy, São Rafael Hospital, Salvador, Brazil.
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Mesenchymal Stem Cell-Based Therapy as an Alternative to the Treatment of Acute Respiratory Distress Syndrome: Current Evidence and Future Perspectives. Int J Mol Sci 2021; 22:ijms22157850. [PMID: 34360616 PMCID: PMC8346146 DOI: 10.3390/ijms22157850] [Citation(s) in RCA: 44] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2021] [Revised: 07/17/2021] [Accepted: 07/19/2021] [Indexed: 12/25/2022] Open
Abstract
Acute respiratory distress syndrome (ARDS) represents a current challenge for medicine due to its incidence, morbidity and mortality and, also, the absence of an optimal treatment. The COVID-19 outbreak only increased the urgent demand for an affordable, safe and effective treatment for this process. Early clinical trials suggest the therapeutic usefulness of mesenchymal stem cells (MSCs) in acute lung injury (ALI) and ARDS. MSC-based therapies show antimicrobial, anti-inflammatory, regenerative, angiogenic, antifibrotic, anti-oxidative stress and anti-apoptotic actions, which can thwart the physiopathological mechanisms engaged in ARDS. In addition, MSC secretome and their derived products, especially exosomes, may reproduce the therapeutic effects of MSC in lung injury. This last strategy of treatment could avoid several safety issues potentially associated with the transplantation of living and proliferative cell populations and may be formulated in different forms. However, the following diverse limitations must be addressed: (i) selection of the optimal MSC, bearing in mind both the heterogeneity among donors and across different histological origins, (ii) massive obtention of these biological products through genetic manipulations of the most appropriate MSC, (iii) bioreactors that allow their growth in 3D, (iv) ideal culture conditions and (v) adequate functional testing of these obtaining biological products before their clinical application.
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48
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Aitong W, Leisheng Z, Hao Y. Visualized analyses of investigations upon mesenchymal stem/stromal cell-based cytotherapy and underlying mechanisms for COVID-19 associated ARDS. Curr Stem Cell Res Ther 2021; 17:2-12. [PMID: 34254927 DOI: 10.2174/1574888x16666210712212421] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2021] [Revised: 05/09/2021] [Accepted: 05/11/2021] [Indexed: 11/22/2022]
Abstract
The outbreak of coronavirus disease 2019 (COVID-19) triggered by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has become a widespread pandemic globally and seriously threatened the public health. Patients with COVID-19 infection, and in particular, those with severe pneumonia-associated acute respiratory distress syndrome (ARDS) manifested rapid disease progression and the resultant high mortality and morbidity. Advances in fundamental and clinical studies have suggested the feasibility of mesenchymal stem/stromal cell (MSC)-based therapy as an inspiring alternative for ARDS administration. However, the systematic characteristics of the MSC-based cytotherapy and underlying mechanism for COVID-19 associated ARDS by bibliometric analyses are still unknowable. Herein, we took advantage of visual analyses to reveal the overview of ARDS-associated updates, core authors and focused issues, as well as to summarize the comprehensive knowledge of the keywords, authors, institutions with the aid of indicated software. Meanwhile, we have provided a brief overview on the molecular mechanisms and discussed the safety and efficacy of MSC-based therapy for ARDS on the basis of clinical trials.
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Affiliation(s)
- Wang Aitong
- National Engineering Research Center of Cell Products, AmCellGene Engineering Co., Ltd, Tianjin 300457, China
| | - Zhang Leisheng
- Institute of Stem Cells, Health-Biotech (Tianjin) Stem Cell Research Institute Co., Ltd., Tianjin, 301700, China
| | - Yu Hao
- The Postdoctoral Research Station, School of Medicine, Nankai University, Tianjin, 300071, China
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49
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Zhang Q, Huang K, Lv J, Fang X, He J, Lv A, Sun X, Cheng L, Zhong Y, Wu S, Dai Y. Case Report: Human Umbilical Cord Mesenchymal Stem Cells as a Therapeutic Intervention for a Critically Ill COVID-19 Patient. Front Med (Lausanne) 2021; 8:691329. [PMID: 34307417 PMCID: PMC8298026 DOI: 10.3389/fmed.2021.691329] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2021] [Accepted: 05/31/2021] [Indexed: 01/22/2023] Open
Abstract
Here we report a critically ill patient who was cured of SARS-CoV-2 infection in Changsha, China. A 66-year-old Chinese woman, with no significant past medical history, developed severe pneumonia-like symptoms and later diagnosed as severe COVID-19 pneumonia. Within 2 months of hospitalization, the patient deteriorated to ARDS including pulmonary edema and SIRS with septic shock. When treatment schemes such as antibiotics plus corticosteroids showed diminished therapeutic value, hUCMSC therapy was compassionately prescribed under the patient's consent of participation. After treatment, there was significant improvement in disease inflammation-related indicators such as IL-4, IL-6, and IL-10. Eventually, it confirmed the therapeutic value that hUCMSCs could dampen the cytokine storm in the critically ill COVID-19 patient and modulated the NK cells. In the continued hUCMSC treatment, gratifying results were achieved in the follow-up of the patient. The data we acquired anticipate a significant therapeutic value of MSC treatment in severe and critically ill patients with COVID-19, while further studies are needed.
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Affiliation(s)
- Quan Zhang
- Department of Pulmonary and Critical Care Medicine, The Second Xiangya Hospital, Central South University, Changsha, China
| | - Kang Huang
- Department of Critical Care Medicine, First Hospital of Changsha, Changsha, China
| | - Jianlei Lv
- Department of Critical Care Medicine, First Hospital of Changsha, Changsha, China
| | - Xiang Fang
- Department of Critical Care Medicine, First Hospital of Changsha, Changsha, China
| | - Jun He
- Department of Critical Care Medicine, First Hospital of Changsha, Changsha, China
| | - Ailian Lv
- Department of Critical Care Medicine, First Hospital of Changsha, Changsha, China
| | - Xuan Sun
- School of Basic Medical Sciences, Institute of Reproductive and Stem Cell Engineering, Central South University, Changsha, China
- National Engineering and Research Center of Human Stem Cells, Changsha, China
| | - Lamei Cheng
- School of Basic Medical Sciences, Institute of Reproductive and Stem Cell Engineering, Central South University, Changsha, China
- National Engineering and Research Center of Human Stem Cells, Changsha, China
| | - Yanjun Zhong
- Department of Critical Care Medicine, The Second Xiangya Hospital, Central South University, Changsha, China
| | - Shangjie Wu
- Department of Pulmonary and Critical Care Medicine, The Second Xiangya Hospital, Central South University, Changsha, China
| | - Yao Dai
- Department of Critical Care Medicine, First Hospital of Changsha, Changsha, China
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50
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Alloreactive Immune Response Associated to Human Mesenchymal Stromal Cells Treatment: A Systematic Review. J Clin Med 2021; 10:jcm10132991. [PMID: 34279481 PMCID: PMC8269175 DOI: 10.3390/jcm10132991] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2021] [Revised: 07/01/2021] [Accepted: 07/01/2021] [Indexed: 02/06/2023] Open
Abstract
The well-known immunomodulatory and regenerative properties of mesenchymal stromal cells (MSCs) are the reason why they are being used for the treatment of many diseases. Because they are considered hypoimmunogenic, MSCs treatments are performed without considering histocompatibility barriers and without anticipating possible immune rejections. However, recent preclinical studies describe the generation of alloantibodies and the immune rejection of MSCs. This has led to an increasing number of clinical trials evaluating the immunological profile of patients after treatment with MSCs. The objective of this systematic review was to evaluate the generation of donor specific antibodies (DSA) after allogeneic MSC (allo-MSC) therapy and the impact on safety or tolerability. Data from 555 patients were included in the systematic review, 356 were treated with allo-MSC and the rest were treated with placebo or control drugs. A mean of 11.51% of allo-MSC-treated patients developed DSA. Specifically, 14.95% of these patients developed DSA and 6.33% of them developed cPRA. Neither the production of DSA after treatment nor the presence of DSA at baseline (presensitization) were correlated with safety and/or tolerability of the treatment. The number of doses administrated and human leucocyte antigen (HLA) mismatches between donor and recipient did not affect the production of DSA. The safety of allo-MSC therapy has been proved in all the studies and the generation of alloantibodies might not have clinical relevance. However, there are very few studies in the area. More studies with adequate designs are needed to confirm these results.
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