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Martínez-Muñoz ME, Payares-Herrera C, Lipperheide I, Malo de Molina R, Salcedo I, Alonso R, Martín-Donaire T, Sánchez R, Zafra R, García-Berciano M, Trisán-Alonso A, Pérez-Torres M, Ramos-Martínez A, Ussetti P, Rubio JJ, Avendaño-Solà C, Duarte RF. Mesenchymal stromal cell therapy for COVID-19 acute respiratory distress syndrome: a double-blind randomised controlled trial. Bone Marrow Transplant 2024; 59:777-784. [PMID: 38409332 DOI: 10.1038/s41409-024-02230-5] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2023] [Revised: 01/23/2024] [Accepted: 01/25/2024] [Indexed: 02/28/2024]
Abstract
Mesenchymal stromal cells (MSC) have immunomodulatory and tissue-regenerative properties and have shown promising results in acute respiratory distress syndrome (ARDS) of multiple causes, including COVID-19. We conducted a randomised (1:1), placebo-controlled, double-blind clinical trial to assess the efficacy and safety of one bone marrow-derived MSC infusion in twenty patients with moderate to severe ARDS caused by COVID-19. The primary endpoint (increase in PaO2/FiO2 ratio from baseline to day 7, MSC 83.3 versus placebo 57.6) was not statistically significant, although a clinical improvement at day 7 in the WHO scale was observed in MSC patients (5, 50% vs 0, 0%, p = 0.033). Median time to discontinuation of supplemental oxygen was also shorter in the experimental arm (14 versus 23 days, p = 0.007), resulting in a shorter hospital stay (17.5 versus 28 days, p = 0.042). No significant differences were observed for other efficacy or safety secondary endpoints. No infusion or treatment-related serious adverse events occurred during the one-year follow-up. This study did not meet the primary endpoint of PaO2/FiO2 increase by day 7, although it suggests that MSC are safe in COVID-19 ARDS and may accelerate patients' clinical recovery and hospital discharge. Larger studies are warranted to elucidate their role in ARDS and other inflammatory lung disorders.Trial Registration: EudraCT Number: 2020-002193-27, registered on July 14th, 2020, https://www.clinicaltrialsregister.eu/ctr-search/trial/2020-002193-27/ES . NCT number: NCT04615429, registered on November 4th, 2020, https://clinicaltrials.gov/ct2/show/NCT04615429 .
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Affiliation(s)
- María E Martínez-Muñoz
- Department of Haematology and GMP Cellular Therapy Unit, Hospital Universitario Puerta de Hierro Majadahonda, Madrid, Spain
- Instituto de Investigación Sanitaria Puerta de Hierro Segovia Arana, Madrid, Spain
| | - Concepción Payares-Herrera
- Instituto de Investigación Sanitaria Puerta de Hierro Segovia Arana, Madrid, Spain
- Department of Clinical Pharmacology, Hospital Universitario Puerta de Hierro Majadahonda, Madrid, Spain
| | - Inés Lipperheide
- Intensive Care Unit, Hospital Universitario Puerta de Hierro Majadahonda, Madrid, Spain
| | - Rosa Malo de Molina
- Department of Pneumology, Hospital Universitario Puerta de Hierro Majadahonda, Madrid, Spain
| | - Isabel Salcedo
- Department of Haematology and GMP Cellular Therapy Unit, Hospital Universitario Puerta de Hierro Majadahonda, Madrid, Spain
- Instituto de Investigación Sanitaria Puerta de Hierro Segovia Arana, Madrid, Spain
| | - Rosalía Alonso
- Instituto de Investigación Sanitaria Puerta de Hierro Segovia Arana, Madrid, Spain
| | - Trinidad Martín-Donaire
- Department of Haematology and GMP Cellular Therapy Unit, Hospital Universitario Puerta de Hierro Majadahonda, Madrid, Spain
- Instituto de Investigación Sanitaria Puerta de Hierro Segovia Arana, Madrid, Spain
| | - Rocío Sánchez
- Department of Haematology and GMP Cellular Therapy Unit, Hospital Universitario Puerta de Hierro Majadahonda, Madrid, Spain
- Instituto de Investigación Sanitaria Puerta de Hierro Segovia Arana, Madrid, Spain
| | - Rocío Zafra
- Department of Haematology and GMP Cellular Therapy Unit, Hospital Universitario Puerta de Hierro Majadahonda, Madrid, Spain
- Instituto de Investigación Sanitaria Puerta de Hierro Segovia Arana, Madrid, Spain
| | - Miguel García-Berciano
- Department of Haematology and GMP Cellular Therapy Unit, Hospital Universitario Puerta de Hierro Majadahonda, Madrid, Spain
- Instituto de Investigación Sanitaria Puerta de Hierro Segovia Arana, Madrid, Spain
| | - Andrea Trisán-Alonso
- Department of Pneumology, Hospital Universitario Puerta de Hierro Majadahonda, Madrid, Spain
| | - Manuel Pérez-Torres
- Intensive Care Unit, Hospital Universitario Puerta de Hierro Majadahonda, Madrid, Spain
| | - Antonio Ramos-Martínez
- Instituto de Investigación Sanitaria Puerta de Hierro Segovia Arana, Madrid, Spain
- Department of Internal Medicine and Infectious Diseases, Hospital Universitario Puerta de Hierro Majadahonda, Madrid, Spain
| | - Piedad Ussetti
- Instituto de Investigación Sanitaria Puerta de Hierro Segovia Arana, Madrid, Spain
- Department of Pneumology, Hospital Universitario Puerta de Hierro Majadahonda, Madrid, Spain
| | - Juan J Rubio
- Intensive Care Unit, Hospital Universitario Puerta de Hierro Majadahonda, Madrid, Spain
| | - Cristina Avendaño-Solà
- Instituto de Investigación Sanitaria Puerta de Hierro Segovia Arana, Madrid, Spain
- Department of Clinical Pharmacology, Hospital Universitario Puerta de Hierro Majadahonda, Madrid, Spain
| | - Rafael F Duarte
- Department of Haematology and GMP Cellular Therapy Unit, Hospital Universitario Puerta de Hierro Majadahonda, Madrid, Spain.
- Instituto de Investigación Sanitaria Puerta de Hierro Segovia Arana, Madrid, Spain.
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Chen J, Ma S, Luo B, Hao H, Li Y, Yang H, Zhu F, Zhang P, Niu R, Pan P. Human umbilical cord mesenchymal stromal cell small extracellular vesicle transfer of microRNA-223-3p to lung epithelial cells attenuates inflammation in acute lung injury in mice. J Nanobiotechnology 2023; 21:295. [PMID: 37626408 PMCID: PMC10464265 DOI: 10.1186/s12951-023-02038-3] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2023] [Accepted: 07/31/2023] [Indexed: 08/27/2023] Open
Abstract
BACKGROUND Acute lung injury (ALI), manifested as strong pulmonary inflammation and alveolar epithelial damage, is a life-threatening disease with high morbidity and mortality. Small extracellular vesicles (sEVs), secreted by multiple types of cells, are critical cellular communication mediators and can inhibit inflammation by transferring bioactive molecules, such as microRNAs (miRNAs). Thus, we hypothesized that sEVs derived from mesenchymal stromal cells (MSC sEVs) could transfer miRNAs to attenuate inflammation of lung epithelial cells during ALI. METHODS C57BL/6 male mice were intratracheally administered LPS (10 mg/kg). Six hours later, the mice were randomly administered with MSC sEVs (40 µg per mouse in 150 µl of saline), which were collected by ultracentrifugation. Control group received saline administration. After 48 h, the mice were sacrificed to evaluate pulmonary microvascular permeability and inflammatory responses. In vitro, A549 cells and primary human small airway epithelial cells (SAECs) were stimulated with LPS with or without MSC sEVs treatment. RESULTS In vitro, MSC sEVs could also inhibit the inflammation induced by LPS in A549 cells and SAECs (reducing TNF-α, IL-1β, IL-6 and MCP-1). Moreover, MSC sEV treatment improved the survival rate, alleviated pulmonary microvascular permeability, and inhibited proinflammatory responses (reducing TNF-α, IL-1β, IL-6 and JE-1) in ALI mice. Notably, miR-223-3p was found to be served as a critical mediator in MSC sEV-induced regulatory effects through inhibition of poly (adenosine diphosphate-ribose) polymerase-1 (PARP-1) in lung epithelial cells. CONCLUSIONS Overall, these findings suggest that MSC sEVs may offer a novel promising strategy for ALI.
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Affiliation(s)
- Jie Chen
- Department of Respiratory Medicine, Clinical Research Center for Respiratory Disease, Xiangya Hospital, National Key Clinical Specialty, Branch of National, Central South University, No.28 Xiangya Road, Kai-Fu District, Changsha, 410008, Hunan, China
- Center of Respiratory Medicine, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, China
- Clinical Research Center for Respiratory Diseases in Hunan Province, Changsha, 410008, Hunan, China
- Hunan Engineering Research Center for Intelligent Diagnosis and Treatment of Respiratory Disease, Chang-sha, 410008, Hunan, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Changsha, 410008, Hunan, P.R. China
| | - Shiyang Ma
- Department of Respiratory Medicine, Clinical Research Center for Respiratory Disease, Xiangya Hospital, National Key Clinical Specialty, Branch of National, Central South University, No.28 Xiangya Road, Kai-Fu District, Changsha, 410008, Hunan, China
- Center of Respiratory Medicine, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, China
- Clinical Research Center for Respiratory Diseases in Hunan Province, Changsha, 410008, Hunan, China
- Hunan Engineering Research Center for Intelligent Diagnosis and Treatment of Respiratory Disease, Chang-sha, 410008, Hunan, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Changsha, 410008, Hunan, P.R. China
| | - Baihua Luo
- Department of Pathology, Xiangya Hospital, Central South University, Changsha, Hunan Province, China
| | - Haojie Hao
- Institute of Basic Medicine Science, Chinese People's Liberation Army General Hospital, Chinese People's Liberation Army Medical College, Beijing, China
| | - Yanqin Li
- Center of Pulmonary & Critical Care Medicine, Chinese People's Liberation Army (PLA) General Hospital, Chinese PLA Medical College, Beijing, China
| | - Hang Yang
- Department of Respiratory Medicine, Clinical Research Center for Respiratory Disease, Xiangya Hospital, National Key Clinical Specialty, Branch of National, Central South University, No.28 Xiangya Road, Kai-Fu District, Changsha, 410008, Hunan, China
- Center of Respiratory Medicine, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, China
- Clinical Research Center for Respiratory Diseases in Hunan Province, Changsha, 410008, Hunan, China
- Hunan Engineering Research Center for Intelligent Diagnosis and Treatment of Respiratory Disease, Chang-sha, 410008, Hunan, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Changsha, 410008, Hunan, P.R. China
| | - Fei Zhu
- Department of Respiratory Medicine, Clinical Research Center for Respiratory Disease, Xiangya Hospital, National Key Clinical Specialty, Branch of National, Central South University, No.28 Xiangya Road, Kai-Fu District, Changsha, 410008, Hunan, China
- Center of Respiratory Medicine, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, China
- Clinical Research Center for Respiratory Diseases in Hunan Province, Changsha, 410008, Hunan, China
- Hunan Engineering Research Center for Intelligent Diagnosis and Treatment of Respiratory Disease, Chang-sha, 410008, Hunan, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Changsha, 410008, Hunan, P.R. China
| | - Peipei Zhang
- Department of Respiratory Medicine, Clinical Research Center for Respiratory Disease, Xiangya Hospital, National Key Clinical Specialty, Branch of National, Central South University, No.28 Xiangya Road, Kai-Fu District, Changsha, 410008, Hunan, China
- Center of Respiratory Medicine, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, China
- Clinical Research Center for Respiratory Diseases in Hunan Province, Changsha, 410008, Hunan, China
- Hunan Engineering Research Center for Intelligent Diagnosis and Treatment of Respiratory Disease, Chang-sha, 410008, Hunan, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Changsha, 410008, Hunan, P.R. China
| | - Ruichao Niu
- Department of Respiratory Medicine, Clinical Research Center for Respiratory Disease, Xiangya Hospital, National Key Clinical Specialty, Branch of National, Central South University, No.28 Xiangya Road, Kai-Fu District, Changsha, 410008, Hunan, China.
- Center of Respiratory Medicine, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, China.
- Clinical Research Center for Respiratory Diseases in Hunan Province, Changsha, 410008, Hunan, China.
- Hunan Engineering Research Center for Intelligent Diagnosis and Treatment of Respiratory Disease, Chang-sha, 410008, Hunan, China.
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Changsha, 410008, Hunan, P.R. China.
- Department of Respiratory Medicine, The Second Affiliated Hospital of Xinjiang Medical University, Xinjiang Uygur Autonomous Region, Urumqi, China.
| | - Pinhua Pan
- Department of Respiratory Medicine, Clinical Research Center for Respiratory Disease, Xiangya Hospital, National Key Clinical Specialty, Branch of National, Central South University, No.28 Xiangya Road, Kai-Fu District, Changsha, 410008, Hunan, China.
- Center of Respiratory Medicine, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, China.
- Clinical Research Center for Respiratory Diseases in Hunan Province, Changsha, 410008, Hunan, China.
- Hunan Engineering Research Center for Intelligent Diagnosis and Treatment of Respiratory Disease, Chang-sha, 410008, Hunan, China.
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Changsha, 410008, Hunan, P.R. China.
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Sanz-Ros J, Mas-Bargues C, Romero-García N, Huete-Acevedo J, Dromant M, Borrás C. Extracellular Vesicles as Therapeutic Resources in the Clinical Environment. Int J Mol Sci 2023; 24:2344. [PMID: 36768664 PMCID: PMC9917082 DOI: 10.3390/ijms24032344] [Citation(s) in RCA: 32] [Impact Index Per Article: 16.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2022] [Revised: 01/19/2023] [Accepted: 01/21/2023] [Indexed: 01/26/2023] Open
Abstract
The native role of extracellular vesicles (EVs) in mediating the transfer of biomolecules between cells has raised the possibility to use them as therapeutic vehicles. The development of therapies based on EVs is now expanding rapidly; here we will describe the current knowledge on different key points regarding the use of EVs in a clinical setting. These points are related to cell sources of EVs, isolation, storage, and delivery methods, as well as modifications to the releasing cells for improved production of EVs. Finally, we will depict the application of EVs therapies in clinical trials, considering the impact of the COVID-19 pandemic on the development of these therapies, pointing out that although it is a promising therapy for human diseases, we are still in the initial phase of its application to patients.
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Affiliation(s)
- Jorge Sanz-Ros
- Freshage Research Group, Department of Physiology, Faculty of Medicine, University of Valencia, Centro de Investigación Biomédica en Red Fragilidad y Envejecimiento Saludable-Instituto de Salud Carlos III (CIBERFES-ISCIII), INCLIVA, 46010 Valencia, Spain
- Department of Cardiology, Hospital Universitari i Politècnic La Fe, 46026 Valencia, Spain
| | - Cristina Mas-Bargues
- Freshage Research Group, Department of Physiology, Faculty of Medicine, University of Valencia, Centro de Investigación Biomédica en Red Fragilidad y Envejecimiento Saludable-Instituto de Salud Carlos III (CIBERFES-ISCIII), INCLIVA, 46010 Valencia, Spain
| | - Nekane Romero-García
- Freshage Research Group, Department of Physiology, Faculty of Medicine, University of Valencia, Centro de Investigación Biomédica en Red Fragilidad y Envejecimiento Saludable-Instituto de Salud Carlos III (CIBERFES-ISCIII), INCLIVA, 46010 Valencia, Spain
- Department of Anesthesiology and Surgical Trauma Intensive Care, Hospital Clinic Universitari de Valencia, University of Valencia, 46010 Valencia, Spain
| | - Javier Huete-Acevedo
- Freshage Research Group, Department of Physiology, Faculty of Medicine, University of Valencia, Centro de Investigación Biomédica en Red Fragilidad y Envejecimiento Saludable-Instituto de Salud Carlos III (CIBERFES-ISCIII), INCLIVA, 46010 Valencia, Spain
| | - Mar Dromant
- Freshage Research Group, Department of Physiology, Faculty of Medicine, University of Valencia, Centro de Investigación Biomédica en Red Fragilidad y Envejecimiento Saludable-Instituto de Salud Carlos III (CIBERFES-ISCIII), INCLIVA, 46010 Valencia, Spain
| | - Consuelo Borrás
- Freshage Research Group, Department of Physiology, Faculty of Medicine, University of Valencia, Centro de Investigación Biomédica en Red Fragilidad y Envejecimiento Saludable-Instituto de Salud Carlos III (CIBERFES-ISCIII), INCLIVA, 46010 Valencia, Spain
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Wang F, Li Y, Wang B, Li J, Peng Z. The safety and efficacy of mesenchymal stromal cells in ARDS: a meta-analysis of randomized controlled trials. Crit Care 2023; 27:31. [PMID: 36670442 PMCID: PMC9857915 DOI: 10.1186/s13054-022-04287-4] [Citation(s) in RCA: 24] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2022] [Accepted: 12/17/2022] [Indexed: 01/22/2023] Open
Abstract
Mesenchymal stromal cells (MSC) have shown potential efficacy in both animal and human trials of acute respiratory distress syndrome (ARDS). Especially during the COVID-19 pandemic, MSC was intensely studied for treating COVID-19-induced ARDS. The purpose of this study is to evaluate the safety and efficacy of MSC in ARDS via a meta-analysis of randomized controlled trials (RCTs). Therefore, a meta-analysis of RCTs of MSC as a therapy for ARDS was conducted. The protocol of this review was registered on Open Science Framework. With no language restriction and according to the "PICOs" principle, searches were conducted on Pubmed and Embase to retrieve any clinical literature on MSC for ARDS. Any RCT, which compared MSC to controls for ARDS, where MSC and controls were intravenously infused, of any dosage, was eligible for inclusion. A total of 13 RCTs, which evaluated MSC versus control for treating ARDS, enrolling a total of 655 cases, met the inclusion criteria and appeared in this meta-analysis. A heterogeneity assessment was carried out using the χ2 test, where a P value less than 0.05 was considered significant. The choice of a fixed-effect or a random-effect model was decided by the I2 value in each of the analyses. This meta-analysis indicated that there was no significant difference in terms of adverse events between MSC and control for ARDS (OR = 0.64, 95% CI [0.34, 1.20], P = 0.17, and I2 = 0%). In comparison with control, MSC could reduce the mortality of ARDS (OR = 0.66, 95% CI [0.46, 0.96], P = 0.03, and I2 = 10%). Based on the results of our meta-analysis, the safety of MSC was demonstrated to be non-inferior to that of standard treatment, and MSC may reduce the mortality rate of ARDS. Though the heterogeneity in the main results was low (I2 < 25%), more high-quality and large-scale clinical trials are needed to further confirm our findings.
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Affiliation(s)
- Fengyun Wang
- grid.49470.3e0000 0001 2331 6153Department of Critical Care Medicine, Zhongnan Hospital, Wuhan University, Wuhan, Hubei Province China ,Clinical Research Center of Hubei Critical Care Medicine, Wuhan, 430071 Hubei China
| | - Yiming Li
- grid.49470.3e0000 0001 2331 6153Department of Critical Care Medicine, Zhongnan Hospital, Wuhan University, Wuhan, Hubei Province China ,Clinical Research Center of Hubei Critical Care Medicine, Wuhan, 430071 Hubei China
| | - Bingqing Wang
- grid.49470.3e0000 0001 2331 6153Department of Critical Care Medicine, Zhongnan Hospital, Wuhan University, Wuhan, Hubei Province China ,Clinical Research Center of Hubei Critical Care Medicine, Wuhan, 430071 Hubei China
| | - Jianguo Li
- grid.49470.3e0000 0001 2331 6153Department of Critical Care Medicine, Zhongnan Hospital, Wuhan University, Wuhan, Hubei Province China ,Clinical Research Center of Hubei Critical Care Medicine, Wuhan, 430071 Hubei China
| | - Zhiyong Peng
- grid.49470.3e0000 0001 2331 6153Department of Critical Care Medicine, Zhongnan Hospital, Wuhan University, Wuhan, Hubei Province China ,Clinical Research Center of Hubei Critical Care Medicine, Wuhan, 430071 Hubei China ,grid.21925.3d0000 0004 1936 9000Department of Critical Care Medicine, Center of Critical Care Nephrology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213 USA
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Askenase PW. Recommendation: Treatment of clinical long COVID encephalopathies with nasal administered mesenchymal stromal cell extracellular vesicles. FRONTIERS IN NANOTECHNOLOGY 2022; 4. [DOI: 10.3389/fnano.2022.987117] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/06/2025] Open
Abstract
We propose therapy with extracellular vesicles (EVs) for dominant central nervous system aspects of chronic Long COVID Syndromes (LCS). These clinical conditions have a delayed onset of 1–3 months following the cessation of active SARS-CoV-2 virus infections that cause an acute disease called COVID-19. The therapy of LCS will be achieved by direct access to the central nervous system (CNS) by nasal administration of small EVs derived from Mesenchymal Stromal Cells (MSC). When administered nasally, they target CNS microglia and endothelia involved in LCS encephalopathy, as indicated by experimental animal models and human autopsy and spinal fluid studies. Underlying this approach is the discovery that MSC-sEV treatment for healing neuro injury targets, microglia, and macrophages that then likely release secondary trophic EVs that affect the local capillary endothelial cells to restore vascular integrity. It is postulated that the pathways of endothelial and neural pathologies in acute SARS-CoV-2 virus infections may carry over to produce underlying vascular and neurological defects mediating LCS that are susceptible to this proposed nasal therapy with MSC-sEVs.
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Mallis P, Chatzistamatiou T, Dimou Z, Sarri EF, Georgiou E, Salagianni M, Triantafyllia V, Andreakos E, Stavropoulos-Giokas C, Michalopoulos E. Mesenchymal stromal cell delivery as a potential therapeutic strategy against COVID-19: Promising evidence from in vitro results. World J Biol Chem 2022; 13:47-65. [PMID: 35432769 PMCID: PMC8966500 DOI: 10.4331/wjbc.v13.i2.47] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/06/2021] [Revised: 12/28/2021] [Accepted: 03/06/2022] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is responsible for the coronavirus disease 2019 (COVID-19) pandemic, which was initiated in December 2019. COVID-19 is characterized by a low mortality rate (< 6%); however, this percentage is higher in elderly people and patients with underlying disorders. COVID-19 is characterized by mild to severe outcomes. Currently, several therapeutic strategies are evaluated, such as the use of anti-viral drugs, prophylactic treatment, monoclonal antibodies, and vaccination. Advanced cellular therapies are also investigated, thus representing an additional therapeutic tool for clinicians. Mesenchymal stromal cells (MSCs), which are known for their immunoregulatory properties, may halt the induced cytokine release syndrome mediated by SARS-CoV-2, and can be considered as a potential stem cell therapy. AIM To evaluate the immunoregulatory properties of MSCs, upon stimulation with COVID-19 patient serum. METHODS MSCs derived from the human Wharton's Jelly (WJ) tissue and bone marrow (BM) were isolated, cryopreserved, expanded, and defined according to the criteria outlined by the International Society for Cellular Therapies. Then, WJ and BM-MSCs were stimulated with a culture medium containing 15% COVID-19 patient serum, 1% penicillin-streptomycin, and 1% L-glutamine for 48 h. The quantification of interleukin (IL)-1 receptor a (Ra), IL-6, IL-10, IL-13, transforming growth factor (TGF)-β1, vascular endothelial growth factor (VEGF)-a, fibroblast growth factor (FGF), platelet-derived growth factor (PDGF), and indoleamine-2,3-dioxygenase (IDO) was performed using commercial ELISA kits. The expression of HLA-G1, G5, and G7 was evaluated in unstimulated and stimulated WJ and BM-MSCs. Finally, the interactions between MSCs and patients' macrophages were established using co-culture experiments. RESULTS Thawed WJ and BM-MSCs exhibited a spindle-shaped morphology, successfully differentiated to "osteocytes", "adipocytes", and "chondrocytes", and in flow cytometric analysis were characterized by positivity for CD73, CD90, and CD105 (> 95%) and negativity for CD34, CD45, and HLA-DR (< 2%). Moreover, stimulated WJ and BM-MSCs were characterized by increased cytoplasmic granulation, in comparison to unstimulated cells. The HLA-G isoforms (G1, G5, and G7) were successfully expressed by the unstimulated and stimulated WJ-MSCs. On the other hand, only weak expression of HLA-G1 was identified in BM-MSCs. Stimulated MSCs secreted high levels of IL-1Ra, IL-6, IL-10, IL-13, TGF-β1, FGF, VEGF, PDGF, and IDO in comparison to unstimulated cells (P < 0.05) after 12 and 24 h. Finally, macrophages derived from COVID-19 patients successfully adapted the M2 phenotype after co-culturing with stimulated WJ and BM-MSCs. CONCLUSION WJ and BM-MSCs successfully produced high levels of immunoregulatory agents, which may efficiently modulate the over-activated immune responses of critically ill COVID-19 patients.
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Affiliation(s)
- Panagiotis Mallis
- Hellenic Cord Blood Bank, Biomedical Research Foundation Academy of Athens, Athens 11527, Greece
| | | | - Zetta Dimou
- Hellenic Cord Blood Bank, Biomedical Research Foundation Academy of Athens, Athens 11527, Greece
| | - Eirini-Faidra Sarri
- Hellenic Cord Blood Bank, Biomedical Research Foundation Academy of Athens, Athens 11527, Greece
| | - Eleni Georgiou
- Hellenic Cord Blood Bank, Biomedical Research Foundation Academy of Athens, Athens 11527, Greece
| | - Maria Salagianni
- Laboratory of Immunobiology, Center for Clinical, Experimental Surgery and Translational Research, Biomedical Research Foundation Academy of Athens, Athens 11527, Greece
| | - Vasiliki Triantafyllia
- Laboratory of Immunobiology, Center for Clinical, Experimental Surgery and Translational Research, Biomedical Research Foundation Academy of Athens, Athens 11527, Greece
| | - Evangelos Andreakos
- Laboratory of Immunobiology, Center for Clinical, Experimental Surgery and Translational Research, Biomedical Research Foundation Academy of Athens, Athens 11527, Greece
| | | | - Efstathios Michalopoulos
- Hellenic Cord Blood Bank, Biomedical Research Foundation Academy of Athens, Athens 11527, Greece
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Lo HY, Cheng SP, Huang JL, Chang KT, Chang YL, Huang CH, Chang CJ, Chiu CH, Chen-Yang YW, Chan CK. High Induction of IL-6 Secretion From hUCMSCs Optimize the Potential of hUCMSCs and TCZ as Therapy for COVID-19-Related ARDS. Cell Transplant 2021; 30:9636897211054481. [PMID: 34757857 PMCID: PMC8586187 DOI: 10.1177/09636897211054481] [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] [Indexed: 11/17/2022] Open
Abstract
Biological and cellular interleukin-6 (IL-6)-related therapies have been used to treat severe COVID-19 pneumonia with hyperinflammatory syndrome and acute respiratory failure, which prompted further exploration of the role of IL-6 in human umbilical cord mesenchymal stem cell (hUCMSC) therapy. Peripheral blood mononuclear cells (PBMCs) were responders cocultured with hUCMSCs or exogenous IL-6. A PBMC suppression assay was used to analyze the anti-inflammatory effects via MTT assay. The IL-6 concentration in the supernatant was measured using ELISA. The correlation between the anti-inflammatory effect of hUCMSCs and IL-6 levels and the relevant roles of IL-6 and IL-6 mRNA expression was analyzed using the MetaCore functional network constructed from gene microarray data. The location of IL-6 and IL-6 receptor (IL-6R) expression was further evaluated. We reported that hUCMSCs did not initially exert any inhibitory effect on PHA-stimulated proliferation; however, a potent inhibitory effect on PHA-stimulated proliferation was observed, and the IL-6 concentration reached approximately 1000 ng/mL after 72 hours. Exogenous 1000 ng/mL IL-6 inhibited PHA-stimulated inflammation but less so than hUCMSCs. The inhibitory effects of hUCMSCs on PHA-stimulated PBMCs disappeared after adding an IL-6 neutralizing antibody or pretreatment with tocilizumab (TCZ), an IL-6R antagonist. hUCMSCs exert excellent anti-inflammatory effects by inducing higher IL-6 levels, which is different from TCZ. High concentration of IL-6 cytokine secretion plays an important role in the anti-inflammatory effect of hUCMSC therapy. Initial hUCMSC therapy, followed by TCZ, seems to optimize the therapeutic potential to treat COVID-19-related acute respiratory distress syndrome (ARDS).
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Affiliation(s)
- Huei-Yu Lo
- Department of Rehabilitation, Taoyuan General Hospital, Ministry of Health and Welfare, Taoyuan.,Department of Chemistry, Chung Yuan Christian University, Taoyuan.,Translational Medicine Center, Taoyuan General Hospital, Ministry of Health and Welfare, Taoyuan
| | - Shun-Ping Cheng
- Department of Rehabilitation, Taoyuan General Hospital, Ministry of Health and Welfare, Taoyuan.,Translational Medicine Center, Taoyuan General Hospital, Ministry of Health and Welfare, Taoyuan
| | - Jing-Long Huang
- Division of Allergy, Asthma and Rheumatology, Department of Pediatrics, Chang Gung Memorial Hospital, Taoyuan
| | - Kuo-Ting Chang
- Translational Medicine Center, Taoyuan General Hospital, Ministry of Health and Welfare, Taoyuan
| | - Yu-Lung Chang
- Translational Medicine Center, Taoyuan General Hospital, Ministry of Health and Welfare, Taoyuan.,Department of Urology, Taoyuan General Hospital, Ministry of Health and Welfare, Taoyuan.,Department of Urology, School of Medicine, National Yang-Ming University, Taipei
| | - Chien-Hsun Huang
- Department of Obstetrics & Gynecology, Taoyuan General Hospital, Ministry of Health and Welfare, Taoyuan
| | - Chia-Jen Chang
- Translational Medicine Center, Taoyuan General Hospital, Ministry of Health and Welfare, Taoyuan.,Department of Food Science, Fu Jen Catholic University, New Taipei City
| | - Chien-Hua Chiu
- Translational Medicine Center, Taoyuan General Hospital, Ministry of Health and Welfare, Taoyuan
| | | | - Chin-Kan Chan
- Translational Medicine Center, Taoyuan General Hospital, Ministry of Health and Welfare, Taoyuan.,Department of Pediatrics, Taoyuan General Hospital, Ministry of Health and Welfare, Taoyuan.,Department of Biotechnology, Ming Chuan University, Taoyuan
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8
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Ligotti ME, Pojero F, Accardi G, Aiello A, Caruso C, Duro G, Candore G. Immunopathology and Immunosenescence, the Immunological Key Words of Severe COVID-19. Is There a Role for Stem Cell Transplantation? Front Cell Dev Biol 2021; 9:725606. [PMID: 34595175 PMCID: PMC8477205 DOI: 10.3389/fcell.2021.725606] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2021] [Accepted: 08/06/2021] [Indexed: 01/08/2023] Open
Abstract
The outcomes of Coronavirus disease-2019 (COVID-19) vary depending on the age, health status and sex of an individual, ranging from asymptomatic to lethal. From an immunologic viewpoint, the final severe lung damage observed in COVID-19 should be caused by cytokine storm, driven mainly by interleukin-6 and other pro-inflammatory cytokines. However, which immunopathogenic status precedes this "cytokine storm" and why the male older population is more severely affected, are currently unanswered questions. The aging of the immune system, i.e., immunosenescence, closely associated with a low-grade inflammatory status called "inflammageing," should play a key role. The remodeling of both innate and adaptive immune response observed with aging can partly explain the age gradient in severity and mortality of COVID-19. This review discusses how aging impacts the immune response to the virus, focusing on possible strategies to rejuvenate the immune system with stem cell-based therapies. Indeed, due to immunomodulatory and anti-inflammatory properties, multipotent mesenchymal stem cells (MSCs) are a worth-considering option against COVID-19 adverse outcomes.
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Affiliation(s)
- Mattia Emanuela Ligotti
- Laboratory of Immunopathology and Immunosenescence, Department of Biomedicine, Neurosciences and Advanced Diagnostics, University of Palermo, Palermo, Italy
- Institute for Biomedical Research and Innovation, National Research Council of Italy, Palermo, Italy
| | - Fanny Pojero
- Laboratory of Immunopathology and Immunosenescence, Department of Biomedicine, Neurosciences and Advanced Diagnostics, University of Palermo, Palermo, Italy
| | - Giulia Accardi
- Laboratory of Immunopathology and Immunosenescence, Department of Biomedicine, Neurosciences and Advanced Diagnostics, University of Palermo, Palermo, Italy
| | - Anna Aiello
- Laboratory of Immunopathology and Immunosenescence, Department of Biomedicine, Neurosciences and Advanced Diagnostics, University of Palermo, Palermo, Italy
| | - Calogero Caruso
- Laboratory of Immunopathology and Immunosenescence, Department of Biomedicine, Neurosciences and Advanced Diagnostics, University of Palermo, Palermo, Italy
- International Society on Aging and Disease, Fort Worth, TX, United States
| | - Giovanni Duro
- Institute for Biomedical Research and Innovation, National Research Council of Italy, Palermo, Italy
| | - Giuseppina Candore
- Laboratory of Immunopathology and Immunosenescence, Department of Biomedicine, Neurosciences and Advanced Diagnostics, University of Palermo, Palermo, Italy
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9
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Moradinasab S, Pourbagheri-Sigaroodi A, Zafari P, Ghaffari SH, Bashash D. Mesenchymal stromal/stem cells (MSCs) and MSC-derived extracellular vesicles in COVID-19-induced ARDS: Mechanisms of action, research progress, challenges, and opportunities. Int Immunopharmacol 2021; 97:107694. [PMID: 33932694 PMCID: PMC8079337 DOI: 10.1016/j.intimp.2021.107694] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2021] [Revised: 04/11/2021] [Accepted: 04/17/2021] [Indexed: 02/06/2023]
Abstract
In late 2019, a novel coronavirus (SARS-CoV-2) emerged in Wuhan city, Hubei province, China. Rapidly escalated into a worldwide pandemic, it has caused an unprecedented and devastating situation on the global public health and society economy. The severity of recent coronavirus disease, abbreviated to COVID-19, seems to be mostly associated with the patients' immune response. In this vein, mesenchymal stromal/stem cells (MSCs) have been suggested as a worth-considering option against COVID-19 as their therapeutic properties are mainly displayed in immunomodulation and anti-inflammatory effects. Indeed, administration of MSCs can attenuate cytokine storm and enhance alveolar fluid clearance, endothelial recovery, and anti-fibrotic regeneration. Despite advantages attributed to MSCs application in lung injuries, there are still several issues __foremost probability of malignant transformation and incidence of MSCs-related coagulopathy__ which should be resolved for the successful application of MSC therapy in COVID-19. In the present study, we review the historical evidence of successful use of MSCs and MSC-derived extracellular vesicles (EVs) in the treatment of acute respiratory distress syndrome (ARDS). We also take a look at MSCs mechanisms of action in the treatment of viral infections, and then through studying both the dark and bright sides of this approach, we provide a thorough discussion if MSC therapy might be a promising therapeutic approach in COVID-19 patients.
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Affiliation(s)
- Susan Moradinasab
- Iranian Blood Transfusion Research Center, High Institute for Research and Education in Transfusion Medicine, Tehran, Iran
| | - Atieh Pourbagheri-Sigaroodi
- Department of Hematology and Blood Banking, School of Allied Medical Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Parisa Zafari
- Department of Immunology, Faculty of Medicine, Mazandaran University of Medical Sciences, Sari, Iran
| | - Seyed H Ghaffari
- Hematology, Oncology and Stem Cell Transplantation Research Center, Shariati Hospital, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Davood Bashash
- Department of Hematology and Blood Banking, School of Allied Medical Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
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10
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Wang LT, Liu KJ, Sytwu HK, Yen ML, Yen BL. Advances in mesenchymal stem cell therapy for immune and inflammatory diseases: Use of cell-free products and human pluripotent stem cell-derived mesenchymal stem cells. Stem Cells Transl Med 2021; 10:1288-1303. [PMID: 34008922 PMCID: PMC8380447 DOI: 10.1002/sctm.21-0021] [Citation(s) in RCA: 80] [Impact Index Per Article: 20.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2021] [Revised: 03/31/2021] [Accepted: 04/20/2021] [Indexed: 02/06/2023] Open
Abstract
Mesenchymal stem cell therapy (MSCT) for immune and inflammatory diseases continues to be popular based on progressive accumulation of preclinical mechanistic evidence. This has led to further expansion in clinical indications from graft rejection, autoimmune diseases, and osteoarthritis, to inflammatory liver and pulmonary diseases including COVID‐19. A clear trend is the shift from using autologous to allogeneic MSCs, which can be immediately available as off‐the‐shelf products. In addition, new products such as cell‐free exosomes and human pluripotent stem cell (hPSC)‐derived MSCs are exciting developments to further prevalent use. Increasing numbers of trials have now published results in which safety of MSCT has been largely demonstrated. While reports of therapeutic endpoints are still emerging, efficacy can be seen for specific indications—including graft‐vs‐host‐disease, strongly Th17‐mediated autoimmune diseases, and osteoarthritis—which are more robustly supported by mechanistic preclinical evidence. In this review, we update and discuss outcomes in current MSCT clinical trials for immune and inflammatory disease, as well as new innovation and emerging trends in the field.
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Affiliation(s)
- Li-Tzu Wang
- Department of Obstetrics & Gynecology, National Taiwan University (NTU) Hospital & College of Medicine, NTU, Taipei, Taiwan, Republic of China
| | - Ko-Jiunn Liu
- National Institute of Cancer Research, National Health Research Institutes (NHRI), Tainan, Taiwan, Republic of China
| | - Huey-Kang Sytwu
- National Institute of Infectious Diseases & Vaccinology, NHRI, Zhunan, Taiwan, Republic of China.,Department & Graduate Institute of Microbiology & Immunology, National Defense Medical Center, Taipei, Taiwan, Republic of China
| | - Men-Luh Yen
- Department of Obstetrics & Gynecology, National Taiwan University (NTU) Hospital & College of Medicine, NTU, Taipei, Taiwan, Republic of China
| | - B Linju Yen
- Regenerative Medicine Research Group, Institute of Cellular & System Medicine, NHRI, Zhunan, Taiwan, Republic of China
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11
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Abstract
PURPOSE OF REVIEW Severe acute respiratory syndrome coronavirus-2-induced hyperinflammation is a major cause of death or end-organ dysfunction in COVID-19 patients. We review adjunct host-directed therapies (HDTs) for COVID-19 management. RECENT FINDINGS The use of umbilical cord-derived mesenchymal stem cells as HDT for COVID-19 has been shown to be safe in phase 1 and 2 trials. Trials of anti-interleukin-6 receptor antibodies show promising mortality benefit in hospitalized COVID-19 patients. Repurposed drugs and monoclonal antibodies targeting specific cytokines acting on different aspects of the pro- and anti-inflammatory cascades are under evaluation. SUMMARY A range of HDTs shows promise for reducing mortality and improving long term disability in patients with severe COVID-19, and require evaluation in randomized, controlled trials.
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Affiliation(s)
- Markus Maeurer
- ImmunoSurgery Unit, Champalimaud Centre for the Unknown, Lisbon, Portugal
- I Medizinische Klinik, Johannes Gutenberg University Mainz, Germany
| | - Renata Ramalho
- Egas Moniz Higher Education School, Instituto Universitário Egas Moniz, Centro de Investigação Interdisciplinar Egas Moniz (CiiEM, U4585-FCT), Applied Nutrition Studies Group (G.E.N.A.-IUEM), Monte de Caparica, Portugal
| | - Fu-Sheng Wang
- Treatment and Research Center for Infectious Diseases, The Fifth Medical Center of PLA General Hospital, National Clinical Research Center for Infectious Diseases, Beijing, China
| | - Alimuddin Zumla
- Department of Infection, Division of Infection and Immunity, University College London, and National Institutes of Health and Research Biomedical Research Centre, University College London Hospitals NHS Foundation Trust, London, UK
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