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Sarvepalli S, Vadarevu S. Non-antiviral therapies for viral infections: Harnessing host mechanisms. Int Immunopharmacol 2025; 153:114521. [PMID: 40139096 DOI: 10.1016/j.intimp.2025.114521] [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: 01/14/2025] [Revised: 03/01/2025] [Accepted: 03/17/2025] [Indexed: 03/29/2025]
Abstract
Despite advancements in the field of directly acting anti-viral (DAA) therapies, viral infections still continue to pose significant global health challenges. The efficacy of DAAs are often hindered by mutations, origin of new strains, development of resistance and lack of broad spectrum effectiveness. Furthermore, patients with advanced-stage diseases may require higher doses and combinations of different DAA therapies, raising concerns about tolerability and safety. To overcome all these constraints, non-antiviral therapies that focuses on host mechanisms (also known as host-focused therapies) are emerging as an innovative approach. Host focused therapy aims to target the host molecules and pathways that are essential for viral infection and disease progression. Along with addressing the above mentioned challenges, these host focused therapies can also modulate excessive inflammatory responses. Recent advancements in understanding host-virus interactions and the pathways involved in the pathogenesis of severe viral infections from viral entry and replication to disease progression, have accelerated the development of host-focused therapies aimed at combating these infections. This review explores the growing rationale and various opportunities for host-focused therapies for severe viral infections including zika virus, dengue, HIV, influenza, and covid-19 to name a few. In addition, current clinical trial information on various classes of host focused therapies are presented, highlighting their therapeutic potential and significance in the field.
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Affiliation(s)
- Sruthi Sarvepalli
- College of Pharmacy and Health Sciences, St John's University, United States.
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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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Zendedel E, Tayebi L, Nikbakht M, Hasanzadeh E, Asadpour S. Clinical Trials of Mesenchymal Stem Cells for the Treatment of COVID 19. Curr Stem Cell Res Ther 2024; 19:1055-1071. [PMID: 37815188 DOI: 10.2174/011574888x260032230925052240] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2023] [Revised: 07/14/2023] [Accepted: 07/31/2023] [Indexed: 10/11/2023]
Abstract
Mesenchymal Stem Cells (MSCs) are being investigated as a treatment for a novel viral disease owing to their immunomodulatory, anti-inflammatory, tissue repair and regeneration characteristics, however, the exact processes are unknown. MSC therapy was found to be effective in lowering immune system overactivation and increasing endogenous healing after SARS-CoV-2 infection by improving the pulmonary microenvironment. Many studies on mesenchymal stem cells have been undertaken concurrently, and we may help speed up the effectiveness of these studies by collecting and statistically analyzing data from them. Based on clinical trial information found on clinicaltrials. gov and on 16 November 2020, which includes 63 clinical trials in the field of patient treatment with COVID-19 using MSCs, according to the trend of increasing studies in this field, and with the help of meta-analysis studies, it is possible to hope that the promise of MSCs will one day be realized. The potential therapeutic applications of MSCs for COVID-19 are investigated in this study.
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Affiliation(s)
- Elham Zendedel
- Department of Tissue Engineering and Applied Cell Sciences, School of Advanced Technologies in Medicine, Shahrekord University of Medical Sciences, Shahrekord, Iran
| | - Lobat Tayebi
- Marquett University School of Dentistry, Milwaukee, WI, 53233, USA
| | - Mohammad Nikbakht
- Department of Medical Biotechnology, School of Advanced Technologies, Shahrekord University of Medical Sciences, Shahrekord, Iran
| | - Elham Hasanzadeh
- Immunogenetics Research Center, Department of Tissue Engineering & Regenerative Medicine, School of Advanced Technologies in Medicine, Mazandaran University of Medical Sciences, Sari, Iran
| | - Shiva Asadpour
- Department of Tissue Engineering and Applied Cell Sciences, School of Advanced Technologies in Medicine, Shahrekord University of Medical Sciences, Shahrekord, Iran
- Cellular and Molecular Research Center, Basic Health Sciences Institute, Shahrekord University of Medical Sciences, Shahrekord, Iran
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de Dios C, Vij R, Kim H, Park H, Chang D. Safety of multiple intravenous infusions of adipose-derived mesenchymal stem cells for hospitalized cases of COVID-19: a randomized controlled trial. Front Med (Lausanne) 2023; 10:1321303. [PMID: 38188343 PMCID: PMC10770855 DOI: 10.3389/fmed.2023.1321303] [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: 10/16/2023] [Accepted: 12/08/2023] [Indexed: 01/09/2024] Open
Abstract
Objective The purpose of the study was to assess the safety of allogeneic, Hope Biosciences Adipose Derived Mesenchymal Stem Cells (HB-adMSCs) for the treatment of hospitalized subjects with COVID-19. Methods N = 48 patients were randomly assigned to HB-adMSC (100 MM) or placebo group. Four intravenous infusions of HB-adMSCs or saline were administered at days 0, 3, 7, 10. The primary safety endpoint was incidence of adverse and serious adverse events (AE/SAEs); secondary endpoints were incidence of specific AEs and alterations in hematology, biochemistry, and coagulation parameters. Results Majority of AEs were mild in severity. HB-adMSC group showed a higher incidence of cardiopulmonary failure, anemia, anxiety, and diarrhea, while placebo group showed a higher incidence of headaches, fatigue, and chest discomfort (posterior probabilities ≥80%). Deaths were attributed to severe complications due to COVID-19 and were unrelated to study drug. No AEs were attributed to the treatment. Hematology and coagulation panel alterations were not associated with HB-adMSCs. Analyses of inflammatory markers showed increased levels of interleukin-6 and C-reactive protein over time in HB-adMSC group (posterior probabilities ≥78%). Conclusion Multiple infusions of 100MM allogeneic HB-adMSCs were considered safe for the study population. More research is needed to determine the safety of MSC therapy. Clinical trial registration (www.ClinicalTrials.gov) identifier NCT04362189.
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Affiliation(s)
- Constanza de Dios
- Department of Psychiatry and Behavioral Sciences, University of Texas Health Science Center, Houston, TX, United States
| | - Ridhima Vij
- Hope Biosciences Research Foundation, Sugar Land, TX, United States
| | - Hosu Kim
- Hope Biosciences, Sugar Land, TX, United States
| | | | - Donna Chang
- Hope Biosciences Research Foundation, Sugar Land, TX, United States
- Hope Biosciences, Sugar Land, TX, United States
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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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Paganelli A, Diomede F, Marconi GD, Pizzicannella J, Rajan TS, Trubiani O, Paganelli R. Inhibition of LPS-Induced Inflammatory Response of Oral Mesenchymal Stem Cells in the Presence of Galectin-3. Biomedicines 2023; 11:1519. [PMID: 37371614 DOI: 10.3390/biomedicines11061519] [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: 04/17/2023] [Revised: 05/18/2023] [Accepted: 05/22/2023] [Indexed: 06/29/2023] Open
Abstract
Galectin-3 (GAL-3) is a beta-galactoside binding lectin produced by mesenchymal stem cells (MSCs) and other cell sources under inflammatory conditions. Several studies have reported that GAL-3 exerts an anti-inflammatory action, regulated by its natural ligand GAL-3 BP. In the present study, we aimed to assess the GAL-3 mediated regulation of the MSC function in an LPS-induced inflammation setting. Human gingival mesenchymal stem cells (hGMSCs) were stimulated in vitro with LPSs; the expression of TLR4, NFκB p65, MyD88 and NALP3 were assessed in the hGMSCs via immunofluorescence imaging using confocal microscopy, Western blot assay, and RT-PCR before and after the addition of GAL-3, both alone and with the addition of its inhibitors. LPSs stimulated the expression of TLR4, NFκB p65, MyD88 and NALP3 in hGMSCs, which was inhibited by GAL-3. The addition of either GAL3-BP or the antibody to GAL-3 were able to revert the GAL-3-mediated effects, restoring the expression of TLR4, NFκB p65, MyD88 and NALP3. GAL-3 induces the downregulation of the LPS-induced inflammatory program in MSCs.
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Affiliation(s)
- Alessia Paganelli
- PhD Course in Clinical and Experimental Medicine, Department of Biomedical, Metabolic and Neural Sciences, University of Modena and Reggio Emilia, 41124 Modena, Italy
| | - Francesca Diomede
- Department of Innovative Technologies in Medicine and Dentistry, University "G. d'Annunzio" Chieti-Pescara, 66100 Chieti, Italy
| | - Guya Diletta Marconi
- Department of Innovative Technologies in Medicine and Dentistry, University "G. d'Annunzio" Chieti-Pescara, 66100 Chieti, Italy
| | - Jacopo Pizzicannella
- Department of Engineering and Geology, University "G. d'Annunzio" Chieti-Pescara, Viale Pindaro, 42, 65127 Pescara, Italy
| | - Thangavelu Soundara Rajan
- Research and Development Unit, Theertha Biopharma Private Limited, KIADB, Industrial Area, Bommasandra, Jigani Link Road, Bangalore 560105, India
| | - Oriana Trubiani
- Department of Innovative Technologies in Medicine and Dentistry, University "G. d'Annunzio" Chieti-Pescara, 66100 Chieti, Italy
| | - Roberto Paganelli
- Saint Camillus International University of Health and Medical Sciences (UniCamillus), 00131 Rome, Italy
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Pizon K, Hampal S, Orzechowska K, Muhammad SN. A Review of Pathology and Analysis of Approaches to Easing Kidney Disease Impact: Host-Pathogen Communication and Biomedical Visualization Perspective : Advanced Microscopy and Visualization of Host-Pathogen Communication. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2023; 1406:41-57. [PMID: 37016110 DOI: 10.1007/978-3-031-26462-7_3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 04/06/2023]
Abstract
INTRODUCTION In addition to affecting the upper respiratory tract, severe acute respiratory syndrome-coronavirus (SARS-CoV) and SARS-CoV-2) can target kidneys resulting in disease impact. There is a lack of effective treatment for SARs-CoV and SARS-CoV-2, and so one approach could be to consider to lower the probable risk and onset of disease amongst immunocompromised and immunosuppressed individuals and patients. Angiotensin Converting Enzyme 2 (ACE2) has a promising impact including acting against SARs-CoV and SARS-CoV-2 symptoms. Current literature states that ACE2 is expressed across several physiological systems, including the lungs, cardiovascular, gut, kidneys, and central nervous, and across endothelia. AIMS This chapter seeks to investigate causes and potential mechanisms during SARS infection (CoV-2), renal interaction, and the effects of acute kidney Injury (AKI). OBJECTIVES This chapter will provide an overview of microscopy and visualization of host-pathogen communication and principles of ACE2 in the context of immunology and impact on renal pathophysiology. DESIGN This chapter focuses to provide basic principles of ACE2 and the analysis and effect of immunology and pathological components important in relation to SARs infection. DISCUSSION There has been a surge in literature surrounding mechanisms attributing to SARS-CoV and SARS-CoV-2 action on immune response to pathogens. There is an advantage to implementing ACE2 treatment to improve immune response against infection. CONCLUSION ACE2 may provide appropriate strategies for the management of symptoms that relate to SARS-CoV and SARS-CoV-2 in most immunocompromised or immunosuppressed patients. Visualization of ACE2 action can be achieved through microscopy to understand host-pathogen communication.
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Affiliation(s)
- Kacper Pizon
- Department of Life Sciences, Coventry University, Coventry, England, UK
- The Renal Patient Support Group (RPSG), Coventry, England, UK
| | - Savita Hampal
- Department of Life Sciences, Coventry University, Coventry, England, UK
- The Renal Patient Support Group (RPSG), Coventry, England, UK
| | - Kamila Orzechowska
- Department of Life Sciences, Coventry University, Coventry, England, UK
- The Renal Patient Support Group (RPSG), Coventry, England, UK
| | - Shahid Nazir Muhammad
- Department of Health, and Life Sciences, Coventry University, Coventry, England, UK.
- University Hospitals Bristol NHS Foundation Trust, Bristol, England, UK.
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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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Grumet M, Sherman J, Dorf BS. Efficacy of MSC in Patients with Severe COVID-19: Analysis of the Literature and a Case Study. Stem Cells Transl Med 2022; 11:1103-1112. [PMID: 36181766 PMCID: PMC9672850 DOI: 10.1093/stcltm/szac067] [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: 05/16/2022] [Accepted: 07/23/2022] [Indexed: 12/12/2022] Open
Abstract
Patients with severe COVID-19 experience cytokine storm, an uncontrolled upregulation of pro-inflammatory cytokines, which if unresolved leads to acute respiratory distress syndrome (ARDS), organ damage, and death. Treatments with mesenchymal stromal cells (MSC) [Viswanathan S, Shi Y, Galipeau J, et al. Mesenchymal stem versus stromal cells: International Society for Cell & Gene Therapy Mesenchymal Stromal Cell committee position statement on nomenclature. Cytotherapy. 2019;21:1019-1024] appear to be effective in reducing morbidity and mortality. MSC respond to pro-inflammatory cytokines by releasing anti-inflammatory factors and mobilizing immune cells. We analyzed 82 COVID-19 clinical trials registered at ClinicalTrials.gov to determine MSC dosing, routes of administration, and outcome measures. Nearly all trials described the use of intravenous delivery with most doses ranging between 50 and 125 million MSC/treatment, which overlaps with a minimal effective dose range that we described previously. We also searched the literature to analyze clinical trial reports that used MSC to treat COVID-19. MSC were found to improve survival and oxygenation, increase discharge from intensive care units and hospitals, and reduce levels of pro-inflammatory markers. We report on a 91-year-old man with severe COVID-19 who responded rapidly to MSC treatment with transient reductions in several pro-inflammatory markers and delayed improvement in oxygenation. The results suggest that frequent monitoring of pro-inflammatory markers for severe COVID-19 will provide improved treatment guidelines by determining relationships between cytokine storms and ARDS. We propose that markers for cytokine storm are leading indicators for ARDS and that measurement of cytokines will indicate earlier treatment with MSC than is performed now for ARDS in severe COVID-19.
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Affiliation(s)
- Martin Grumet
- W. M. Keck Center for Collaborative Neuroscience, Rutgers Stem Cell Research Center, Department of Cell Biology & Neuroscience, Rutgers University, Piscataway, NJ, USA
| | - Jason Sherman
- W. M. Keck Center for Collaborative Neuroscience, Rutgers Stem Cell Research Center, Department of Cell Biology & Neuroscience, Rutgers University, Piscataway, NJ, USA
| | - Barry S Dorf
- W. M. Keck Center for Collaborative Neuroscience, Rutgers Stem Cell Research Center, Department of Cell Biology & Neuroscience, Rutgers University, Piscataway, NJ, USA.,Department of Medicine, North Shore University Hospital, 300 Community Dr, Manhasset, NY, USA
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Bors LA, Orsolits B, Ahmed NM, Cho H, Merkely B, Földes G. SARS-CoV-2 infection in cardiovascular disease: Unmet need of stem cell models. Physiol Int 2022. [PMID: 36057101 DOI: 10.1556/2060.2022.00010] [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: 01/20/2022] [Revised: 03/12/2022] [Accepted: 04/25/2022] [Indexed: 02/18/2024]
Abstract
This review aims to summarise new approaches in SARS-CoV-2-related research in cardiology. We provide a head-to-head comparison of models, such as animal research and human pluripotent stem cells, to investigate the pathomechanisms of COVID-19 and find an efficient therapy. In vivo methods were useful for studying systemic processes of the disease; however, due to differences in animal and human biology, the clinical translation of the results remains a complex task. In vitro stem cell research makes cellular events more observable and effective for finding new drugs and therapies for COVID-19, including the use of stem cells. Furthermore, multicellular 3D organoids even make it possible to observe the effects of drugs to treat SARS-CoV-2 infection in human organ models.
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Affiliation(s)
- Luca Anna Bors
- Heart and Vascular Center, Semmelweis University, Budapest, Hungary
| | - Barbara Orsolits
- Heart and Vascular Center, Semmelweis University, Budapest, Hungary
| | | | - Hyunsoo Cho
- Heart and Vascular Center, Semmelweis University, Budapest, Hungary
| | - Béla Merkely
- Heart and Vascular Center, Semmelweis University, Budapest, Hungary
| | - Gábor Földes
- Heart and Vascular Center, Semmelweis University, Budapest, Hungary
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Linkova DD, Rubtsova YP, Egorikhina MN. Cryostorage of Mesenchymal Stem Cells and Biomedical Cell-Based Products. Cells 2022; 11:cells11172691. [PMID: 36078098 PMCID: PMC9454587 DOI: 10.3390/cells11172691] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2022] [Revised: 08/15/2022] [Accepted: 08/24/2022] [Indexed: 11/16/2022] Open
Abstract
Mesenchymal stem cells (MSCs) manifest vast opportunities for clinical use due both to their ability for self-renewal and for effecting paracrine therapeutic benefits. At the same time, difficulties with non-recurrent generation of large numbers of cells due to the necessity for long-term MSC expansion ex vivo, or the requirement for repeated sampling of biological material from a patient significantly limits the current use of MSCs in clinical practice. One solution to these problems entails the creation of a biobank using cell cryopreservation technology. This review is aimed at analyzing and classifying literature data related to the development of protocols for the cryopreservation of various types of MSCs and tissue-engineered structures. The materials in the review show that the existing techniques and protocols for MSC cryopreservation are very diverse, which significantly complicates standardization of the entire process. Here, the selection of cryoprotectors and of cryoprotective media shows the greatest variability. Currently, it is the cryopreservation of cell suspensions that has been studied most extensively, whereas there are very few studies in the literature on the freezing of intact tissues or of tissue-engineered structures. However, even now it is possible to develop general recommendations to optimize the cryopreservation process, making it less traumatic for cells.
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12
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Yao W, Shi L, Zhang Y, Dong H, Zhang Y. Mesenchymal stem/stromal cell therapy for COVID-19 pneumonia: potential mechanisms, current clinical evidence, and future perspectives. Stem Cell Res Ther 2022; 13:124. [PMID: 35321737 PMCID: PMC8942612 DOI: 10.1186/s13287-022-02810-6] [Citation(s) in RCA: 12] [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: 11/11/2021] [Accepted: 02/07/2022] [Indexed: 12/20/2022] Open
Abstract
The coronavirus disease 2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has spread into more than 200 countries and infected approximately 203 million people globally. COVID-19 is associated with high mortality and morbidity in some patients, and this disease still does not have effective treatments with reproducibly appreciable outcomes. One of the leading complications associated with COVID-19 is acute respiratory distress syndrome (ARDS); this is an anti-viral host inflammatory response, and it is usually caused by a cytokine storm syndrome which may lead to multi-organ failure and death. Currently, COVID-19 patients are treated with approaches that mostly fall into two major categories: immunomodulators, which promote the body's fight against viruses efficiently, and antivirals, which slow or stop viruses from multiplying. These treatments include a variety of novel therapies that are currently being tested in clinical trials, including serum, IL-6 antibody, and remdesivir; however, the outcomes of these therapies are not consistently appreciable and remain a subject of debate. Mesenchymal stem/stromal cells (MSCs), the multipotent stem cells that have previously been used to treat viral infections and various respiratory diseases such as ARDS exhibit immunomodulatory properties and can ameliorate tissue damage. Given that SARS-CoV-2 targets the immune system and causes tissue damage, it is presumable that MSCs are being explored to treat COVID-19 patients. This review summarizes the potential mechanisms of action of MSC therapy, progress of MSC, and its related products in clinical trials for COVID-19 therapy based on the outcomes of these clinical studies.
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Affiliation(s)
- Weiqi Yao
- Department of Hematology, Union Hospital, Tong Ji Medical College, Hua Zhong University of Science and Technology, Hubei, China
- State Industrial Base for Stem Cell Engineering Products, No. 12 Meiyuan Road, Tianjin, 300384, China
- Hubei Engineering Research Center for Human Stem Cell Preparation, Application and Resource Preservation, Wuhan, China
| | - Lei Shi
- Department of Infectious Diseases, Fifth Medical Center of Chinese, PLA General Hospital, National Clinical Research Center for Infectious Diseases, Beijing, China
| | - Yun Zhang
- State Industrial Base for Stem Cell Engineering Products, No. 12 Meiyuan Road, Tianjin, 300384, China
- Tianjin Key Laboratory for Stem Cell and Regenerative Medicine, Tianjin, China
| | - Haibo Dong
- Hubei Engineering Research Center for Human Stem Cell Preparation, Application and Resource Preservation, Wuhan, China
- Wuhan Optics Valley VCANBIO Cell & Gene Technology Co., Ltd., Hubei, China
| | - Yu Zhang
- State Industrial Base for Stem Cell Engineering Products, No. 12 Meiyuan Road, Tianjin, 300384, China.
- Hubei Engineering Research Center for Human Stem Cell Preparation, Application and Resource Preservation, Wuhan, China.
- Tianjin Key Laboratory for Stem Cell and Regenerative Medicine, Tianjin, China.
- Tianjin Key Laboratory for Blood Cell Therapy Technology, Tianjin, China.
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13
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Mesenchymal stem cell-based treatments for COVID-19: status and future perspectives for clinical applications. Cell Mol Life Sci 2022; 79:142. [PMID: 35187617 PMCID: PMC8858603 DOI: 10.1007/s00018-021-04096-y] [Citation(s) in RCA: 29] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2021] [Revised: 11/17/2021] [Accepted: 12/13/2021] [Indexed: 01/08/2023]
Abstract
As a result of cross-species transmission in December 2019, the coronavirus disease 2019 (COVID-19) became a serious endangerment to human health and the causal agent of a global pandemic. Although the number of infected people has decreased due to effective management, novel methods to treat critical COVID-19 patients are still urgently required. This review describes the origins, pathogenesis, and clinical features of COVID-19 and the potential uses of mesenchymal stem cells (MSCs) in therapeutic treatments for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-infected patients. MSCs have previously been shown to have positive effects in the treatment of lung diseases, such as acute lung injury, idiopathic pulmonary fibrosis, acute respiratory distress syndrome, lung cancer, asthma, and chronic obstructive pulmonary disease. MSC mechanisms of action involve differentiation potentials, immune regulation, secretion of anti-inflammatory factors, migration and homing, anti-apoptotic properties, antiviral effects, and extracellular vesicles. Currently, 74 clinical trials are investigating the use of MSCs (predominately from the umbilical cord, bone marrow, and adipose tissue) to treat COVID-19. Although most of these trials are still in their early stages, the preliminary data are promising. However, long-term safety evaluations are still lacking, and large-scale and controlled trials are required for more conclusive judgments regarding MSC-based therapies. The main challenges and prospective directions for the use of MSCs in clinical applications are discussed herein. In summary, while the clinical use of MSCs to treat COVID-19 is still in the preliminary stages of investigation, promising results indicate that they could potentially be utilized in future treatments.
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14
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Paganelli A, Trubiani O, Diomede F, Pisciotta A, Paganelli R. Immunomodulating Profile of Dental Mesenchymal Stromal Cells: A Comprehensive Overview. FRONTIERS IN ORAL HEALTH 2022; 2:635055. [PMID: 35047993 PMCID: PMC8757776 DOI: 10.3389/froh.2021.635055] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2020] [Accepted: 02/23/2021] [Indexed: 12/12/2022] Open
Abstract
Dental mesenchymal stromal cells (MSCs) are multipotent cells present in dental tissues, characterized by plastic adherence in culture and specific surface markers (CD105, CD73, CD90, STRO-1, CD106, and CD146), common to all other MSC subtypes. Dental pulp, periodontal ligament, apical papilla, human exfoliated deciduous teeth, alveolar bone, dental follicle, tooth germ, and gingiva are all different sources for isolation and expansion of MSCs. Dental MSCs have regenerative and immunomodulatory properties; they are scarcely immunogenic but actively modulate T cell reactivity. in vitro studies and animal models of autoimmune diseases have provided evidence for the suppressive effects of dental MSCs on peripheral blood mononuclear cell proliferation, clearance of apoptotic cells, and promotion of a shift in the Treg/Th17 cell ratio. Appropriately stimulated MSCs produce anti-inflammatory mediators, such as transforming growth factor-β (TGF-β), prostaglandin E2, and interleukin (IL)-10. A particular mechanism through which MSCs exert their immunomodulatory action is via the production of extracellular vesicles containing such anti-inflammatory mediators. Recent studies demonstrated MSC-mediated inhibitory effects both on monocytes and activated macrophages, promoting their polarization to an anti-inflammatory M2-phenotype. A growing number of trials focusing on MSCs to treat autoimmune and inflammatory conditions are ongoing, but very few use dental tissue as a cellular source. Recent results suggest that dental MSCs are a promising therapeutic tool for immune-mediated disorders. However, the exact mechanisms responsible for dental MSC-mediated immunosuppression remain to be clarified, and impairment of dental MSCs immunosuppressive function in inflammatory conditions and aging must be assessed before considering autologous MSCs or their secreted vesicles for therapeutic purposes.
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Affiliation(s)
- Alessia Paganelli
- PhD Program in Clinical and Experimental Medicine, University of Modena and Reggio Emilia, Modena, Italy.,Surgical, Medical and Dental Department of Morphological Sciences Related to Transplant, Oncology and Regenerative Medicine, University of Modena and Reggio Emilia, Modena, Italy
| | - Oriana Trubiani
- Department of Medical, Oral and Biotechnological Sciences, University "G. D'Annunzio" Chieti-Pescara, Chieti, Italy
| | - Francesca Diomede
- Department of Medical, Oral and Biotechnological Sciences, University "G. D'Annunzio" Chieti-Pescara, Chieti, Italy
| | - Alessandra Pisciotta
- Surgical, Medical and Dental Department of Morphological Sciences Related to Transplant, Oncology and Regenerative Medicine, University of Modena and Reggio Emilia, Modena, Italy
| | - Roberto Paganelli
- Department of Medicine and Aging Sciences, University "G. D'Annunzio" Chieti-Pescara, Chieti, Italy.,YDA, Institute of Clinical Immunotherapy and Advanced Biological Treatments, Pescara, Italy
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15
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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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16
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Staniowski T, Zawadzka-Knefel A, Skośkiewicz-Malinowska K. Therapeutic Potential of Dental Pulp Stem Cells According to Different Transplant Types. Molecules 2021; 26:7423. [PMID: 34946506 PMCID: PMC8707085 DOI: 10.3390/molecules26247423] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2021] [Revised: 12/02/2021] [Accepted: 12/04/2021] [Indexed: 12/13/2022] Open
Abstract
Stem cells are unspecialised cells capable of perpetual self-renewal, proliferation and differentiation into more specialised daughter cells. They are present in many tissues and organs, including the stomatognathic system. Recently, the great interest of scientists in obtaining stem cells from human teeth is due to their easy availability and a non-invasive procedure of collecting the material. Three key components are required for tissue regeneration: stem cells, appropriate scaffold material and growth factors. Depending on the source of the new tissue or organ, there are several types of transplants. In this review, the following division into four transplant types is applied due to genetic differences between the donor and the recipient: xenotransplantation, allotransplantation, autotransplantation and isotransplantation (however, due to the lack of research, type was not included). In vivo studies have shown that Dental Pulp Stem Cells (DPSCs)can form a dentin-pulp complex, nerves, adipose, bone, cartilage, skin, blood vessels and myocardium, which gives hope for their use in various biomedical areas, such as immunotherapy and regenerative therapy. This review presents the current in vivo research and advances to provide new biological insights and therapeutic possibilities of using DPSCs.
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Affiliation(s)
| | - Anna Zawadzka-Knefel
- Department of Conservative Dentistry with Endodontics, Wroclaw Medical University, 50-425 Wrocław, Poland; (T.S.); (K.S.-M.)
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17
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Kiselevskii MV, Vlasenko RY, Stepanyan NG, Shubina IZ, Sitdikova SM, Kirgizov KI, Varfolomeeva SR. Secretome of Mesenchymal Bone Marrow Stem Cells: Is It Immunosuppressive or Proinflammatory? Bull Exp Biol Med 2021; 172:250-253. [PMID: 34855084 PMCID: PMC8636784 DOI: 10.1007/s10517-021-05371-5] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2021] [Indexed: 11/30/2022]
Abstract
Mesenchymal stem cells (MSC) are characterized by tolerogenic potential and therefore, are used in the treatment of autoimmune diseases such as graft-versus-host disease (GVHD) reactions after allogeneic hematopoietic cell transplantation to improve the transplant functions, as well as for the therapy and prevention of cytokine storm in COVID-19 patients and some other conditions. However, MSC can exhibit proinflammatory activity, which causes risks for their clinical use. We studied the cytokine profile of bone marrow MSC culture and demonstrate intensive production of IL-6, IL-8, and chemokine MCP-1, which participate in the pathogenesis of cytokine storm and GVHD. At the same time, no anti-inflammatory IL-4 and IL-10 were detected. To reduce the risks of MSC application in the GVHD therapeutic protocols, further studies of the conditions promoting generation of MSC with tolerogenic potential and approved clinical standards of MSC use are required.
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Affiliation(s)
- M V Kiselevskii
- N. N. Blokhin National Medical Research Center of Oncology, Ministry of Health of the Russian Federation, Moscow, Russia.
| | - R Ya Vlasenko
- N. N. Blokhin National Medical Research Center of Oncology, Ministry of Health of the Russian Federation, Moscow, Russia
| | - N G Stepanyan
- N. N. Blokhin National Medical Research Center of Oncology, Ministry of Health of the Russian Federation, Moscow, Russia
| | - I Zh Shubina
- N. N. Blokhin National Medical Research Center of Oncology, Ministry of Health of the Russian Federation, Moscow, Russia
| | - S M Sitdikova
- N. N. Blokhin National Medical Research Center of Oncology, Ministry of Health of the Russian Federation, Moscow, Russia
| | - K I Kirgizov
- N. N. Blokhin National Medical Research Center of Oncology, Ministry of Health of the Russian Federation, Moscow, Russia
| | - S R Varfolomeeva
- N. N. Blokhin National Medical Research Center of Oncology, Ministry of Health of the Russian Federation, Moscow, Russia
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18
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Mesenchymal Stem Cells in the Treatment of COVID-19, a Promising Future. Cells 2021; 10:cells10102588. [PMID: 34685567 PMCID: PMC8533906 DOI: 10.3390/cells10102588] [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: 08/18/2021] [Revised: 09/11/2021] [Accepted: 09/17/2021] [Indexed: 12/20/2022] Open
Abstract
Mesenchymal stem cells (MSCs) are multipotent adult stem cells present in virtually all tissues; they have a potent self-renewal capacity and can differentiate into multiple cell types. They also affect the ambient tissue by the paracrine secretion of numerous factors in vivo, including the induction of other stem cells’ differentiation. In vitro, the culture media supernatant is named secretome and contains soluble molecules and extracellular vesicles that retain potent biological function in tissue regeneration. MSCs are considered safe for human treatment; their use does not involve ethical issues, as embryonic stem cells do not require genetic manipulation as induced pluripotent stem cells, and after intravenous injection, they are mainly found in the lugs. Therefore, these cells are currently being tested in various preclinical and clinical trials for several diseases, including COVID-19. Several affected COVID-19 patients develop induced acute respiratory distress syndrome (ARDS) associated with an uncontrolled inflammatory response. This condition causes extensive damage to the lungs and may leave serious post-COVID-19 sequelae. As the disease may cause systemic alterations, such as thromboembolism and compromised renal and cardiac function, the intravenous injection of MSCs may be a therapeutic alternative against multiple pathological manifestations. In this work, we reviewed the literature about MSCs biology, focusing on their function in pulmonary regeneration and their use in COVID-19 treatment.
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19
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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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20
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Mesenchymal stem cell therapy for severe COVID-19. Signal Transduct Target Ther 2021; 6:339. [PMID: 34497264 PMCID: PMC8424619 DOI: 10.1038/s41392-021-00754-6] [Citation(s) in RCA: 63] [Impact Index Per Article: 15.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2021] [Revised: 07/27/2021] [Accepted: 08/24/2021] [Indexed: 02/07/2023] Open
Abstract
The coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has placed a global public burden on health authorities. Although the virological characteristics and pathogenesis of COVID-19 has been largely clarified, there is currently no specific therapeutic measure. In severe cases, acute SARS-CoV-2 infection leads to immune disorders and damage to both the adaptive and innate immune responses. Having roles in immune regulation and regeneration, mesenchymal stem cells (MSCs) serving as a therapeutic option may regulate the over-activated inflammatory response and promote recovery of lung damage. Since the outbreak of the COVID-19 pandemic, a series of MSC-therapy clinical trials has been conducted. The findings indicate that MSC treatment not only significantly reduces lung damage, but also improves patient recovery with safety and good immune tolerance. Herein, we summarize the recent progress in MSC therapy for COVID-19 and highlight the challenges in the field.
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21
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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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22
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Yousefi Dehbidi M, Goodarzi N, Azhdari MH, Doroudian M. Mesenchymal stem cells and their derived exosomes to combat Covid-19. Rev Med Virol 2021; 32:e2281. [PMID: 34363275 PMCID: PMC8420536 DOI: 10.1002/rmv.2281] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2021] [Revised: 07/20/2021] [Accepted: 07/22/2021] [Indexed: 12/22/2022]
Abstract
Severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) is causing an ongoing pandemic of coronavirus disease 2019 (Covid‐19). Effective therapies are required for the treatment of patients with severe stages of the disease. Mesenchymal stem cells (MSCs) have been evaluated in numerous clinical trials, but present challenges, such as carcinogenic risk and special storage conditions, coupled with insufficient data about their mechanism of action. The majority of unique properties of MSCs are related to their paracrine activity and especially to their exosomes. The impact of MSCs‐derived exosomes (MSC‐Es) on complications of Covid‐19 has been investigated in several studies. MSC‐Es may improve some complications of Covid‐19 such as cytokine storm, acute respiratory distress syndrome (ARDS) and acute lung injury (ALI). Additionally, these exosomes can be evaluated as an applicable nano‐size carrier for antiviral therapeutic agents. Herein, we consider several potential applications of MSCs and their derived exosomes in the treatment of Covid‐19.
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Affiliation(s)
- Maryam Yousefi Dehbidi
- Department of Cell and Molecular Sciences, Faculty of Biological Sciences, Kharazmi University, Tehran, Iran
| | - Nima Goodarzi
- Department of Cell and Molecular Sciences, Faculty of Biological Sciences, Kharazmi University, Tehran, Iran
| | - Mohammad H Azhdari
- Department of Cell and Molecular Sciences, Faculty of Biological Sciences, Kharazmi University, Tehran, Iran
| | - Mohammad Doroudian
- Department of Cell and Molecular Sciences, Faculty of Biological Sciences, Kharazmi University, Tehran, Iran
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23
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Abstract
Mesenchymal stem cells (MSCs), a kind of multipotent stem cells with self-renewal ability and multi-differentiation ability, have become the “practical stem cells” for the treatment of diseases. MSCs have immunomodulatory properties and can be used to treat autoimmune diseases, such as systemic lupus erythematosus (SLE) and Crohn’s disease. MSCs also can be used in cancer and aging. At present, many clinical experiments are using MSCs. MSCs can reduce the occurrence of inflammation and apoptosis of tissue cells, and promote the proliferation of endogenous tissue and organ cells, so as to achieve the effect of repairing tissue and organs. MSCs presumably also play an important role in Corona Virus Disease 2019 (COVID-19) infection.
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24
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Samarelli AV, Tonelli R, Heijink I, Martin Medina A, Marchioni A, Bruzzi G, Castaniere I, Andrisani D, Gozzi F, Manicardi L, Moretti A, Cerri S, Fantini R, Tabbì L, Nani C, Mastrolia I, Weiss DJ, Dominici M, Clini E. Dissecting the Role of Mesenchymal Stem Cells in Idiopathic Pulmonary Fibrosis: Cause or Solution. Front Pharmacol 2021; 12:692551. [PMID: 34290610 PMCID: PMC8287856 DOI: 10.3389/fphar.2021.692551] [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: 04/08/2021] [Accepted: 06/21/2021] [Indexed: 12/15/2022] Open
Abstract
Idiopathic pulmonary fibrosis (IPF) is one of the most aggressive forms of idiopathic interstitial pneumonias, characterized by chronic and progressive fibrosis subverting the lung's architecture, pulmonary functional decline, progressive respiratory failure, and high mortality (median survival 3 years after diagnosis). Among the mechanisms associated with disease onset and progression, it has been hypothesized that IPF lungs might be affected either by a regenerative deficit of the alveolar epithelium or by a dysregulation of repair mechanisms in response to alveolar and vascular damage. This latter might be related to the progressive dysfunction and exhaustion of the resident stem cells together with a process of cellular and tissue senescence. The role of endogenous mesenchymal stromal/stem cells (MSCs) resident in the lung in the homeostasis of these mechanisms is still a matter of debate. Although endogenous MSCs may play a critical role in lung repair, they are also involved in cellular senescence and tissue ageing processes with loss of lung regenerative potential. In addition, MSCs have immunomodulatory properties and can secrete anti-fibrotic factors. Thus, MSCs obtained from other sources administered systemically or directly into the lung have been investigated for lung epithelial repair and have been explored as a potential therapy for the treatment of lung diseases including IPF. Given these multiple potential roles of MSCs, this review aims both at elucidating the role of resident lung MSCs in IPF pathogenesis and the role of administered MSCs from other sources for potential IPF therapies.
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Affiliation(s)
- Anna Valeria Samarelli
- Laboratory of Cell Therapies and Respiratory Medicine, Department of Medical and Surgical Sciences for Children and Adults University Hospital of Modena and Reggio Emilia, Modena, Italy
- University Hospital of Modena, Respiratory Diseases Unit, Department of Medical and Surgical Sciences, University of Modena Reggio Emilia, Modena, Italy
| | - Roberto Tonelli
- Laboratory of Cell Therapies and Respiratory Medicine, Department of Medical and Surgical Sciences for Children and Adults University Hospital of Modena and Reggio Emilia, Modena, Italy
- University Hospital of Modena, Respiratory Diseases Unit, Department of Medical and Surgical Sciences, University of Modena Reggio Emilia, Modena, Italy
- Clinical and Experimental Medicine PhD Program, University of Modena Reggio Emilia, Modena, Italy
| | - Irene Heijink
- University of Groningen, Departments of Pathology & Medical Biology and Pulmonology, GRIAC Research Institute, University Medical Center Groningen, Groningen, Netherlands
| | - Aina Martin Medina
- IdISBa (Institut d’Investigacio Sanitaria Illes Balears), Palma de Mallorca, Spain
| | - Alessandro Marchioni
- Laboratory of Cell Therapies and Respiratory Medicine, Department of Medical and Surgical Sciences for Children and Adults University Hospital of Modena and Reggio Emilia, Modena, Italy
- University Hospital of Modena, Respiratory Diseases Unit, Department of Medical and Surgical Sciences, University of Modena Reggio Emilia, Modena, Italy
| | - Giulia Bruzzi
- Laboratory of Cell Therapies and Respiratory Medicine, Department of Medical and Surgical Sciences for Children and Adults University Hospital of Modena and Reggio Emilia, Modena, Italy
- University Hospital of Modena, Respiratory Diseases Unit, Department of Medical and Surgical Sciences, University of Modena Reggio Emilia, Modena, Italy
| | - Ivana Castaniere
- Laboratory of Cell Therapies and Respiratory Medicine, Department of Medical and Surgical Sciences for Children and Adults University Hospital of Modena and Reggio Emilia, Modena, Italy
- University Hospital of Modena, Respiratory Diseases Unit, Department of Medical and Surgical Sciences, University of Modena Reggio Emilia, Modena, Italy
- Clinical and Experimental Medicine PhD Program, University of Modena Reggio Emilia, Modena, Italy
| | - Dario Andrisani
- Laboratory of Cell Therapies and Respiratory Medicine, Department of Medical and Surgical Sciences for Children and Adults University Hospital of Modena and Reggio Emilia, Modena, Italy
- University Hospital of Modena, Respiratory Diseases Unit, Department of Medical and Surgical Sciences, University of Modena Reggio Emilia, Modena, Italy
- Clinical and Experimental Medicine PhD Program, University of Modena Reggio Emilia, Modena, Italy
| | - Filippo Gozzi
- Laboratory of Cell Therapies and Respiratory Medicine, Department of Medical and Surgical Sciences for Children and Adults University Hospital of Modena and Reggio Emilia, Modena, Italy
- University Hospital of Modena, Respiratory Diseases Unit, Department of Medical and Surgical Sciences, University of Modena Reggio Emilia, Modena, Italy
- Clinical and Experimental Medicine PhD Program, University of Modena Reggio Emilia, Modena, Italy
| | - Linda Manicardi
- Laboratory of Cell Therapies and Respiratory Medicine, Department of Medical and Surgical Sciences for Children and Adults University Hospital of Modena and Reggio Emilia, Modena, Italy
- University Hospital of Modena, Respiratory Diseases Unit, Department of Medical and Surgical Sciences, University of Modena Reggio Emilia, Modena, Italy
| | - Antonio Moretti
- Laboratory of Cell Therapies and Respiratory Medicine, Department of Medical and Surgical Sciences for Children and Adults University Hospital of Modena and Reggio Emilia, Modena, Italy
- University Hospital of Modena, Respiratory Diseases Unit, Department of Medical and Surgical Sciences, University of Modena Reggio Emilia, Modena, Italy
| | - Stefania Cerri
- Laboratory of Cell Therapies and Respiratory Medicine, Department of Medical and Surgical Sciences for Children and Adults University Hospital of Modena and Reggio Emilia, Modena, Italy
- University Hospital of Modena, Respiratory Diseases Unit, Department of Medical and Surgical Sciences, University of Modena Reggio Emilia, Modena, Italy
| | - Riccardo Fantini
- University Hospital of Modena, Respiratory Diseases Unit, Department of Medical and Surgical Sciences, University of Modena Reggio Emilia, Modena, Italy
| | - Luca Tabbì
- University Hospital of Modena, Respiratory Diseases Unit, Department of Medical and Surgical Sciences, University of Modena Reggio Emilia, Modena, Italy
| | - Chiara Nani
- University Hospital of Modena, Respiratory Diseases Unit, Department of Medical and Surgical Sciences, University of Modena Reggio Emilia, Modena, Italy
| | - Ilenia Mastrolia
- Laboratory of Cellular Therapy, Program of Cell Therapy and Immuno-Oncology, Division of Oncology, Department of Medical and Surgical Sciences for Children & Adults, University Hospital of Modena and Reggio Emilia, Modena, Italy
| | - Daniel J. Weiss
- Department of Medicine, University of Vermont, Burlington, VT, United States
| | - Massimo Dominici
- Oncology Unit, University Hospital of Modena, University of Modena and Reggio Emilia, Modena, Italy
| | - Enrico Clini
- Laboratory of Cell Therapies and Respiratory Medicine, Department of Medical and Surgical Sciences for Children and Adults University Hospital of Modena and Reggio Emilia, Modena, Italy
- University Hospital of Modena, Respiratory Diseases Unit, Department of Medical and Surgical Sciences, University of Modena Reggio Emilia, Modena, Italy
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Sang L, Guo X, Shi J, Hou S, Fan H, Lv Q. Characteristics and Developments in Mesenchymal Stem Cell Therapy for COVID-19: An Update. Stem Cells Int 2021; 2021:5593584. [PMID: 34211556 PMCID: PMC8205583 DOI: 10.1155/2021/5593584] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2021] [Revised: 04/23/2021] [Accepted: 04/30/2021] [Indexed: 02/06/2023] Open
Abstract
The outbreak of coronavirus disease 2019 (COVID-19) has so far resulted in over a hundred million people being infected. COVID-19 poses a threat to human health around the world. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been confirmed as the pathogenic virus of COVID-19. SARS-CoV-2 belongs to the β-coronavirus family of viruses and is mainly transmitted through the respiratory tract. It has been proven that SARS-CoV-2 mainly targets angiotensin-converting enzyme II (ACE2) receptors on the surface of various cells in humans. The main clinical symptoms of COVID-19 include fever, cough, and severe acute respiratory distress syndrome (ARDS). Current evidence suggests that the damage caused by the virus may be closely related to the induction of cytokine storms in COVID-19. No specific drugs or measures have yet to be shown to cure COVID-19 completely. Cell-based approaches, primarily mesenchymal stem cells (MSCs), have been identified to have anti-inflammatory and immune functions in COVID-19. Clinical studies about using MSCs and its derivatives-exosomes for COVID-19 treatment-are under investigation. Here, we review the current progress of the biological characteristics, clinical manifestations, and cell-based treatment development for COVID-19. Providing up-to-date information on COVID-19 and potential MSC therapies will help highlight routes to prevent and treat the disease.
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Affiliation(s)
- Lu Sang
- Institute of Disaster Medicine, Tianjin University, Tianjin, China
- Tianjin Key Laboratory of Disaster Medicine Technology, Tianjin, China
| | - Xiaoqin Guo
- Institute of Disaster Medicine, Tianjin University, Tianjin, China
- Tianjin Key Laboratory of Disaster Medicine Technology, Tianjin, China
| | - Jie Shi
- Institute of Disaster Medicine, Tianjin University, Tianjin, China
- Tianjin Key Laboratory of Disaster Medicine Technology, Tianjin, China
| | - Shike Hou
- Institute of Disaster Medicine, Tianjin University, Tianjin, China
- Tianjin Key Laboratory of Disaster Medicine Technology, Tianjin, China
| | - Haojun Fan
- Institute of Disaster Medicine, Tianjin University, Tianjin, China
- Tianjin Key Laboratory of Disaster Medicine Technology, Tianjin, China
| | - Qi Lv
- Institute of Disaster Medicine, Tianjin University, Tianjin, China
- Tianjin Key Laboratory of Disaster Medicine Technology, Tianjin, China
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Justice JN, Gubbi S, Kulkarni AS, Bartley JM, Kuchel GA, Barzilai N. A geroscience perspective on immune resilience and infectious diseases: a potential case for metformin. GeroScience 2021; 43:1093-1112. [PMID: 32902818 PMCID: PMC7479299 DOI: 10.1007/s11357-020-00261-6] [Citation(s) in RCA: 34] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2020] [Accepted: 08/27/2020] [Indexed: 12/18/2022] Open
Abstract
We are in the midst of the global pandemic. Though acute respiratory coronavirus (SARS-COV2) that leads to COVID-19 infects people of all ages, severe symptoms and mortality occur disproportionately in older adults. Geroscience interventions that target biological aging could decrease risk across multiple age-related diseases and improve outcomes in response to infectious disease. This offers hope for a new host-directed therapeutic approach that could (i) improve outcomes following exposure or shorten treatment regimens; (ii) reduce the chronic pathology associated with the infectious disease and subsequent comorbidity, frailty, and disability; and (iii) promote development of immunological memory that protects against relapse or improves response to vaccination. We review the possibility of this approach by examining available evidence in metformin: a generic drug with a proven safety record that will be used in a large-scale multicenter clinical trial. Though rigorous translational research and clinical trials are needed to test this empirically, metformin may improve host immune defenses and confer protection against long-term health consequences of infectious disease, age-related chronic diseases, and geriatric syndromes.
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Affiliation(s)
- Jamie N Justice
- Sticht Center for Healthy Aging and Alzheimer's Prevention, Internal Medicine - Gerontology and Geriatric Medicine, Wake Forest School of Medicine, Medical Center Blvd, Winston-Salem, NC, 27157, USA.
| | - Sriram Gubbi
- Metabolic Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, 20814, USA
| | - Ameya S Kulkarni
- Department of Medicine, Division of Endocrinology, Albert Einstein College of Medicine, Bronx, NY, 10461, USA
- Institute for Aging Research, Albert Einstein College of Medicine, Bronx, NY, 10461, USA
| | - Jenna M Bartley
- Center on Aging, University of Connecticut School of Medicine, Farmington, CT, 06030, USA
- Department of Immunology, University of Connecticut School of Medicine, Farmington, CT, 06030, USA
| | - George A Kuchel
- Center on Aging, University of Connecticut School of Medicine, Farmington, CT, 06030, USA
| | - Nir Barzilai
- Department of Medicine, Division of Endocrinology, Albert Einstein College of Medicine, Bronx, NY, 10461, USA
- Institute for Aging Research, Albert Einstein College of Medicine, Bronx, NY, 10461, USA
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Fundamental and Advanced Therapies, Vaccine Development against SARS-CoV-2. Pathogens 2021; 10:pathogens10060636. [PMID: 34064300 PMCID: PMC8224379 DOI: 10.3390/pathogens10060636] [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: 04/15/2021] [Revised: 05/11/2021] [Accepted: 05/19/2021] [Indexed: 01/08/2023] Open
Abstract
Coronavirus disease (COVID-19) caused by the SARS-CoV-2 virus has been affecting the world since the end of 2019. The severity of the disease can range from an asymptomatic or mild course to acute respiratory distress syndrome (ARDS) with respiratory failure, which may lead to death. Since the outbreak of the pandemic, scientists around the world have been studying the genome and molecular mechanisms of SARS-CoV-2 infection to develop effective therapies and prevention. In this review, we summarize the progressive development of various treatments and vaccines as they have emerged, a year after the outbreak of the pandemic. Initially for COVID-19, patients were recommended drugs with presumed antiviral, anti-inflammatory, and antimicrobial effects that were previously used to treat other diseases. Thereafter, therapeutic interventions were supplemented with promising approaches based on antibodies, peptides, and stem cells. However, licensed COVID-19 vaccines remain the most effective weapon in combating the pandemic. While there is an enormous effort to enhance the vaccination rate to increase the entire population immunity, the production and delivery of vaccines is becoming limited in several countries. In this regard, there are new challenges needing to be addressed by combining non-pharmacological intervention with effective therapies until vaccination is accessible to all.
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Cai Q, Yin F, Hao L, Jiang W. Research Progress of Mesenchymal Stem Cell Therapy for Severe COVID-19. Stem Cells Dev 2021; 30:459-472. [PMID: 33715385 DOI: 10.1089/scd.2020.0198] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
Corona virus disease 2019 (COVID-19) refers to a type of pneumonia caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Sixty million confirmed cases have been reported worldwide until November 29, 2020. Unfortunately, the novel coronavirus is extremely contagious and the mortality rate of severe and critically ill patients is high. Thus, there is no definite and effective treatment in clinical practice except for antiviral therapy and supportive therapy. Mesenchymal stem cells (MSCs) are not only characterized by low immunogenicity and homing but also have anti-inflammatory and immunomodulation characteristics. Furthermore, they can inhibit the occurrence and development of a cytokine storm, inhibit lung injury, and exert antipulmonary fibrosis and antioxidative stress, therefore MSC therapy is expected to become one of the effective therapies to treat severe COVID-19. This article will review the possible mechanisms of MSCs in the treatment of severe COVID-19.
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Affiliation(s)
- Qiqi Cai
- Department of Histology and Embryology, Basic Medical College of Jilin University, Changchun, China
| | - Fei Yin
- Department of Histology and Embryology, Basic Medical College of Jilin University, Changchun, China
| | - Liming Hao
- Department of Histology and Embryology, Basic Medical College of Jilin University, Changchun, China
| | - Wenhua Jiang
- Department of Histology and Embryology, Basic Medical College of Jilin University, Changchun, China
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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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Lou S, Duan Y, Nie H, Cui X, Du J, Yao Y. Mesenchymal stem cells: Biological characteristics and application in disease therapy. Biochimie 2021; 185:9-21. [PMID: 33711361 DOI: 10.1016/j.biochi.2021.03.003] [Citation(s) in RCA: 38] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2020] [Revised: 03/05/2021] [Accepted: 03/05/2021] [Indexed: 12/12/2022]
Abstract
Mesenchymal stem cells (MSCs) are multipotent stem cells. In addition to the capacity for self-renewal and multipotential differentiation, MSCs also have the following characteristics. MSCs can exert immunomodulatory functions through interaction with innate or adaptive immune cells, MSCs with poor immunogenicity can be used for allogeneic transplantation, and MSCs can "home" to inflammation and tumour sites. Based on these biological properties, MSCs demonstrate broad clinical application prospects in the treatment of tissue injury, autoimmune diseases, transplantation, cancer and other inflammation-related diseases. In this review we describe the biological characteristics of MSCs and discuss the research advances of MSCs in regenerative medicine, immunomodulation, oncology, and COVID-19, to fully understand the range of diseases in which MSC therapy may be beneficial.
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Affiliation(s)
- Songyue Lou
- School of Pharmaceutical Science, Zhengzhou University, Zhengzhou, Henan, 450001, China.
| | - Yongtao Duan
- Henan Provincial Key Laboratory of Children's Genetics and Metabolic Diseases, Children's Hospital Affiliated to Zhengzhou University, Zhengzhou University, Henan, 450018, China.
| | - Huizong Nie
- School of Life Science, Zhengzhou University, Zhengzhou, Henan, 450001, China.
| | - Xujie Cui
- School of Life Science, Zhengzhou University, Zhengzhou, Henan, 450001, China.
| | - Jialing Du
- School of Pharmaceutical Science, Zhengzhou University, Zhengzhou, Henan, 450001, China.
| | - Yongfang Yao
- Henan Provincial Key Laboratory of Children's Genetics and Metabolic Diseases, Children's Hospital Affiliated to Zhengzhou University, Zhengzhou University, Henan, 450018, China; School of Pharmaceutical Science, Zhengzhou University, Zhengzhou, Henan, 450001, China.
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Rocha JLM, de Oliveira WCF, Noronha NC, Dos Santos NCD, Covas DT, Picanço-Castro V, Swiech K, Malmegrim KCR. Mesenchymal Stromal Cells in Viral Infections: Implications for COVID-19. Stem Cell Rev Rep 2021; 17:71-93. [PMID: 32895900 PMCID: PMC7476649 DOI: 10.1007/s12015-020-10032-7] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Mesenchymal stromal cells (MSCs) constitute a heterogeneous population of stromal cells with immunomodulatory and regenerative properties that support their therapeutic use. MSCs isolated from many tissue sources replicate vigorously in vitro and maintain their main biological properties allowing their widespread clinical application. To date, most MSC-based preclinical and clinical trials targeted immune-mediated and inflammatory diseases. Nevertheless, MSCs have antiviral properties and have been used in the treatment of various viral infections in the last years. Here, we revised in detail the biological properties of MSCs and their preclinical and clinical applications in viral diseases, including the disease caused by the severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) infection (COVID-19). Notably, rapidly increasing numbers of MSC-based therapies for COVID-19 have recently been reported. MSCs are theoretically capable of reducing inflammation and promote lung regeneration in severe COVID-19 patients. We critically discuss the rationale, advantages and disadvantages of MSC-based therapies for viral infections and also specifically for COVID-19 and point out some directions in this field. Finally, we argue that MSC-based therapy may be a promising therapeutic strategy for severe COVID-19 and other emergent respiratory tract viral infections, beyond the viral infection diseases in which MSCs have already been clinically applied.
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