Generic placeholder image

Current Stem Cell Research & Therapy


ISSN (Print): 1574-888X
ISSN (Online): 2212-3946

Review Article

Mesenchymal Stem Cells as a Treatment Strategy for Coronavirus Disease 2019 (COVID-19): Need for Authority Regulations and Clinical Guidelines

Author(s): Ahmet Cevik Tufan*

Volume 16, Issue 4, 2021

Published on: 24 November, 2020

Page: [465 - 480] Pages: 16

DOI: 10.2174/1574888X16999201124224816

Price: $65


The cause of Coronavirus Disease 2019 (COVID-19) known as the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2, formerly designated 2019-nCoV) was first discovered in December 2019 in Wuhan, China. It then spread rapidly worldwide. Investigation for the discovery of drugs to cure this disease continues. The currently accepted treatments are supportive, but there is no specific disease curing intervention found yet. Since mid-February, therapies involving Mesenchymal Stem/Stromal Cells (MSCs) have been proposed for the treatment of patients with COVID-19. In light of these recent developments, this review will focus on: i) the mechanism of SARS-CoV-2 action and the subsequent pathology in COVID-19, ii) the proposed mechanism( s) of outcome-improving action of MSCs or MSC-derived extracellular vesicles in COVID-19 pneumonia, iii) registered MSC-based clinical trials and interventions for the treatment of COVID-19, iv) published case studies/series/trials reporting the use of MSC-based treatments in COVID-19 cases, and finally v) the need for authority regulations and clinical guidelines for MSCbased treatment strategies for COVID-19.

Keywords: COVID-19, SARS-CoV-2, mesenchymal stem/stromal cells, allogeneic cell transplantation, immunomodulation, regulations and clinical guidelines.

Zhu N, Zhang D, Wang W, et al. China Novel Coronavirus Investigating and Research Team. A novel coronavirus from patients with pneumonia in China, 2019. N Engl J Med 2020; 382(8): 727-33.
[] [PMID: 31978945]
World Health Organization: Coronavirus disease (COVID-19) Pandemic
World Health Organization, International Clinical Trials Registry Platform (ICTRP)
Released by National Health Commission & National Administration of Traditional Chinese Medicine on March 3, 2020. Diagnosis and treatment protocol for novel coronavirus pneumonia (Trial Version 7). Chin Med J (Engl) 2020; 133(9): 1087-95.
[] [PMID: 32358325]
Kruse RL. Therapeutic strategies in an outbreak scenario to treat the novel coronavirus originating in Wuhan, China. F1000 Res 2020; 9: 72.
[] [PMID: 32117569]
Tortorici MA, Veesler D. Structural insights into coronavirus entry. Adv Virus Res 2019; 105: 93-116.
[] [PMID: 31522710]
Casadevall A, Pirofski LA. The Ebola epidemic crystallizes the potential of passive antibody therapy for infectious diseases. PLoS Pathog 2015; 11(4): e1004717.
[] [PMID: 25905897]
Shin YW, Chang KH, Hong GW, et al. Selection of vaccinia virus-neutralizing antibody from a phage-display humanantibody library. J Microbiol Biotechnol 2019; 29(4): 651-7.
[] [PMID: 30856707]
Keck ZY, Wang Y, Lau P, Foung SKH. Isolation of HCV neutralizing antibodies by yeast display. Methods Mol Biol 2019; 1911: 395-419.
[] [PMID: 30593641]
Tsai CH, Lee PY, Stollar V, Li ML. Antiviral therapy targeting viral polymerase. Curr Pharm Des 2006; 12(11): 1339-55.
[] [PMID: 16611119]
Anderson J, Schiffer C, Lee SK, Swanstrom R. Viral protease inhibitors. Handb Exp Pharmacol 2009; 189(189): 85-110.
[] [PMID: 19048198]
Sheahan TP, Sims AC, Leist SR, et al. Comparative therapeutic efficacy of remdesivir and combination lopinavir, ritonavir, and interferon beta against MERS-CoV. Nat Commun 2020; 11(1): 222.
[] [PMID: 31924756]
Li CC, Wang XJ, Wang HR. Repurposing host-based therapeutics to control coronavirus and influenza virus. Drug Discov Today 2019; 24(3): 726-36.
[] [PMID: 30711575]
Dyall J, Coleman CM, Hart BJ, et al. Repurposing of clinically developed drugs for treatment of Middle East respiratory syndrome coronavirus infection. Antimicrob Agents Chemother 2014; 58(8): 4885-93.
[] [PMID: 24841273]
Marano G, Vaglio S, Pupella S, et al. Convalescent plasma: New evidence for an old therapeutic tool? Blood Transfus 2016; 14(2): 152-7.
[PMID: 26674811]
Multicenter Collaboration Group of Department of Science and Technology of Guangdong Province and Health Commission of Guangdong Province for Chloroquine in The Treatment of Novel Coronavirus Pneumonia. Expert consensus on chloroquine phosphate for the treatment of novel coronavirus pneumonia. Zhonghua Jie He He Hu Xi Za Zhi 2020; 43: 185-8.
Li H, Wang YM, Xu JY, Cao B. Potential antiviral therapeutics for 2019 Novel Coronavirus. Zhonghua Jie He He Hu Xi Za Zhi 2020; 43(3): 170-2.
[PMID: 32164080]
Wang M, Cao R, Zhang L, et al. Remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus (2019-nCoV) in vitro. Cell Res 2020; 30(3): 269-71.
[] [PMID: 32020029]
Gao J, Tian Z, Yang X. Breakthrough: Chloroquine phosphate has shown apparent efficacy in treatment of COVID-19 associated pneumonia in clinical studies. Biosci Trends 2020; 14(1): 72-3.
[] [PMID: 32074550]
Wong SK, Li W, Moore MJ, Choe H, Farzan M. A 193-amino acid fragment of the SARS coronavirus S protein efficiently binds angiotensin-converting enzyme 2. J Biol Chem 2004; 279(5): 3197-201.
[] [PMID: 14670965]
Li W, Moore MJ, Vasilieva N, et al. Angiotensin-converting enzyme 2 is a functional receptor for the SARS coronavirus. Nature 2003; 426(6965): 450-4.
[] [PMID: 14647384]
Xu X, Chen P, Wang J, et al. Evolution of the novel coronavirus from the ongoing Wuhan outbreak and modeling of its spike protein for risk of human transmission. Sci China Life Sci 2020; 63(3): 457-60.
[] [PMID: 32009228]
Lu R, Zhao X, Li J, et al. Genomic characterisation and epidemiology of 2019 novel coronavirus: Implications for virus origins and receptor binding. Lancet 2020; 395(10224): 565-74.
[] [PMID: 32007145]
Duan Y, Zhu HL, Zhou C. Advance of promising targets and agents against COVID-19 in China. Drug Discov Today 2020; 25(5): 810-2.
[] [PMID: 32198066]
Sahraei Z, Shabani M, Shokouhi S, Saffaei A. Aminoquinolines against coronavirus disease 2019 (COVID-19): Chloroquine or Hydroxychloroquine. Int J Antimicrob Agents 2020; 55(4): 105945.
[] [PMID: 32194152]
Baden LR, Rubin EJ. Covid-19 - The Search for Effective Therapy. N Engl J Med 2020; 382(19): 1851-2.
[] [PMID: 32187463]
Dong L, Hu S, Gao J. Discovering drugs to treat coronavirus disease 2019 (COVID-19). Drug Discov Ther 2020; 14(1): 58-60.
[] [PMID: 32147628]
Liu J, Cao R, Xu M, et al. Hydroxychloroquine, a less toxic derivative of chloroquine, is effective in inhibiting SARS-CoV-2 infection in vitro. Cell Discov 2020; 6: 16.
[] [PMID: 32194981]
Touret F, de Lamballerie X. Of chloroquine and COVID-19. Antiviral Res 2020; 177: 104762.
[] [PMID: 32147496]
Matthay MA, Aldrich JM, Gotts JE. Treatment for severe acute respiratory distress syndrome from COVID-19. Lancet Respir Med 2020; 8(5): 433-4.
[] [PMID: 32203709]
Mitjà O, Clotet B. Use of antiviral drugs to reduce COVID-19 transmission. Lancet Glob Health 2020; 8(5): e639-40.
[] [PMID: 32199468]
Atluri S, Manchikanti L, Hirsch JA. Expanded umbilical cord mesenchymal stem cells (uc-mscs) as a therapeutic strategy in managing critically ill covid-19 patients: The case for compassionate use. Pain Physician 2020; 23(2): E71-83.
[PMID: 32214286]
Shetty AK. Mesenchymal stem cell infusion shows promise for combating Coronavirus (COVID-19)- induced pneumonia. Aging Dis 2020; 11(2): 462-4.
[] [PMID: 32257554]
Leng Z, Zhu R, Hou W, et al. Transplantation of ACE2- Mesenchymal stem/stromal cells improves the outcomes of patients with COVID-19 pneumonia. Aging Dis 2020; 11(2): 216-28.
[] [PMID: 32257537]
Liang B, Chen J, Li T, et al. Clinical remission of a critically ill COVID-19 patient treated by human umbilical cord mesenchymal stem cells: A case report. Medicine (Baltimore) 2020; 99(31): e21429.
[] [PMID: 32756149]
Li H, Zhou Y, Zhang M, et al. Updated approaches against SARS-CoV-2. Antimicrobial Agents and Chemotherapy 2020; 64(6): e00483-20.
National Institutes of Health: Coronavirus Disease 2019 (COVID-19) Treatment Guidelines 2020.
Bhimraj A, Morgan RL, Shumaker AH. Infectious Diseases Society of America Guidelines on the Treatment and Management of Patients with COVID-19 2020.
Centers for Disease Control and Prevention, Interim Clinical Guidance for Management of Patients with Confirmed Coronavirus Disease (COVID-19). 2020.
Zhang Y, Ding J, Ren S, et al. Intravenous infusion of human umbilical cord Wharton’s jelly-derived mesenchymal stem cells as a potential treatment for patients with COVID-19 pneumonia. Stem Cell Res Ther 2020; 11(1): 207.
[] [PMID: 32460839]
Guo Z, Chen Y, Luo X, He X, Zhang Y, Wang J. Administration of umbilical cord mesenchymal stem cells in patients with severe COVID-19 pneumonia. Crit Care 2020; 24(1): 420.
[] [PMID: 32653043]
Peng H, Gong T, Huang X, et al. A synergistic role of convalescent plasma and mesenchymal stem cells in the treatment of severely ill COVID-19 patients: A clinical case report. Stem Cell Res Ther 2020; 11(1): 291.
[] [PMID: 32678017]
Rich RS, Tarruella JR, Camarero MTM. Expanded Mesenchymal Stem Cells: a novel therapeutic approach of SARS-CoV-2 pneumonia (COVID-19). Concepts regarding a first case in Spain Med Clin (Barc) 2020.
Tang L, Jiang Y, Zhu M, et al. Clinical study using mesenchymal stem cells for the treatment of patients with severe COVID-19. Front Med 2020; 14(5): 664-73.
[] [PMID: 32761491]
Shu L, Niu C, Li R, et al. Treatment of severe COVID-19 with human umbilical cord mesenchymal stem cells. Stem Cell Res Ther 2020; 11(1): 361.
[] [PMID: 32811531]
Sánchez-Guijo F, García-Arranz M, López-Parra M, et al. Adipose-derived mesenchymal stromal cells for the treatment of patients with severe SARS-CoV-2 pneumonia requiring mechanical ventilation. A proof of concept study. EClinicalMedicine 2020; 25: 100454.
[] [PMID: 32838232]
Meng F, Xu R, Wang S, et al. Human umbilical cord-derived mesenchymal stem cell therapy in patients with COVID-19: A phase 1 clinical trial. Signal Transduct Target Ther 2020; 5(1): 172.
[] [PMID: 32855385]
Sengupta V, Sengupta S, Lazo A, Woods P, Nolan A, Bremer N. Exosomes derived from bone marrow mesenchymal stem cells as treatment for severe COVID-19. Stem Cells Dev 2020; 29(12): 747-54.
[] [PMID: 32380908]
Börger V, Weiss DJ, Anderson JD, et al. International Society for Extracellular Vesicles and International Society for Cell and Gene Therapy statement on extracellular vesicles from mesenchymal stromal cells and other cells: Considerations for potential therapeutic agents to suppress coronavirus disease-19. Cytotherapy 2020; 22(9): 482-5.
[] [PMID: 32425691]
Zhou P, Yang XL, Wang XG, et al. A pneumonia outbreak associated with a new coronavirus of probable bat origin. Nature 2020; 579(7798): 270-3.
[] [PMID: 32015507]
Kuba K, Imai Y, Rao S, et al. A crucial role of angiotensin converting enzyme 2 (ACE2) in SARS coronavirus-induced lung injury. Nat Med 2005; 11(8): 875-9.
[] [PMID: 16007097]
Ge XY, Li JL, Yang XL, et al. Isolation and characterization of a bat SARS-like coronavirus that uses the ACE2 receptor. Nature 2013; 503(7477): 535-8.
[] [PMID: 24172901]
Hamming I, Timens W, Bulthuis ML, Lely AT, Navis G, van Goor H. Tissue distribution of ACE2 protein, the functional receptor for SARS coronavirus. A first step in understanding SARS pathogenesis. J Pathol 2004; 203(2): 631-7.
[] [PMID: 15141377]
Hoffmann M, Kleine-Weber H, Krüger N, et al. The novel coronavirus 2019 (2019-nCoV) uses the SARS-coronavirus receptor ACE2 and the cellular protease TMPRSS2 for entry into target cells. BioRxiv 2020.
Iwata-Yoshikawa N, Okamura T, Shimizu Y, Hasegawa H, Takeda M, Nagata N. TMPRSS2 contributes to virus spread and immunopathology in the airways of murine models after coronavirus infection. J Virol 2019; 93(6): 6.
[] [PMID: 30626688]
Inoue Y, Tanaka N, Tanaka Y, et al. Clathrin-dependent entry of severe acute respiratory syndrome coronavirus into target cells expressing ACE2 with the cytoplasmic tail deleted. J Virol 2007; 81(16): 8722-9.
[] [PMID: 17522231]
Wang H, Yang P, Liu K, et al. SARS coronavirus entry into host cells through a novel clathrin- and caveolae-independent endocytic pathway. Cell Res 2008; 18(2): 290-301.
[] [PMID: 18227861]
Horie S, Gonzalez HE, Laffey JG, Masterson CH. Cell therapy in acute respiratory distress syndrome. J Thorac Dis 2018; 10(9): 5607-20.
[] [PMID: 30416812]
Thompson BT, Chambers RC, Liu KD. Acute Respiratory Distress Syndrome. N Engl J Med 2017; 377(6): 562-72.
[] [PMID: 28792873]
Shi Y, Wang Y, Shao C, et al. COVID-19 infection: The perspectives on immune responses. Cell Death Differ 2020; 27(5): 1451-4.
[] [PMID: 32205856]
Zhou YFB, Zheng X, Wang D, et al. Aberrant pathogenic GM-CSF+ T cells and inflammatory CD14+CD16+ monocytes in severe pulmonary syndrome patients of a new coronavirus. bioRxiv 2020.
Ding Y, He L, Zhang Q, et al. Organ distribution of severe acute respiratory syndrome (SARS) associated coronavirus (SARS-CoV) in SARS patients: Implications for pathogenesis and virus transmission pathways. J Pathol 2004; 203(2): 622-30.
[] [PMID: 15141376]
Metcalfe SM. Mesenchymal stem cells and management of COVID-19 pneumonia. Med Drug Discov 2020; 5: 100019.
[] [PMID: 32296777]
Huang C, Wang Y, Li X, et al. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet 2020; 395(10223): 497-506.
[] [PMID: 31986264]
Friedenstein AJ, Chailakhyan RK, Latsinik NV, Panasyuk AF, Keiliss-Borok IV. Stromal cells responsible for transferring the microenvironment of the hemopoietic tissues. Cloning in vitro and retransplantation in vivo. Transplantation 1974; 17(4): 331-40.
[] [PMID: 4150881]
Friedenstein AJ, Gorskaja JF, Kulagina NN. Fibroblast precursors in normal and irradiated mouse hematopoietic organs. Exp Hematol 1976; 4(5): 267-74.
[PMID: 976387]
Galipeau J, Sensébé L. Mesenchymal Stromal Cells: Clinical Challenges and Therapeutic Opportunities. Cell Stem Cell 2018; 22(6): 824-33.
[] [PMID: 29859173]
Moll G, Ankrum JA, Kamhieh-Milz J, et al. Intravascular mesenchymal stromal/stem cell therapy product diversification: Time for new clinical guidelines. Trends Mol Med 2019; 25(2): 149-63.
[] [PMID: 30711482]
Pittenger MF, Mackay AM, Beck SC, et al. Multilineage potential of adult human mesenchymal stem cells. Science 1999; 284(5411): 143-7.
[] [PMID: 10102814]
da Silva Meirelles L, Chagastelles PC, Nardi NB. Mesenchymal stem cells reside in virtually all post-natal organs and tissues. J Cell Sci 2006; 119(Pt 11): 2204-13.
[] [PMID: 16684817]
Crisan M, Yap S, Casteilla L, et al. A perivascular origin for mesenchymal stem cells in multiple human organs. Cell Stem Cell 2008; 3(3): 301-13.
[] [PMID: 18786417]
Yorukoglu AC, Kiter AE, Akkaya S, Satiroglu-Tufan NL, Tufan AC. A concise review on the use of mesenchymal stem cells in cell sheet-based tissue engineering with special emphasis on bone tissue regeneration. Stem Cells Int 2017; 2017: 2374161.
[] [PMID: 29230248]
Dominici M, Le Blanc K, Mueller I, et al. Minimal criteria for defining multipotent mesenchymal stromal cells. The International Society for Cellular Therapy position statement. Cytotherapy 2006; 8(4): 315-7.
[] [PMID: 16923606]
Ullah I, Subbarao RB, Rho GJ. Human mesenchymal stem cells - current trends and future prospective. Biosci Rep 2015; 35(2): e00191.
[] [PMID: 25797907]
Zuk PA, Zhu M, Ashjian P, et al. Human adipose tissue is a source of multipotent stem cells. Mol Biol Cell 2002; 13(12): 4279-95.
[] [PMID: 12475952]
Abdulrazzak H, Moschidou D, Jones G, Guillot PV. Biological characteristics of stem cells from foetal, cord blood and extraembryonic tissues. J R Soc Interface 2010; 7(Suppl. 6): S689-706.
[] [PMID: 20739312]
Hashmi S, Ahmed M, Murad MH, et al. Survival after mesenchymal stromal cell therapy in steroid-refractory acute graft-versus-host disease: Systematic review and meta-analysis. Lancet Haematol 2016; 3(1): e45-52.
[] [PMID: 26765648]
Kamen DL, Nietert PJ, Wang H, et al. CT-04 Safety and efficacy of allogeneic umbilical cord-derived mesenchymal stem/stromal cells (MSCs) in patients with systemic lupus erythematosus: results of an open-label phase I study. Lupus Sci Med 2018; 5: A46-7.
Marino L, Castaldi MA, Rosamilio R, et al. Mesenchymal stem cells from the wharton’s jelly of the human umbilical cord: Biological properties and therapeutic potential. Int J Stem Cells 2019; 12(2): 218-26.
[] [PMID: 31022994]
Lightner AL, García-Olmo D. Mesenchymal stem/stromal cell therapy can transcend perianal crohn’s disease: How colorectal surgeons can help in the covid-19 crisis. Dis Colon Rectum 2020; 63(7): 874-8.
[] [PMID: 32251143]
Golchin A, Seyedjafari E, Ardeshirylajimi A. Mesenchymal stem cell therapy for COVID-19: Present or future. Stem Cell Rev Rep 2020; 16(3): 427-33.
[] [PMID: 32281052]
Öztürk S, Elçin AE, Elçin YM. Mesenchymal stem cells for coronavirus (COVID-19)-induced pneumonia: Revisiting the paracrine hypothesis with new hopes? Aging Dis 2020; 11(3): 477-9.
[] [PMID: 32489694]
Karaahmet F, Kocaman SA. Endothelial progenitor cells and mesenchymal stem cells to overcome vascular deterioration and cytokine storm in critical patients with COVID-19. Med Hypotheses 2020; 144: 109973.
[] [PMID: 32590321]
Akkoc T. COVID-19 and Mesenchymal Stem Cell Treatment; Mystery or Not. Adv Exp Med Biol 2020; 1298: 167-76.
[] [PMID: 32648245]
Gu J, Zhao Q, Han Z, Han Z. The Promise of Mesenchymal stem cells therapy for acute Respiratory Distress Syndrome Caused by COVID-19. Curr Stem Cell Res Ther 2020.
[] [PMID: 32729428]
Choudhery MS, Harris DT. Stem cell therapy for COVID-19: Possibilities and challenges. Cell Biol Int 2020; 44(11): 2182-91.
[] [PMID: 32767687]
Can A, Coskun H. The rationale of using mesenchymal stem cells in patients with COVID-19-related acute respiratory distress syndrome: What to expect. Stem Cells Transl Med 2020; 9(11): 1287-302.
[] [PMID: 32779878]
Rocha JLM, de Oliveira WCF, Noronha NC, et al. Mesenchymal Stromal Cells in Viral Infections: Implications for COVID-19 2020; 17(1): 71-93.
Alnefaie A, Albogami S. Current approaches used in treating COVID-19 from a molecular mechanisms and immune response perspective. Saudi Pharm J 2020; 28(11): 1333-52.
[] [PMID: 32905015]
Bulut Ö, GÜrsel İ. Mesenchymal stem cell derived extracellular vesicles: Promising immunomodulators against autoimmune, autoinflammatory disorders and SARS-CoV-2 infection. Turk J Biol 2020; 44(3): 273-82.
[] [PMID: 32595362]
Muraca M, Pessina A, Pozzobon M, et al. Mesenchymal stromal cells and their secreted extracellular vesicles as therapeutic tools for COVID-19 pneumonia? J Control Release 2020; 325: 135-40.
[] [PMID: 32622963]
Jayaramayya K, Mahalaxmi I, Subramaniam MD, et al. Immunomodulatory effect of mesenchymal stem cells and mesenchymal stem-cell-derived exosomes for COVID-19 treatment. BMB Rep 2020; 53(8): 400-12.
[] [PMID: 32731913]
Gupta A, Kashte S, Gupta M, Rodriguez HC, Gautam SS, Kadam S. Mesenchymal stem cells and exosome therapy for COVID-19: current status and future perspective. Hum Cell 2020; 33(4): 907-18.
[] [PMID: 32780299]
Akbari A, Rezaie J. Potential therapeutic application of mesenchymal stem cell-derived exosomes in SARS-CoV-2 pneumonia. Stem Cell Res Ther 2020; 11(1): 356.
[] [PMID: 32795359]
Qu W, Wang Z, Hare JM, et al. Cell-based therapy to reduce mortality from COVID-19: Systematic review and meta-analysis of human studies on acute respiratory distress syndrome. Stem Cells Transl Med 2020; 9(9): 1007-22.
[] [PMID: 32472653]

Rights & Permissions Print Export Cite as
© 2022 Bentham Science Publishers | Privacy Policy