Mesenchymal Stem Cell Therapy and COVID-19

Fazliny Bt Abd. Rahman

International Journal of Biomedicine. 2022;12(3):329-338.
DOI: 10.21103/Article12(3)_RA1
Originally published September 5, 2022


The coronavirus disease 2019 (COVID-19) caused by the novel, severe acute respiratory coronavirus 2 (SARS-CoV-2) has been spreading since late 2019 and has infected more than 360 million people worldwide. Infected individuals often develop severe illnesses, such as hypoxic respiratory failure and acute respiratory distress syndrome, which can lead to multiple organ failure. To manage the COVID-19 pandemic, vaccination programs have been conducted around the globe. In addition to supportive and antiviral medications, much attention has been focused on immunotherapies aimed at reducing pathological changes in the lungs. Currently, mesenchymal stem cells (MSCs) have received extensive attention as an option in treating COVID-19 because of their immunomodulatory, anti-inflammatory, and regenerative properties. This article discusses how MSCs play a major role in the battle against COVID-19, their pathological characteristics, their safety, and their possible effectiveness in treating the disease.

COVID-19 • cytokine • mesenchymal stem cells • treatment
  1. Li Q, Guan X, Wu P, Wang X, Zhou L, Tong Y, et al. Early Transmission Dynamics in Wuhan, China, of Novel Coronavirus-Infected Pneumonia. N Engl J Med. 2020;382(13):1199-207. Epub 20200129. doi: 10.1056/NEJMoa2001316. PubMed PMID: 31995857; PubMed Central PMCID: PMC7121484.
  2. Zhou P, Yang XL, Wang XG, Hu B, Zhang L, Zhang W, et al. Addendum: A pneumonia outbreak associated with a new coronavirus of probable bat origin. Nature. 2020;588(7836):E6. doi: 10.1038/s41586-020-2951-z. PubMed PMID: 33199918.
  3. McEnery T, Gough C, Costello RW. COVID-19: Respiratory support outside the intensive care unit. Lancet Respir Med. 2020;8(6):538-9. Epub 20200409. doi: 10.1016/s2213-2600(20)30176-4. PubMed PMID: 32278367; PubMed Central PMCID: PMC7146718.
  4. Huang C, Wang Y, Li X, Ren L, Zhao J, Hu Y, et al. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet. 2020;395(10223):497-506. Epub 20200124. doi: 10.1016/s0140-6736(20)30183-5. PubMed PMID: 31986264; PubMed Central PMCID: PMC7159299.
  5. Jiang S, Shi ZL. The First Disease X is Caused by a Highly Transmissible Acute Respiratory Syndrome Coronavirus. Virol Sin. 2020;35(3):263-5. Epub 20200214. doi: 10.1007/s12250-020-00206-5. PubMed PMID: 32060789; PubMed Central PMCID: PMC7091198.
  6. Chen G, Wu D, Guo W, Cao Y, Huang D, Wang H, et al. Clinical and immunological features of severe and moderate coronavirus disease 2019. J Clin Invest. 2020;130(5):2620-9. doi: 10.1172/jci137244. PubMed PMID: 32217835; PubMed Central PMCID: PMC7190990.
  7. Zumla A, Hui DS, Azhar EI, Memish ZA, Maeurer M. Reducing mortality from 2019-nCoV: host-directed therapies should be an option. Lancet. 2020;395(10224):e35-e6. Epub 20200205. doi: 10.1016/s0140-6736(20)30305-6. PubMed PMID: 32035018; PubMed Central PMCID: PMC7133595.
  8. Ali MJ, Hanif M, Haider MA, Ahmed MU, Sundas F, Hirani A, et al. Treatment Options for COVID-19: A Review. Front Med (Lausanne). 2020;7:480. Epub 20200731. doi: 10.3389/fmed.2020.00480. PubMed PMID: 32850922; PubMed Central PMCID: PMC7412857.
  9. Pascarella G, Strumia A, Piliego C, Bruno F, Del Buono R, Costa F, et al. COVID-19 diagnosis and management: a comprehensive review. J Intern Med. 2020;288(2):192-206. Epub 20200513. doi: 10.1111/joim.13091. PubMed PMID: 32348588; PubMed Central PMCID: PMC7267177.
  10. Leng Z, Zhu R, Hou W, Feng Y, Yang Y, Han Q, et al. Transplantation of ACE2(-) Mesenchymal Stem Cells Improves the Outcome of Patients with COVID-19 Pneumonia. Aging Dis. 2020;11(2):216-28. doi: 10.14336/AD.2020.0228. PubMed PMID: 32257537.
  11. Munir H, McGettrick HM. Mesenchymal Stem Cell Therapy for Autoimmune Disease: Risks and Rewards. Stem Cells Dev. 2015;24(18):2091-100. Epub 20150728. doi: 10.1089/scd.2015.0008. PubMed PMID: 26068030.
  12. Watson LM, Wong MM, Becker EB. Induced pluripotent stem cell technology for modelling and therapy of cerebellar ataxia. Open Biol. 2015;5(7):150056. doi: 10.1098/rsob.150056. PubMed PMID: 26136256; PubMed Central PMCID: PMC4632502.
  13. Mezey É, Nemeth K. Mesenchymal stem cells and infectious diseases: Smarter than drugs. Immunol Lett. 2015;168(2):208-14. Epub 20150604. doi: 10.1016/j.imlet.2015.05.020. PubMed PMID: 26051681.
  14. Choudhery MS, Harris DT. Stem cell therapy for COVID-19: Possibilities and challenges. Cell Biol Int. 2020;44(11):2182-91. Epub 20200822. doi: 10.1002/cbin.11440. PubMed PMID: 32767687; PubMed Central PMCID: PMC7436138.
  15. 1Liu S, Peng D, Qiu H, Yang K, Fu Z, Zou L. Mesenchymal stem cells as a potential therapy for COVID-19. Stem Cell Research & Therapy. 2020;11(1):169. doi: 10.1186/s13287-020-01678-8.
  16. Choudhery MS, Badowski M, Muise A, Pierce J, Harris DT. Donor age negatively impacts adipose tissue-derived mesenchymal stem cell expansion and differentiation. J Transl Med. 2014;12:8. Epub 20140107. doi: 10.1186/1479-5876-12-8. PubMed PMID: 24397850; PubMed Central PMCID: PMC3895760.
  17. Uccelli A, Moretta L, Pistoia V. Mesenchymal stem cells in health and disease. Nat Rev Immunol. 2008;8(9):726-36. doi: 10.1038/nri2395. PubMed PMID: 19172693.
  18. Nauta AJ, Fibbe WE. Immunomodulatory properties of mesenchymal stromal cells. Blood. 2007;110(10):3499-506. Epub 20070730. doi: 10.1182/blood-2007-02-069716. PubMed PMID: 17664353.
  19. Meng F, Xu R, Wang S, Xu Z, Zhang C, Li Y, 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. Epub 20200827. doi: 10.1038/s41392-020-00286-5. PubMed PMID: 32855385; PubMed Central PMCID: PMC7450163.
  20. Häberle H, Magunia H, Lang P, Gloeckner H, Körner A, Koeppen M, et al. Mesenchymal Stem Cell Therapy for Severe COVID-19 ARDS. J Intensive Care Med. 2021;36(6):681-8. Epub 20210305. doi: 10.1177/0885066621997365. PubMed PMID: 33663244; PubMed Central PMCID: PMC8145440.
  21. Ercelen NO, Bilgili B, Monteleone B, Gul F, Gulay GR, Alpaydin N, et al. MSC transplantation in eight severe COVID-19 patients: Can cytokine storm be reversed. Stem Cell Research & Therapy. 2020;10:460.
  22. Xu X, Jiang W, Chen L, Xu Z, Zhang Q, Zhu M, et al. Evaluation of the safety and efficacy of using human menstrual blood-derived mesenchymal stromal cells in treating severe and critically ill COVID-19 patients: An exploratory clinical trial. Clin Transl Med. 2021;11(2):e297. doi: 10.1002/ctm2.297. PubMed PMID: 33634996; PubMed Central PMCID: PMC7839959.
  23. Kenry, Lee WC, Loh KP, Lim CT. When stem cells meet graphene: Opportunities and challenges in regenerative medicine. Biomaterials. 2018;155:236-50. Epub 20171004. doi: 10.1016/j.biomaterials.2017.10.004. PubMed PMID: 29195230.
  24. Rajabzadeh N, Fathi E, Farahzadi R. Stem cell-based regenerative medicine. Stem Cell Investig. 2019;6:19. Epub 20190718. doi: 10.21037/sci.2019.06.04. PubMed PMID: 31463312; PubMed Central PMCID: PMC6691074.
  25. Mallis P, Michalopoulos E, Chatzistamatiou T, Stavropoulos-Giokas C. Mesenchymal stromal cells as potential immunomodulatory players in severe acute respiratory distress syndrome induced by SARS-CoV-2 infection. World J Stem Cells. 2020;12(8):731-51. doi: 10.4252/wjsc.v12.i8.731. PubMed PMID: 32952855; PubMed Central PMCID: PMC7477656.
  26. Börger V, Weiss DJ, Anderson JD, Borràs FE, Bussolati B, Carter DRF, 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. Epub 20200516. doi: 10.1016/j.jcyt.2020.05.002. PubMed PMID: 32425691; PubMed Central PMCID: PMC7229942.
  27. Song J-W, Zhang C, Fan X, Meng F-P, Xu Z, Xia P, et al. Immunological and inflammatory profiles in mild and severe cases of COVID-19. Nature Communications. 2020;11(1):3410. doi: 10.1038/s41467-020-17240-2.
  28. Qin C, Zhou L, Hu Z, Zhang S, Yang S, Tao Y, et al. Dysregulation of Immune Response in Patients With Coronavirus 2019 (COVID-19) in Wuhan, China. Clin Infect Dis. 2020;71(15):762-8. doi: 10.1093/cid/ciaa248. PubMed PMID: 32161940; PubMed Central PMCID: PMC7108125.
  29. Chen N, Zhou M, Dong X, Qu J, Gong F, Han Y, et al. Epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia in Wuhan, China: a descriptive study. Lancet. 2020;395(10223):507-13. Epub 20200130. doi: 10.1016/s0140-6736(20)30211-7. PubMed PMID: 32007143; PubMed Central PMCID: PMC7135076.
  30. Xu R, Feng Z, Wang FS. Mesenchymal stem cell treatment for COVID-19. EBioMedicine. 2022;77:103920. Epub 20220310. doi: 10.1016/j.ebiom.2022.103920. PubMed PMID: 35279630; PubMed Central PMCID: PMC8907937.
  31. Magro C, Mulvey JJ, Berlin D, Nuovo G, Salvatore S, Harp J, et al. Complement associated microvascular injury and thrombosis in the pathogenesis of severe COVID-19 infection: A report of five cases. Transl Res. 2020;220:1-13. Epub 20200415. doi: 10.1016/j.trsl.2020.04.007. PubMed PMID: 32299776; PubMed Central PMCID: PMC7158248.
  32. Varga Z, Flammer AJ, Steiger P, Haberecker M, Andermatt R, Zinkernagel AS, et al. Endothelial cell infection and endotheliitis in COVID-19. Lancet. 2020;395(10234):1417-8. Epub 20200421. doi: 10.1016/s0140-6736(20)30937-5. PubMed PMID: 32325026; PubMed Central PMCID: PMC7172722.
  33. Ackermann M, Verleden SE, Kuehnel M, Haverich A, Welte T, Laenger F, et al. Pulmonary Vascular Endothelialitis, Thrombosis, and Angiogenesis in Covid-19. N Engl J Med. 2020;383(2):120-8. Epub 20200521. doi: 10.1056/NEJMoa2015432. PubMed PMID: 32437596; PubMed Central PMCID: PMC7412750.
  34. 3Szabo PA, Dogra P, Gray JI, Wells SB, Connors TJ, Weisberg SP, et al. Longitudinal profiling of respiratory and systemic immune responses reveals myeloid cell-driven lung inflammation in severe COVID-19. Immunity. 2021;54(4):797-814.e6. Epub 20210311. doi: 10.1016/j.immuni.2021.03.005. PubMed PMID: 33765436; PubMed Central PMCID: PMC7951561.
  35. Li S, Zhu H, Zhao M, Liu W, Wang L, Zhu B, et al. When stem cells meet COVID-19: recent advances, challenges and future perspectives. Stem Cell Res Ther. 2022;13(1):9. Epub 20220110. doi: 10.1186/s13287-021-02683-1. PubMed PMID: 35012650; PubMed Central PMCID: PMC8744050.
  36. Ben-Mordechai T, Palevski D, Glucksam-Galnoy Y, Elron-Gross I, Margalit R, Leor J. Targeting macrophage subsets for infarct repair. J Cardiovasc Pharmacol Ther. 2015;20(1):36-51. Epub 20140617. doi: 10.1177/1074248414534916. PubMed PMID: 24938456.
  37. He X, Hong W, Yang J, Lei H, Lu T, He C, et al. Spontaneous apoptosis of cells in therapeutic stem cell preparation exert immunomodulatory effects through release of phosphatidylserine. Signal Transduction and Targeted Therapy. 2021;6(1):270. doi: 10.1038/s41392-021-00688-z.

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Received June 22, 2022.
Accepted July 4, 2022.
©2022 International Medical Research and Development Corporation.