Skip to main content
SpringerLink
Log in

The Main Mechanisms of Mesenchymal Stem Cell-Based Treatments against COVID-19

  • Review Article
  • Published:
Tissue Engineering and Regenerative Medicine Aims and scope

Abstract

Background

Coronavirus disease 2019 (COVID-19) has a clinical manifestation of hypoxic respiratory failure and acute respiratory distress syndrome. However, COVID-19 still lacks of effective clinical treatments so far. As a promising potential treatment against COVID-19, stem cell therapy raised recently and had attracted much attention. Here we review the mechanisms of mesenchymal stem cell-based treatments against COVID-19, and provide potential cues for the effective control of COVID-19 in the future.

Methods

Literature is obtained from databases PubMed and Web of Science. Key words were chosen for COVID- 19, acute respiratory syndrome coronavirus 2, mesenchymal stem cells, stem cell therapy, and therapeutic mechanism. Then we summarize and critically analyze the relevant articles retrieved.

Results

Mesenchymal stem cell therapy is a potential effective treatment against COVID-19. Its therapeutic efficacy is mainly reflected in reducing severe pulmonary inflammation, reducing lung injury, improving pulmonary function, protecting and repairing lung tissue of the patients. Possible therapeutic mechanisms might include immunoregulation, anti-inflammatory effect, tissue regeneration, anti-apoptosis effect, antiviral, and antibacterial effect, MSC - EVs, and so on.

Conclusion

Mesenchymal stem cells can effectively treat COVID-19 through immunoregulation, anti-inflammatory, tissue regeneration, anti-apoptosis, anti-virus and antibacterial, MSC - EVs, and other ways. Systematically elucidating the mechanisms of mesenchymal stem cell-based treatments for COVID-19 will provide novel insights into the follow-up research and development of new therapeutic strategies in next step.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

Data availability

The datasets generated during and/or analysed during the current study are available from the corresponding author on reasonable request.

References

  1. Faust JS, Du C, Liang C, Mayes KD, Renton B, Panthagani K, et al. Excess mortality in Massachusetts during the delta and omicron waves of COVID-19. JAMA. 2022;328:74–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Golchin A, Seyedjafari E, Ardeshirylajimi A. Mesenchymal stem cell therapy for COVID-19: present or future. Stem Cell Rev Rep. 2020;16:427–33.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Su S, Wong G, Shi W, Liu J, Lai ACK, Zhou J, et al. Epidemiology, genetic recombination, and pathogenesis of coronaviruses. Trends Microbiol. 2016;24:490–502.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Zhou P, Yang XL, Wang XG, Hu B, Zhang L, Zhang W, et al. A pneumonia outbreak associated with a new coronavirus of probable bat origin. Nature. 2020;579:270–3.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Zhu N, Zhang D, Wang W, Li X, Yang B, Song J, et al. A novel coronavirus from patients with pneumonia in China, 2019. N Engl J Med. 2020;382:727–33.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Chen Y, Liu Q, Guo D. Emerging coronaviruses: genome structure, replication, and pathogenesis. J Med Virol. 2020;92:418–23.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Coronaviridae Study Group of the International Committee on Taxonomy of Viruses. The species Severe acute respiratory syndrome-related coronavirus: classifying 2019-nCoV and naming it SARS-CoV-2. Nat Microbiol. 2020;5:536–44.

  8. Lu R, Zhao X, Li J, Niu P, Yang B, Wu H, et al. Genomic characterisation and epidemiology of 2019 novel coronavirus: implications for virus origins and receptor binding. Lancet. 2020;395:565–74.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Chan JF, Yuan S, Kok KH, To KK, Chu H, Yang J, et al. A familial cluster of pneumonia associated with the 2019 novel coronavirus indicating person-to-person transmission: a study of a family cluster. Lancet. 2020;395:514–23.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Rabaan AA, Al-Ahmed SH, Haque S, Sah R, Tiwari R, Malik YS, et al. SARS-CoV-2, SARS-CoV, and MERS-COV: a comparative overview. Infez Med. 2020;28:174–84.

    CAS  PubMed  Google Scholar 

  11. Buchrieser J, Dufloo J, Hubert M, Monel B, Planas D, Rajah MM, et al. Syncytia formation by SARS-CoV-2-infected cells. EMBO J. 2020;39:e106267.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Gerard L, Lecocq M, Bouzin C, Hoton D, Schmit G, Pereira JP, et al. Increased angiotensin-converting enzyme 2 and loss of alveolar type II Cells in COVID-19-related acute respiratory distress syndrome. Am J Respir Crit Care Med. 2021;204:1024–34.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Zou X, Chen K, Zou J, Han P, Hao J, Han Z. Single-cell RNA-seq data analysis on the receptor ACE2 expression reveals the potential risk of different human organs vulnerable to 2019-nCoV infection. Front Med. 2020;14:185–92.

    Article  PubMed  PubMed Central  Google Scholar 

  14. Varga Z, Flammer AJ, Steiger P, Haberecker M, Andermatt R, Zinkernagel AS, et al. Endothelial cell infection and endotheliitis in COVID-19. Lancet. 2020;395:1417–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Yang L, Han Y, Jaffré F, Nilsson-Payant BE, Bram Y, Wang P, et al. An immuno-cardiac model for macrophage-mediated inflammation in COVID-19 hearts. Circ Res. 2021;129:33–46.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Nelemans T, Kikkert M. Viral innate immune evasion and the pathogenesis of emerging RNA virus infections. Viruses. 2019;11:961.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Baruah V, Bose S. Immunoinformatics-aided identification of T cell and B cell epitopes in the surface glycoprotein of 2019-nCoV. J Med Virol. 2020;92:495–500.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. 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;395:497–506.

    Article  CAS  PubMed  Google Scholar 

  19. Zhang W, Li L, Liu J, Chen L, Zhou F, Jin T, et al. The characteristics and predictive role of lymphocyte subsets in COVID-19 patients. Int J Infect Dis. 2020;99:92–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Henderson LA, Canna SW, Schulert GS, Volpi S, Lee PY, Kernan KF, et al. On the alert for cytokine storm: immunopathology in COVID-19. Arthritis Rheumatol. 2020;72:1059–63.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Han PL, Pang T, Diao KY, Yang ZG. Corona virus disease 2019 (COVID-19): the image tells the truth. Infection. 2020;48:981–4.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. To KK, Sridhar S, Chiu KH, Hung DL, Li X, Hung IF, et al. Lessons learned 1 year after SARS-CoV-2 emergence leading to COVID-19 pandemic. Emerg Microbes Infect. 2021;10:507–35.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. 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;11:216–28.

    Article  PubMed  PubMed Central  Google Scholar 

  24. Hoffmann M, Kleine-Weber H, Schroeder S, Krüger N, Herrler T, Erichsen S, 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. https://doi.org/10.1101/2020.01.31.929042.

    Article  PubMed  PubMed Central  Google Scholar 

  25. Chang D, Lin M, Wei L, Xie L, Zhu G, Dela Cruz CS, et al. Epidemiologic and clinical characteristics of novel coronavirus infections involving 13 patients outside Wuhan, China. JAMA. 2020;323:1092–3.

    Article  PubMed  PubMed Central  Google Scholar 

  26. Xu Z, Shi L, Wang Y, Zhang J, Huang L, Zhang C, et al. Pathological findings of COVID-19 associated with acute respiratory distress syndrome. Lancet Respir Med. 2020;8:420–2.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Liu Q, Qin C, Liu M, Liu J. Effectiveness and safety of SARS-CoV-2 vaccine in real-world studies: a systematic review and meta-analysis. Infect Dis Poverty. 2021;10:132.

    Article  PubMed  PubMed Central  Google Scholar 

  28. Choi JY, Smith DM. SARS-CoV-2 variants of concern. Yonsei Med J. 2021;62:961–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Huang C, Huang L, Wang Y, Li X, Ren L, Gu X, et al. 6-month consequences of COVID-19 in patients discharged from hospital: a cohort study. Lancet. 2021;397:220–32.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Wu X, Liu X, Zhou Y, Yu H, Li R, Zhan Q, et al. 3-month, 6-month, 9-month, and 12-month respiratory outcomes in patients following COVID-19-related hospitalisation: a prospective study. Lancet Respir Med. 2021;9:747–54.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Behnke J, Kremer S, Shahzad T, Chao CM, Böttcher-Friebertshäuser E, Morty RE, et al. MSC based therapies-new perspectives for the injured lung. J Clin Med. 2020;9:682.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Cruz FF, Rocco P. The potential of mesenchymal stem cell therapy for chronic lung disease. Expert Rev Respir Med. 2020;14:31–9.

    Article  CAS  PubMed  Google Scholar 

  33. Abraham A, Krasnodembskaya A. Mesenchymal stem cell-derived extracellular vesicles for the treatment of acute respiratory distress syndrome. Stem Cells Transl Med. 2020;9:28–38.

    Article  CAS  PubMed  Google Scholar 

  34. Liang P, Ye F, Hou CC, Pi L, Chen F. Mesenchymal stem cell therapy for patients with ischemic heart failure- past, present, and future. Curr Stem Cell Res Ther. 2021;16:608–21.

    CAS  PubMed  Google Scholar 

  35. Shafei AE, Ali MA, Ghanem HG, Shehata AI, Abdelgawad AA, Handal HR, et al. Mesenchymal stem cell therapy: a promising cell-based therapy for treatment of myocardial infarction. J Gene Med. 2017;19:e2995.

    Article  Google Scholar 

  36. Hu C, Zhao L, Wu Z, Li L. Transplantation of mesenchymal stem cells and their derivatives effectively promotes liver regeneration to attenuate acetaminophen-induced liver injury. Stem Cell Res Ther. 2020;11:88.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Heydari Z, Najimi M, Mirzaei H, Shpichka A, Ruoss M, Farzaneh Z, et al. Tissue engineering in liver regenerative medicine: insights into novel translational technologies. Cells. 2020;9:304.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Missoum A. Recent updates on mesenchymal stem cell based therapy for acute renal failure. Curr Urol. 2020;13:189–99.

    Article  PubMed  PubMed Central  Google Scholar 

  39. Yen BL, Yen ML, Wang LT, Liu KJ, Sytwu HK. Current status of mesenchymal stem cell therapy for immune/inflammatory lung disorders: Gleaning insights for possible use in COVID-19. Stem Cells Transl Med. 2020;9:1163–73.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Han Y, Li X, Zhang Y, Han Y, Chang F, Ding J. Mesenchymal stem cells for regenerative medicine. Cells. 2019;8:886.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Liesveld JL, Sharma N, Aljitawi OS. Stem cell homing: From physiology to therapeutics. Stem Cells. 2020;38:1241–53.

    Article  PubMed  Google Scholar 

  42. Fong CY, Chak LL, Biswas A, Tan JH, Gauthaman K, Chan WK, et al. Human Wharton’s jelly stem cells have unique transcriptome profiles compared to human embryonic stem cells and other mesenchymal stem cells. Stem Cell Rev Rep. 2011;7:1–16.

    Article  CAS  PubMed  Google Scholar 

  43. El Omar R, Beroud J, Stoltz JF, Menu P, Velot E, Decot V. Umbilical cord mesenchymal stem cells: the new gold standard for mesenchymal stem cell-based therapies? Tissue Eng Part B Rev. 2014;20:523–44.

    Article  PubMed  Google Scholar 

  44. Cardenes N, Aranda-Valderrama P, Carney JP, Sellares Torres J, Alvarez D, Kocyildirim E, et al. Cell therapy for ARDS: efficacy of endobronchial versus intravenous administration and biodistribution of MAPCs in a large animal model. BMJ Open Respir Res. 2019;6:e308.

    Google Scholar 

  45. Du J, Li H, Lian J, et al. Stem cell therapy: a potential approach for treatment of influenza virus and coronavirus-induced acute lung injury. Stem Cell Res Ther. 2020;11:192.

    Article  PubMed  PubMed Central  Google Scholar 

  46. Chen L, Qu J, Kalyani FS, Zhang Q, Fan L, Fang Y, et al. Mesenchymal stem cell-based treatments for COVID-19: status and future perspectives for clinical applications. Cell Mol Life Sci. 2022;79:142.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Matthay MA, Calfee CS, Zhuo H, Thompson BT, Wilson JG, Levitt JE, et al. Treatment with allogeneic mesenchymal stromal cells for moderate to severe acute respiratory distress syndrome (START study): a randomised phase 2a safety trial. Lancet Respir Med. 2019;7:154–62.

    Article  PubMed  Google Scholar 

  48. Wilson JG, Liu KD, Zhuo H, Caballero L, McMillan M, Fang X, et al. Mesenchymal stem (stromal) cells for treatment of ARDS: a phase 1 clinical trial. Lancet Respir Med. 2015;191:24–32.

    Article  Google Scholar 

  49. Mehta P, McAuley DF, Brown M, Sanchez E, Tattersall RS, Manson JJ. COVID-19: consider cytokine storm syndromes and immunosuppression. Lancet. 2020;395:1033–4.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Liu J, Li S, Liu J, Liang B, Wang X, Wang H, et al. Longitudinal characteristics of lymphocyte responses and cytokine profiles in the peripheral blood of SARS-CoV-2 infected patients. EBioMedicine. 2020;55:102763.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Leiva-Juarez MM, Kolls JK, Evans SE. Lung epithelial cells: therapeutically inducible effectors of antimicrobial defense. Mucosal Immunol. 2018;11:21–34.

    Article  CAS  PubMed  Google Scholar 

  52. Li M, Yin H, Yan Z, Li H, Wu J, Wang Y, et al. The immune microenvironment in cartilage injury and repair. Acta Biomater. 2022;140:23–42.

    Article  CAS  PubMed  Google Scholar 

  53. Kim GU, Sung SE, Kang KK, Choi JH, Lee S, Sung M, et al. Therapeutic potential of mesenchymal stem cells (MSCs) and MSC-derived extracellular vesicles for the treatment of spinal cord injury. Int J Mol Sci. 2021;22:13672.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Shin S, Lee J, Kwon Y, Park KS, Jeong JH, Choi SJ, et al. Comparative proteomic analysis of the mesenchymal stem cells secretome from adipose, bone marrow, placenta and Wharton’s jelly. Int J Mol Sci. 2021;22:845–61.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Liu Y, Zhang Z, Wang B, Dong Y, Zhao C, Zhao Y, et al. Inflammation-stimulated msc-derived small extracellular vesicle miR-27b-3p regulates macrophages by targeting CSF-1 to promote temporomandibular joint condylar regeneration. Small. 2022;18:e2107354.

    Article  PubMed  Google Scholar 

  56. Choi J, Park JE, Tsagkogeorga G, Yanagita M, Koo BK, Han N, et al. Inflammatory signals induce AT2 cell-derived damage-associated transient progenitors that mediate alveolar regeneration. Cell Stem Cell. 2020;27:366–82.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Dutra Silva J, Su Y, Calfee CS, Delucchi KL, Weiss D, McAuley DF, et al. Mesenchymal stromal cell extracellular vesicles rescue mitochondrial dysfunction and improve barrier integrity in clinically relevant models of ARDS. Eur Respir J. 2021;58:2002978.

    Article  PubMed  PubMed Central  Google Scholar 

  58. Wei Z, Chen Z, Zhao Y, Fan F, Xiong W, Song S, et al. Mononuclear phagocyte system blockade using extracellular vesicles modified with CD47 on membrane surface for myocardial infarction reperfusion injury treatment. Biomaterials. 2021;275:121000.

    Article  CAS  PubMed  Google Scholar 

  59. Wang S, Yao X, Ma S, Ping Y, Fan Y, Sun S, et al. A single-cell transcriptomic landscape of the lungs of patients with COVID-19. Nat Cell Biol. 2021;23:1314–28.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Marofi F, Alexandrovna KI, Margiana R, Bahramali M, Suksatan W, Abdelbasset WK, et al. MSCs and their exosomes: a rapidly evolving approach in the context of cutaneous wounds therapy. Stem Cell Res Ther. 2021;12:597–617.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Li C, Jin Y, Wei S, Sun Y, Jiang L, Zhu Q, et al. Hippo signaling controls NLR family pyrin domain containing 3 activation and governs immunoregulation of mesenchymal stem cells in mouse liver injury. Hepatology. 2019;70:1714–31.

    Article  CAS  PubMed  Google Scholar 

  62. Jiang Y, Zhang P, Zhang X, Lv L, Zhou Y. Advances in mesenchymal stem cell transplantation for the treatment of osteoporosis. Cell Prolif. 2021;54:e12956.

    Article  PubMed  Google Scholar 

  63. Stamatopoulos A, Stamatopoulos T, Gamie Z, Kenanidis E, Ribeiro RDC, Rankin KS, et al. Mesenchymal stromal cells for bone sarcoma treatment: roadmap to clinical practice. J Bone Oncol. 2019;16:100231.

    Article  PubMed  PubMed Central  Google Scholar 

  64. Gao F, Chiu SM, Motan DA, Zhang Z, Chen L, Ji HL, et al. Mesenchymal stem cells and immunomodulation: current status and future prospects. Cell Death Dis. 2016;7:e2062.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. 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;5:172.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Wang L, Shi M, Tong L, Wang J, Ji S, Bi J, et al. Lung-resident mesenchymal stem cells promote repair of LPS-induced acute lung injury via regulating the balance of regulatory T cells and Th17 cells. Inflammation. 2019;42:199–210.

    Article  CAS  PubMed  Google Scholar 

  67. Li N, Hua J. Interactions between mesenchymal stem cells and the immune system. Cell Mol Life Sci. 2017;74:2345–60.

    Article  CAS  PubMed  Google Scholar 

  68. Pittenger MF, Discher DE, Péault BM, Phinney DG, Hare JM, Caplan AI. Mesenchymal stem cell perspective: cell biology to clinical progress. NPJ Regen Med. 2019;4:22–37.

    Article  PubMed  PubMed Central  Google Scholar 

  69. Tsuchiya A, Takeuchi S, Iwasawa T, Kumagai M, Sato T, Motegi S, et al. Therapeutic potential of mesenchymal stem cells and their exosomes in severe novel coronavirus disease 2019 (COVID-19) cases. Inflamm Regen. 2020;40:14–20.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Liang B, Chen J, Li T, Wu H, Yang W, Li Y, 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:e21429.

    Article  CAS  PubMed  Google Scholar 

  71. Zhu R, Yan T, Feng Y, Liu Y, Cao H, Peng G, et al. Mesenchymal stem cell treatment improves outcome of COVID-19 patients via multiple immunomodulatory mechanisms. Cell Res. 2021;31:1244–62.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Merad M, Martin JC. Pathological inflammation in patients with COVID-19: a key role for monocytes and macrophages. Nat Rev Immunol. 2020;20:355–62.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Hu C, Li L. Preconditioning influences mesenchymal stem cell properties in vitro and in vivo. J Cell Mol Med. 2018;22:1428–42.

    Article  PubMed  PubMed Central  Google Scholar 

  74. Pouya S, Heidari M, Baghaei K, Asadzadeh Aghdaei H, Moradi A, Namaki S, et al. Study the effects of mesenchymal stem cell conditioned medium injection in mouse model of acute colitis. Int Immunopharmacol. 2018;54:86–94.

    Article  CAS  PubMed  Google Scholar 

  75. Taghavi-Farahabadi M, Mahmoudi M, Soudi S, Hashemi SM. Hypothesis for the management and treatment of the COVID-19-induced acute respiratory distress syndrome and lung injury using mesenchymal stem cell-derived exosomes. Med Hypotheses. 2020;144:109865.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Khoury M, Cuenca J, Cruz FF, Figueroa FE, Rocco PRM, Weiss DJ. Current status of cell-based therapies for respiratory virus infections: applicability to COVID-19. Eur Respir J. 2020;55:2000858.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Ercelen ON, Pekkoc-Uyanik KC, Alpaydin N, Gulay GR, Simsek M. Clinical experience on umbilical cord mesenchymal stem cell treatment in 210 severe and critical COVID-19 cases in Turkey. Stem Cell Rev Rep. 2021;17:1917–25.

    Article  Google Scholar 

  78. Rogers CJ, Harman RJ, Bunnell BA, Schreiber MA, Xiang C, Wang FS, et al. Rationale for the clinical use of adipose-derived mesenchymal stem cells for COVID-19 patients. J Transl Med. 2020;18:203–22.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Shi L, Wang L, Xu R, Zhang C, Xie YB, Liu K, et al. Mesenchymal stem cell therapy for severe COVID-19. Signal Transduct Target Ther. 2021;6:339–44.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Li X, Yue S, Luo Z. Mesenchymal stem cells in idiopathic pulmonary fibrosis. Oncotarget. 2017;8:102600–16.

    Article  PubMed  PubMed Central  Google Scholar 

  81. Hu S, Park J, Liu A, Lee J, Zhang X, Hao Q, et al. Mesenchymal stem cell microvesicles restore protein permeability across primary cultures of injured human lung microvascular endothelial cells. Stem Cells Transl Med. 2018;7:615–24.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Harrell CR, Sadikot R, Pascual J, Fellabaum C, Jankovic MG, Jovicic N, et al. Mesenchymal stem cell-based therapy of inflammatory lung diseases: current understanding and future perspectives. Stem Cells Int. 2019;2019:4236973.

    Article  PubMed  PubMed Central  Google Scholar 

  83. Carcaterra M, Caruso C. Alveolar epithelial cell type II as main target of SARS-CoV-2 virus and COVID-19 development via NF-Kb pathway deregulation: a physio-pathological theory. Med Hypotheses. 2021;146:110412.

    Article  CAS  PubMed  Google Scholar 

  84. Xu T, Zhang Y, Chang P, Gong S, Shao L, Dong L. Mesenchymal stem cell-based therapy for radiation-induced lung injury. Stem Cell Res Ther. 2018;9:18–25.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Lee JW, Krasnodembskaya A, McKenna DH, Song Y, Abbott J, Matthay MA. Therapeutic effects of human mesenchymal stem cells in ex vivo human lungs injured with live bacteria. Am J Respir Crit Care Med. 2013;187:751–60.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Shi L, Yuan X, Yao W, Wang S, Zhang C, Zhang B, et al. Human mesenchymal stem cells treatment for severe COVID-19: 1-year follow-up results of a randomized, double-blind, placebo-controlled trial. EBioMedicine. 2022;75:103789.

    Article  CAS  PubMed  Google Scholar 

  87. Bernard O, Jeny F, Uzunhan Y, Dondi E, Terfous R, Label R, et al. Mesenchymal stem cells reduce hypoxia-induced apoptosis in alveolar epithelial cells by modulating HIF and ROS hypoxic signaling. Am J Physiol Lung Cell Mol Physiol. 2018;314:360–71.

    Article  CAS  Google Scholar 

  88. Yang Y, Hu S, Xu X, Li J, Liu A, Han J, et al. The vascular endothelial growth factors-expressing character of mesenchymal stem cells plays a positive role in treatment of acute lung injury in vivo. Mediators Inflamm. 2016;2016:2347938.

    Article  PubMed  PubMed Central  Google Scholar 

  89. Li F, Karlsson H. Antiviral effect of IDO in mouse fibroblast cells during influenza virus infection. Viral Immunol. 2017;30:542–4.

    Article  CAS  PubMed  Google Scholar 

  90. Tripathi S, Tecle T, Verma A, Crouch E, White M, Hartshorn KL. The human cathelicidin LL-37 inhibits influenza A viruses through a mechanism distinct from that of surfactant protein D or defensins. J Gen Virol. 2013;94:40–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Esfandiyari R, Halabian R, Behzadi E, Sedighian H, Jafari R, Imani Fooladi AA. Performance evaluation of antimicrobial peptide ll-37 and hepcidin and β-defensin-2 secreted by mesenchymal stem cells. Heliyon. 2019;5:e02652.

    Article  PubMed  PubMed Central  Google Scholar 

  92. Alcayaga-Miranda F, Cuenca J, Khoury M. Antimicrobial activity of mesenchymal stem cells: current status and new perspectives of antimicrobial peptide-based therapies. Front Immunol. 2017;8:339.

    Article  PubMed  PubMed Central  Google Scholar 

  93. Worthington EN, Hagood JS. Therapeutic use of extracellular vesicles for acute and chronic lung disease. Int J Mol Sci. 2020;21:2318.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Li S, Xu J, Qian J, Gao X. Engineering extracellular vesicles for cancer therapy: recent advances and challenges in clinical translation. Biomater Sci. 2020;8:6978–91.

    Article  CAS  PubMed  Google Scholar 

  95. Robbins PD, Dorronsoro A, Booker CN. Regulation of chronic inflammatory and immune processes by extracellular vesicles. J Clin Invest. 2016;126:1173–80.

    Article  PubMed  PubMed Central  Google Scholar 

  96. Yudintceva N, Mikhailova N, Fedorov V, Samochernych K, Vinogradova T, Muraviov A, Shevtsov M. Mesenchymal stem cells and MSCs-derived extracellular vesicles in infectious diseases: from basic research to clinical practice. Bioengineering (Basel). 2022;9:662.

    Article  CAS  PubMed  Google Scholar 

  97. Ardalan M, Chodari L, Zununi Vahed S, Hosseiniyan Khatibi SM, Eftekhari A, Davaran S, Cucchiarini M, Roshangar L, Ahmadian E. Stem cell-derived biofactors fight against coronavirus infection. World J Stem Cells. 2021;13:1813–25.

    Article  PubMed  PubMed Central  Google Scholar 

  98. Meldolesi J. News about the extracellular vesicles from mesenchymal stem cells: functions, therapy and protection from COVID-19. J Exp Pathol (Wilmington). 2021;2:47–52.

    PubMed  Google Scholar 

  99. Wang J, Huang R, Xu Q, Zheng G, Qiu G, Ge M, Shu Q, Xu J. Mesenchymal stem cell-derived extracellular vesicles alleviate acute lung injury via transfer of miR-27a-3p. Crit Care Med. 2020;48:e599–610.

    Article  CAS  PubMed  Google Scholar 

  100. 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;29:747–54.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Cloer C, Roudsari L, Rochelle L, Petrie T, Welch M, Charest J, Tan K, Fugang L, Petersen T, Ilagan R, Hogan S. Mesenchymal stromal cell-derived extracellular vesicles reduce lung inflammation and damage in nonclinical acute lung injury: implications for COVID-19. PLoS ONE. 2021;16:e0259732.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Zhao R, Wang L, Wang T, Xian P, Wang H, Long Q. Inhalation of MSC-EVs is a noninvasive strategy for ameliorating acute lung injury. J Control Release. 2022;345:214–30.

    Article  CAS  PubMed  Google Scholar 

  103. Akbari A, Rezaie J. Potential therapeutic application of mesenchymal stem cell-derived exosomes in SARS-CoV-2 pneumonia. Stem Cell Res Ther. 2020;11:356.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Jamshidi E, Babajani A, Soltani P, Niknejad H. Proposed mechanisms of targeting COVID-19 by delivering mesenchymal stem cells and their exosomes to damaged organs. Stem Cell Rev Rep. 2021;17:176–92.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Li J, Liu ZP, Xu C, Guo A. TGF-β1-containing exosomes derived from bone marrow mesenchymal stem cells promote proliferation, migration and fibrotic activity in rotator cuff tenocytes. Regen Ther. 2020;15:70–6.

    Article  PubMed  PubMed Central  Google Scholar 

  106. Li JW, Wei L, Han Z, Chen Z. Mesenchymal stromal cells-derived exosomes alleviate ischemia/reperfusion injury in mouse lung by transporting anti-apoptotic miR-21-5p. Eur J Pharmacol. 2019;852:68–76.

    Article  CAS  PubMed  Google Scholar 

  107. Khatri M, Richardson LA, Meulia T. Mesenchymal stem cell-derived extracellular vesicles attenuate influenza virus-induced acute lung injury in a pig model. Stem Cell Res Ther. 2018;9:17.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Hao Q, Gudapati V, Monsel A, Park JH, Hu S, Kato H, Lee JH, Zhou L, He H, Lee JW. Mesenchymal stem cell-derived extracellular vesicles decrease lung injury in mice. J Immunol. 2019;203:1961–72.

    Article  CAS  PubMed  Google Scholar 

  109. Krueger TEG, Thorek DLJ, Denmeade SR, Isaacs JT, Brennen WN. Concise review: mesenchymal stem cell-based drug delivery: the good, the bad, the ugly, and the promise. Stem Cells Transl Med. 2018;7:651–63.

    Article  PubMed  PubMed Central  Google Scholar 

  110. Le Blanc K, Tammik C, Rosendahl K, Zetterberg E, Ringdén O. HLA expression and immunologic properties of differentiated and undifferentiated mesenchymal stem cells. Exp Hematol. 2003;31:890–6.

    Article  PubMed  Google Scholar 

  111. Thanaskody K, Jusop AS, Tye GJ, Wan Kamarul Zaman WS, Dass SA, Nordin F. MSCs vs iPSCs: potential in therapeutic applications. Front Cell Dev Biol. 2022;10:1005926.

    Article  PubMed  PubMed Central  Google Scholar 

  112. Kolios G, Moodley Y. Introduction to stem cells and regenerative medicine. Respiration. 2013;85:3–10.

    Article  PubMed  Google Scholar 

  113. Yu B, Zhang X, Li X. Exosomes derived from mesenchymal stem cells. Int J Mol Sci. 2014;15:4142–57.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Su Y, Guo H, Liu Q. Effects of mesenchymal stromal cell-derived extracellular vesicles in acute respiratory distress syndrome (ARDS): current understanding and future perspectives. J Leukoc Biol. 2021;110:27–38.

    Article  CAS  PubMed  Google Scholar 

  115. Kou M, Huang L, Yang J, Chiang Z, Chen S, Liu J, Guo L, Zhang X, Zhou X, Xu X, Yan X, Wang Y, Zhang J, Xu A, Tse HF, Lian Q. Mesenchymal stem cell-derived extracellular vesicles for immunomodulation and regeneration: a next generation therapeutic tool? Cell Death Dis. 2022;13:580.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. Kalluri R. The biology and function of exosomes in cancer. J Clin Invest. 2016;126:1208–15.

    Article  PubMed  PubMed Central  Google Scholar 

  117. Phinney DG, Pittenger MF. Concise review: MSC-derived exosomes for cell-free therapy. Stem Cells. 2017;35:851–8.

    Article  CAS  PubMed  Google Scholar 

  118. Shi L, Huang H, Lu X, Yan X, Jiang X, Xu R, et al. Effect of human umbilical cord-derived mesenchymal stem cells on lung damage in severe COVID-19 patients: a randomized, double-blind, placebo-controlled phase 2 trial. Signal Transduct Target Ther. 2021;6:58–67.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. Lanzoni G, Linetsky E, Correa D, Messinger Cayetano S, Alvarez RA, Kouroupis D, et al. Umbilical cord mesenchymal stem cells for COVID-19 acute respiratory distress syndrome: a double-blind, phase 1/2a, randomized controlled trial. Stem Cells Transl Med. 2021;10:660–73.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. Hu B, Huang S, Yin L. The cytokine storm and COVID-19. J Med Virol. 2021;93:250–6.

    Article  CAS  PubMed  Google Scholar 

  121. Rahmati S, Shojaei F, Shojaeian A, Rezakhani L, Dehkordi MB. An overview of current knowledge in biological functions and potential theragnostic applications of exosomes. Chem Phys Lipids. 2020;226:104836.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

This study was funded by The National Nature Science Foundation of China (Grant No. 81860256), Fok Ying-Tong Education Foundation for Young Teachers in the Higher Education Institutions of China (Grant No. 171098) and Youth Science Foundation of Guangxi Medical University (Grant No. GXMUYSF 202319).

Author information

Authors and Affiliations

  1. Collaborative Innovation Centre of Regenerative Medicine and Medical BioResource Development and Application Co-Constructed by the Province and Ministry, Guangxi Key Laboratory of Regenerative Medicine and Key Laboratory of Longevity and Aging-Related Diseases of Chinese Ministry of Education, Guangxi Medical University, Shuangyong Road, Nanning, 530021, Guangxi, People’s Republic of China

    Jinling Li, Shipei He, Hang Yang, Lizeai Zhang, Jie Xiao, Chaoyi Liang & Sijia Liu

  2. Guangxi Colleges and Universities Key Laboratory of Biological Molecular Medicine Research, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Guangxi Medical University, Shuangyong Road, Nanning, 530021, Guangxi, People’s Republic of China

    Shipei He, Hang Yang, Jie Xiao, Chaoyi Liang & Sijia Liu

  3. Laboratory of Basic Medicine Center, Guangxi Medical University, Shuangyong Road, Nanning, 530021, Guangxi, People’s Republic of China

    Jinling Li

Authors
  1. Jinling Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Shipei He
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Hang Yang
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Lizeai Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Jie Xiao
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Chaoyi Liang
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Sijia Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Sijia Liu.

Ethics declarations

Conflict of interest

All authors declared no conflict of interests.

Ethical statement

This article does not contain any studies with human participants or animals performed by any of the author.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Li, J., He, S., Yang, H. et al. The Main Mechanisms of Mesenchymal Stem Cell-Based Treatments against COVID-19. Tissue Eng Regen Med 21, 545–556 (2024). https://doi.org/10.1007/s13770-024-00633-5

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s13770-024-00633-5

Keywords

Search

Navigation