Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2021 Aug:97:107694.
doi: 10.1016/j.intimp.2021.107694. Epub 2021 Apr 28.

Mesenchymal stromal/stem cells (MSCs) and MSC-derived extracellular vesicles in COVID-19-induced ARDS: Mechanisms of action, research progress, challenges, and opportunities

Susan Moradinasab  1 , Atieh Pourbagheri-Sigaroodi  2 , Parisa Zafari  3 , Seyed H Ghaffari  4 , Davood Bashash  5
Affiliations
Review

Mesenchymal stromal/stem cells (MSCs) and MSC-derived extracellular vesicles in COVID-19-induced ARDS: Mechanisms of action, research progress, challenges, and opportunities

Susan Moradinasab et al. Int Immunopharmacol. 2021 Aug.

Abstract

In late 2019, a novel coronavirus (SARS-CoV-2) emerged in Wuhan city, Hubei province, China. Rapidly escalated into a worldwide pandemic, it has caused an unprecedented and devastating situation on the global public health and society economy. The severity of recent coronavirus disease, abbreviated to COVID-19, seems to be mostly associated with the patients' immune response. In this vein, mesenchymal stromal/stem cells (MSCs) have been suggested as a worth-considering option against COVID-19 as their therapeutic properties are mainly displayed in immunomodulation and anti-inflammatory effects. Indeed, administration of MSCs can attenuate cytokine storm and enhance alveolar fluid clearance, endothelial recovery, and anti-fibrotic regeneration. Despite advantages attributed to MSCs application in lung injuries, there are still several issues __foremost probability of malignant transformation and incidence of MSCs-related coagulopathy__ which should be resolved for the successful application of MSC therapy in COVID-19. In the present study, we review the historical evidence of successful use of MSCs and MSC-derived extracellular vesicles (EVs) in the treatment of acute respiratory distress syndrome (ARDS). We also take a look at MSCs mechanisms of action in the treatment of viral infections, and then through studying both the dark and bright sides of this approach, we provide a thorough discussion if MSC therapy might be a promising therapeutic approach in COVID-19 patients.

Keywords: Acute respiratory distress syndrome; COVID-19; Extracellular vesicles; Immunomodulation; Mesenchymal stem cells; SARS-CoV-2.

PubMed Disclaimer

Conflict of interest statement

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Figures

None
Graphical abstract
Fig. 1
Fig. 1
A glance at the history beyond the application of MSCs in lung injuries. MSC: Mesenchymal stem cell; LPS: Lipopolysaccharide; ARDS: Acute respiratory distress syndrome; ALI: Acute lung injury; BM: Bone marrow; COPD: Chronic obstructive pulmonary disease; UC: Umbilical cord; AD-MSC: Adipocyte-derived MSC; IPF: Idiopathic pulmonary fibrosis.
Fig. 2
Fig. 2
A schematic overview of the potential mechanisms of action of MSCs against viral infections. MSCs can promote tissue regeneration and enhance alveolar fluid clearance through secretion of HGFs, KGFs, VEGFs, and Ang-1 which reduce fibrosis and facilitate injured endothelium repair. Also, MSCs may attenuate cytokine storm by regulating the immune cells in the inflammatory environment through secretion of anti-inflammatory factors leading to Treg induction, as well as TH2, PDC, and M2 macrophage polarization. Soluble factors from MSCs can prevent oxidative burst in neutrophils and reduce tissue damage via inhibition of extracellular release of elastase and myeloperoxidase.Ang-1: Angiopoietin-1; HGF: Hepatocyte growth factor; KGF: Keratinocyte growth factor; VEGF: Vascular endothelial growth factor; PGE2: Prostaglandin E2; TGF- β: Transforming growth factor-B; TH: T Helper; Treg: Regulatory T cell; IDO: Indoleamine 2,3-dioxygenase; NK cell: Natural killer cell; PD-1-PD-L1: Programmed death receptor and ligand; DC: Dendritic cell; PDC: Plasmacytoid DC; PC: Plasma cell; ROS: Reactive oxygen species; SOD: Superoxide dismutase; Neu: Neutrophil.
Fig. 3
Fig. 3
A Schematic representation of the role of MSC-derived EVs in lung injuries. Microvesicles and exosomes transfer miRNA, mRNA, protein, and mitochondria from their parents to the injured alveolus. EVs containing mitochondria and the mRNAs of KGF, HGF, and Ang-1 can decrease lung edema and enhance the tissue repair process. Mitochondrial transfer not only may hamper LPS-lung injury also inhibit cytokine storm by its modulatory effect on a variety of immune cells. EV: Extracellular vesicle; MVB: Multi-vesicular Bodies Mt: Mitochondria; Ang-1: Angiopoietin-1; HGF: Hepatocyte growth factor; KGF: Keratinocyte growth factor; LPS: Lipopolysaccharide; DC: Dendritic cell; Neu: Neutrophil; MQ: Macrophage.
Fig. 4
Fig. 4
A schematic summary of clinical application of MSCs and their EVs from different sources in COVID-19 patients. A) BM-MSCs could modulate inflammation via downregulation of cytokine storm induced by the overactivation of pro-inflammatory immune cells. B) Administration of UC-MSCs could return immune cells to the normal range, decrease CRP level, and improve lung and kidney function. C) Human embryo-derived stem cells not only could improve lung function also prevent fibrosis and pulmonary inflammation. D) AD-MSC therapy resulted in a decreased level of inflammatory factors and increased B and T cell populations. E) Following menstrual blood-derived MSCs injection, the inflammatory factors were decreased, however, the patients underwent several treatment-associated side effects. F) Administration of BM-MSC-derived exosomes could improve the outcome of the disease through their significant attenuating effect on D-dimer, inflammation, and cytokine storm.Mon: Monocyte; DC: Dendritic Cell; MQ: Macrophage; UC-MSC: Umbilical cord MSC; CRP: C- reactive protein; Neu: Neutrophil; P/F ratio: Arterial oxygen partial pressure to fractional inspired oxygen; hESC: Human embryonic stem cell; GM-CSF: Granulocyte-macrophage colony-stimulating factor; TNF- α: Tumor necrosis factor-Α; TGF- β: Transforming growth factor-Β; AD-MSC: Adipocyte-derived MSC; LDH: Lactate dehydrogenase.
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. W.H. Organization, Summary of probable SARS cases with onset of illness from 1 November 2002 to 31 July 2003, http://www. who. int/csr/sars/country/table2004_04_21/en/index. html (2003).
    1. W.H. Organization, Middle East respiratory syndrome coronavirus (MERS-CoV), 2019.
    1. Baud D., Qi X., Nielsen-Saines K., Musso D., Pomar L., Favre G. Real estimates of mortality following COVID-19 infection. Lancet. Infect. Dis. 2020 - PMC - PubMed
    1. Sun J., He W.-T., Wang L., Lai A., Ji X., Zhai X., Li G., Suchard M.A., Tian J., Zhou J. COVID-19: epidemiology, evolution, and cross-disciplinary perspectives. Trends Mol. Med. 2020;26(5):483–495. - PMC - PubMed
    1. Wu Z., McGoogan J.M. Characteristics of and important lessons from the coronavirus disease 2019 (COVID-19) outbreak in China: summary of a report of 72 314 cases from the Chinese Center for Disease Control and Prevention. JAMA. 2020;323(13):1239–1242. - PubMed

MeSH terms

Substances