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Review
. 2021 Apr;73(2):253-298.
doi: 10.1007/s10616-021-00461-8. Epub 2021 Mar 22.

Taming of Covid-19: potential and emerging application of mesenchymal stem cells

Nima Najafi-Ghalehlou  1 , Mehryar Habibi Roudkenar  2   3 , Habib Zayeni Langerodi  4 , Amaneh Mohammadi Roushandeh  2   5
Affiliations
Review

Taming of Covid-19: potential and emerging application of mesenchymal stem cells

Nima Najafi-Ghalehlou et al. Cytotechnology. 2021 Apr.

Abstract

Coronavirus Disease 2019 (COVID-19) caused by the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) has turned out to cause a pandemic, with a sky scraping mortality. The virus is thought to cause tissue injury by affecting the renin-angiotensin system. Also, the role of the over-activated immune system is noteworthy, leading to severe tissue injury via the cytokine storms. Thus it would be feasible to modulate the immune system response in order to attenuate the disease severity, as well as treating the patients. Today different medicines are being administered to the patients, but regardless of the efficacy of these treatments, adverse effects are pretty probable. Meanwhile, mesenchymal stem cells (MSCs) prove to be an effective candidate for treating the patients suffering from COVID-19 pneumonia, owing to their immunomodulatory and tissue-regenerative potentials. So far, several experiments have been conducted; transplanting MSCs and results are satisfying with no adverse effects being reported. This paper aims to review the recent findings regarding the novel coronavirus and the conducted experiments to treat patients suffering from COVID-19 pneumonia utilizing MSCs.

Keywords: COVID-19; Cytokine storms; Mesenchymal stem cells; Renin-angiotensin system; SARS-CoV-2.

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Conflict of interest statement

Conflict of interestThe authors declare that they have no conflict of interest.

Figures

Fig. 1
Fig. 1
Shows how the virus exerts its toxicity in cells. As the virus enters the cell after being recognized by the ACE2 receptor, along with the viral replication and transcription to produce viral proteins, the expression of the ACE2 is also suppressed, resulting in pro-inflammatory, vasoconstriction, and finally tissue injury. Furthermore, over-activation of the immune system leads into diapedesis and accumulation of the immune cells, such as T cell, B cell, macrophage, and monocyte in the site of injury, which results in cytokine storms and high level of expression of inflammatory cytokines, such as IL-2, IL-6, TNF-α, and the secreted antibodies from B cell-derived plasma cells, causing cytotoxic effects on the epithelial cells in the respiratory tract, as well as other organs infected by the virus, such as the heart, liver, and kidney. This in turn would cause clinical manifestations of the disease. ACE2 angiotensin-converting enzyme 2, IL-2 interleukin 2, IL-6 interleukin 6, TNF-α tumor necrosis factor alpha
Fig. 2
Fig. 2
Immunosuppressive and immunomodulatory properties of MSCs. IL-10 prevents the production of pro-inflammatory cytokines, T cell proliferation, memory T cell formation, APC maturation, as well as the expression of MHC and co-stimulatory factors, which are produced by MSCs in a quiescent state. Its expression is elevated under the influence of TLR ligands and PEG2. PGE2 can suppress inflammation by inducing Foxp3+ Treg cells production. Also inhibits the proliferation of T cells by elevating DCs’ maturation and exhibit a pro-inflammatory effect, so low levels of this chemokine can cause an inflammatory response. PGE2 can suppress natural killers and inhibit CD8+ T cell activity by stimulating TGF-β secretion from monocytes. Also, the expression of PGE2, IL-6, and IDO by MSCs modulates the direct differentiation of monocytes into M2 type macrophages. TGF-β is a cytokine that is primarily secreted by MSCs and is upregulated by inflammatory factors such as IFN-γ and TNF-α. This chemokine can inhibit the differentiation of T cells into Th1 and Th2 and promote the production of Treg and Breg cells, thus disrupting the expression of IL-2, MHC-II and stimulatory cofactors in DCs and T cells. MSCs produce Treg by changing DCs phenotype into the Tolurogenic phenotype. By inducing MSCs-produced IDO, T cell proliferation is inhibited and Treg is stimulated. IL-10 interleukin 10, MHC major histocompatibility complex, APC antigen-presenting cell, MSC mesenchymal stem cell, TLR toll-like receptor, PEG2 prostaglandin E2, DC dendritic cell, TGF-β transforming growth factor beta, IL-6 interleukin 6, IDO indoleamine-pyrrole 2,3-dioxygenase, IFN-γ interferon gamma, TNF-α tumor necrosis factor alpha, Th1 T helper cell type 1, Th2 T helper cell type 2, Treg regulatory T cell, Breg regulatory B cell, IL-2 interleukin 2
Fig. 3
Fig. 3
The immunomodulating potential of MSCs in lung. HGFs are involved in inflammatory damage reduction, autophagy promotion, fibrosis attenuation, enhance alveolar epithelium repair, as well as the modulation of IL-10 production in monocytes via the ERK1/2 pathway. TNF-α is involved in further activation of MSCs by IL-10, which is responsible for decreasing the neutrophil inflow and aggregation into the lungs, and reduce the production of TNF-α. Also, HLA-G5 secretion of which is dependent on IL-10, which functions as T cell and NK cell suppressor, as well as Treg activator. In fact, a shift from Th1 to Th2 phenotype is accomplished through secretion of IL-10 and TGF-β, growth factors, soluble factors like and the inhibition of pro-inflammatory cytokines. In addition, T cell suppression may be accomplished by the secretion of Gal-1 and Sema-3A by MSCs. Gal-1 is involved in regulating the release of TNF-α, IFN-γ, IL-2, and IL-10. PGE2 inhibits the antigen presentation by DCs and proliferations of T-effector cells and together with TGF-β functions to repolarize the macrophages from the proinflammatory M1-phenotype towards the anti-inflammatory M2-phenotype in an LPS-dependent manner, which is further accompanied by decrease inflammatory reactions, enhance phagocytic activity through the Akt/FoxO1 pathway, and progress tissue repair. TGF-β also triggers the proliferation of Tregs, induces IL-6, and stimulates PGE2. IL-6 is also recognized as an inhibitor of neutrophil proliferation. MSCs-secreted IDO is involved in the enhancement of pulmonary antimicrobial activity, differentiation of CD14+/CD206+ monocytes into IL-10-secreting immunosuppressive M2 macrophages, as well as the inhibition of IFN-secreting Th1 cells expansion, along with PGE2, to stop NK cell activity. To increase the exposure of MSCs to immunosuppressive effect inducing IL-1β, TNF-α, and IFN-γ, MSCs secrete IL-1Ra and PDL1, which are involved in inhibiting Th17 polarization and supporting the cell–cell contact through MSC-mediated inhibition of Th17, respectively. Induction of MSCs by IL-1β, TNF-α, and NO in the alveolar endothelial cells further leads to enhanced paracrine potential and increased secretion of regenerative, immunomodulatory, and trafficking molecules, including the IGF-1, HO-1, FGF-10, and KGF-2. HO-1 is a stress-response protein overexpression which further leads to increase production of trophic molecules, such as FGF2, IGF-1, and VEGF, as well as promote anti-inflammatory, anti-apoptotic, anti-oxidative, and vascular remodeling properties. Regulation of the epithelial-mesenchyme interactions and lung development is accomplished by FGF-10 and KGF-2, as FGF-10 inhibits viral replication and exerts a role in lung resident MSC propagation, mobilization, and the protective effects against acute lung injury, whereas KGF2 promotes AFC, restores sodium dependent alveolar fluid transport, reduces injury, promotes proliferation and repair of alveolar epithelial cells by increasing surface-active substances, such as matrix metalloprotein MMP-9, IL-1Ra, and GM-CSF, facilitates phagocytosis together with PGE2, GM-CSF, IL-6, and IL-13, protects the alveolar cells along with VEGF and HGF, and reduces apoptosis of the alveolar epithelial cells and endothelial cell in collaboration with Ang-1 and HGF. FGF-7 is thought to regulate the function of membrane channels and transporters to improve the AFC. Of note, VEGF, IGF, HGF, neurotrophin-3, and nerve growth factor are the MSCs-secreted bioactive factors to exert an anti-apoptotic effect. In addition, VEGF together with HGF restores pulmonary capillary permeability to stabilize the endothelial barrier function, and together with PDGF induce proliferation of vascular endothelial cells and angiogenesis. Overexpression of anti-inflammatory and anti-oxidative molecules, including sST2, Del-1, and manganese superoxide dismutase, enhances the regenerative ability of lung injury. AFC alveolar fluid clearance, Ang-1 angiopoietin-1, DC dendritic cell, Del-1 developmental endothelial locus-1, FGF fibroblast growth factor, Gal-1 Galectin-1, GM-CSF granulocyte–macrophage colony-stimulating factor, HGF hepatocyte growth factor, HLA-G5 human leukocyte antigen class I molecule G5, HO-1 haem oxygenase 1, IDO indoleamine 2,3‐dioxygenase, IFN-γ interferon gamma, IGF insulin-like growth factor 1, IL-10 interleukin 10, IL-13 interleukin 13, IL-1Ra interleukin-1 receptor antagonist, IL-1β interleukin 1 beta, IL-2 interleukin 2, IL-6 interleukin 6, KGF2 keratinocyte growth factor 2, LPS lipopolysaccharide, MMP-9 metalloprotein, MSC mesenchymal stem cell, NK natural killer, NO nitric oxide, PDGF platelet-derived growth factor, PDL1 programmed cell death ligands 1, PGE2 prostaglandin E2, Sema-3A Semaphorin-3A, sST2 soluble IL-1 receptor-like-1, TGF-β transforming growth factor-beta, Th1 T helper type 1, TNF-α tumor necrosis factor alpha, Treg regulatory T cell, VEGF vascular endothelial growth factor
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