A brief review on potential application of mesenchymal stem cell and secretome in combating mortality and morbidity in COVID-19 patients

Abstract

Coronavirus disease 2019 (COVID-19) caused by novel Severe Acute Respiratory Syndrome-Coronavirus 2 (SARS-CoV2), is typically associated with severe respiratory distress and has claimed more than 525,000 lives already. The most fearful aspect is the unavailability of any concrete guidelines and treatment or protective strategies for reducing mortality or morbidity caused by this virus. Repurposing of drugs, antivirals, convalescent plasma and neutralizing antibodies are being considered for treatment but are still questionable in lieu of the conflicting data, study design and induction of secondary infections. Stem cell therapy has seen substantial advancements over the past decade for the treatment of various diseases including pulmonary disorders with severe complications similar to COVID-19. Recently, mesenchymal stem cells (MSCs) have received particular attention as a potential therapeutic modality for SARS-CoV2 infection due to their ability to inhibit cytokine storm, a hallmark of severe COVID-19. MSCs secretion of trophic factors and extracellular vesicles mediated intercellular signaling are considered as principal contributing factors for tissue recovery. Although, recent preliminary studies have established the safety and efficacy of these cells without any severe secondary complications in the treatment of SARS-CoV2 infection, the rational use of MSCs on a large scale would still require additional relevant clinical investigations and validation of postulated mechanisms of these cells. This review presents the current clinical findings and update on the potential use of stem cell therapy and its secretome in combating the symptoms associated with COVID-19.

Keywords: COVID-19; Mesenchymal stem cells; Organ dysfunction; Respiratory distress; SARS-CoV2; Secretome.

Fig. 1

Proposed mechanism of SARS-CoV2 infection. SARS-CoV2 can directly infect AT2 cells, capillary endothelial cells, macrophages and T-cells. ACE2 receptor + mediated endocytosis of the virus activates NFκB-IRF pathway, which results in the expression of IFN-α. IFN-α translocates to the nucleus, and results in the activation of interferon − stimulated genes, which have anti-viral activity. CoV2 evades this killing, and results in delayed activation of IFN-α. This causes excessive infiltration of hyper-inflammatory neutrophils. These together with hyper-active T cells and macrophages result in the excessive secretion of pro-inflammatory mediators which also lead to excessive fibrosis. Hyper-inflammation causes increased expression of hyaluronan synthase 2, and production of hyaluronan which is associated with fluid absorption, resulting in pneumonia, resulting in the development of ARDS. The entry of the virus in the blood results in its translocation to its target organs, such as heart, kidney and GI tract resulting in multiple organ dysfunctions.

Fig. 2

Proposed mechanisms of MSCs alleviation of SARS-CoV2 infection. MSCs induce antiviral response due to the high expression of ISG genes and prevent virus shedding in the lungs. MSCs primarily act by secretion and EVs mediated transfer of anti-inflammatory and immunomodulatory mediators and other proteins and miRNAs, which result in the production of M2 macrophages and regulatory lymphocytes. MSCs can also directly differentiate into pneumocytes and other lung epithelial cells, or provide cues to direct the differentiation of host tissue resident stem cells, and secrete various angiogenic and growth factors to promote revascularization, and thus restoring the structural damage. Direct transfer of functional mitochondria to the alveolar cells restores their metabolic capacity and ATP stores, resulting in their functional recovery. Additionally, high expression of anti-fibrotic cytokines and factors reduce collagen fibres and lung fibrosis caused as a result of hyper-inflammation and oxidative stress.

Fig. 3

Immunomodulation by MSCs secretome. Secretion of various immunomodulatory factors alters the behavior of immune cells. SOD3 secreted by MSCs inhibits leukocytes infiltration and activation of neutrophils. MSCs favor the polarization of macrophages to M2 phenotype by secreting PGE2, IL-10 and SDF-1. MSCs also inhibit T-cell proliferation by constitutive expression of HGF, TGF-β1, IL-10, COX2, PGE2 and IDO. They also induce a shift to Th2 population mediated by IL-4 secretion, and CD⁴⁺ CD²⁵⁺ T_reg population via HLAG5 secretion. They prevent proliferation of inactivated NK cells by secretion of IL-2; and prevent cytokine secretion by NK cells via secretion of TGF-β1, PGE2, IDO and HLAG5. MSCs also result in arrest of B cells in G₀/G₁ phase, reduction in the levels of circulating immunoglobulins and CXCR4, CXCR5, CXCR7 secretion by B cells.