Therapeutic potential of mesenchymal stem cells in multiple organs affected by COVID-19

Abstract

Currently, the world has been devastated by an unprecedented pandemic in this century. The Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), the agent of coronavirus disease 2019 (COVID-19), has been causing disorders, dysfunction and morphophysiological alterations in multiple organs as the disease evolves. There is a great scientific community effort to obtain a therapy capable of reaching the multiple affected organs in order to contribute for tissue repair and regeneration. In this regard, mesenchymal stem cells (MSCs) have emerged as potential candidates concerning the promotion of beneficial actions at different stages of COVID-19. MSCs are promising due to the observed therapeutic effects in respiratory preclinical models, as well as in cardiac, vascular, renal and nervous system models. Their immunomodulatory properties and secretion of paracrine mediators, such as cytokines, chemokines, growth factors and extracellular vesicles allow for long range tissue modulation and, particularly, blood-brain barrier crossing. This review focuses on SARS-CoV-2 impact to lungs, kidneys, heart, vasculature and central nervous system while discussing promising MSC's therapeutic mechanisms in each tissue. In addition, MSC's therapeutic effects in high-risk groups for COVID-19, such as obese, diabetic and hypertensive patients are also explored.

Keywords: Cell therapy; Cytokine storm; Immunomodulation; MSC; SARS-CoV-2.

Graphical abstract

Fig. 1

SARS-CoV-2 structure and infection. Infection and associated inflammatory triggering by SARS-CoV-2. SARS-CoV-2 virion representation displaying its spike (S) glycoprotein, membrane protein and envelope protein composing the external envelope, while the viral RNA is located internally, surrounded by nucleocapsid protein. During alveolar epithelium infection, SARS-CoV-2′ S protein binds to ACE2 receptors and is modified by serine protease TMPRSS2, present on the cell's surface. Then, SARS-CoV-2 infects the cell, triggering cellular damage that progresses to pyroptosis. Cell death releases multiple proinflammatory cytokines, such as IL-2, IL-6, TNF-α and MCP-1, that in dysregulated immune responses may cause persistent tissue inflammation. ACE2 - angiotensin-converting enzyme 2; IFN-γ - interferon-gamma; IL - interleukin; IP-10 - CXCL10; TNF-α - tumor necrosis factor-alpha; MCP-1 - monocyte chemoattractant protein-1; MIP-1α - macrophage inflammatory protein.

Fig. 2

MSC's therapeutic mechanisms. MSC's main therapeutic mechanisms. MSC paracrine signaling either through soluble growth factors or through EV carrying multiple molecules, promotes angiogenesis and induces resident tissue cells to survive and proliferate, while inhibiting inflammation progression and cell apoptosis. Direct viral damage to the tissue and dysregulated immune responses are key pathophysiologic mechanisms in multiple organ dysfunctions in COVID-19. Therefore, MSC's ability to induce tissue remodeling may be beneficial to patients with COVID-19, improving recovery and restraining long-term dysfunction. VEGF – vascular endothelial growth factor; FGF – fibroblast growth factor; HGF – hepatocyte growth factor; IGF-1 – insulin-like growth factor-1.