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MSCs for COVID-19

COVID-19 mortality is associated with Acute Respiratory Distress Syndrome (ARDS) and multiple organ failure. Both of these pathologies have been demonstrated to be caused by unrestrained cytokine release, also known “cytokine storm” which causes fluid leakage and disseminated intravascular coagulation. ARDS is a rapidly progressive disease characterized by diffuse inflammation and increased vascular permeability of the lung parenchyma, leading to impaired alveolar gas exchange. ARDS mortality has been estimated to be in the range of 35% to 46%. Although health care advancements have improved patient outcomes, no pharmacological treatment has shown therapeutic effectiveness to date.

Mesenchymal Stem Cells and Immunomodulation

Mesenchymal stem cells (MSCs) are multipotent progenitor cells that can developmental plasticity and can give rise to diverse mesodermal cell lineages. These cells were originally cultured from total mouse bone marrow by Arnold Caplan, who was also the first scientist to grow these cells from human tissues. Today, MSCs can be isolated from multiple biological tissues – adult bone marrow and adipose tissues, and neonatal tissues such as umbilical cord and placenta. MSCs can differentiate into a variety of cell types such as adipocytes, osteoblasts, chondrocytes, myocytes, β-pancreatic islets cells and, potentially, neuronal cells. Importantly, MSCs can regulate the immune response in many diseases, by modulation of immune T- and B-cell responses. Specifically, MSCs can cause suppression of T-cell proliferation, cytokine secretion and cytotoxicity, and regulation of the balance of Th1/Th2 cells. In addition, adult MSCs can regulate the functions of regulatory T cells, and affect the secretion of antibodies and production of co-stimulatory molecules of B cells. Finally, MSCs can inhibit the maturation, activation and antigen presentation of dendritic cells, and also inhibit interleukin-2 (IL-2)-induced natural killer (NK) cell activation. Similar to adult MSCs, pluripotent stem cell-derived MSCs such as embryonic stem cells (ESCs) or induced pluripotent stem cells (iPSCs) also demonstrate immunomodulatory properties.

Recent data strongly demonstrate variable immunomodulatory effects of MSCs on the same types of immune cell depending on the local microenvironment and/or disease status. Further, studies have shown that Inflammatory conditions also affect the immunomodulation driven by MSCs. Though the exact immunomodulatory effects of MSCs may vary, it is clear that MSCs drive immune responses based on multiple factors. A better understanding of these factors will help manipulation of MSCs for therapeutic purposes. 

MSC therapy for ARDS

Mesenchymal stem cells (MSCs) have been shown to possess a comprehensive powerful immunomodulatory function to suppress the excessive activation of the immune system, promote endogenouse repair by improving the microenvironment. MSCs can inhibit the progress of acute inflammation in the lungs and alleviate symptoms of respiratory distress. The feasibility of utilizing MSCs to ARDS has been demonstrated in animal models, and extracorporeal lung models. For example, mesenchymal stem cells of adipose, bone marrow, placental, amniotic membrane, menstrual blood, and lung, origin, as well as conditioned media which include secreted exosome, have demonstrated reduction of pulmonary injury, water leakage, and neutrophil accumulation. 

An analysis of 342 systemic infusions and 57 bronchial instillations (204 recipients) of cells of various origins for ARDS and other pulmonary issues demonstrated safety in early clinical trials. It has been demonstrated that systematically administrated MSCs improved resoltution of respiratory, hemodynamic, and multigorgan failure in two patients with severe refractory ARDS on a compassionate use.  Most recently, a small study on patients in Wuhan, China has shown that MSCs could cure or significantly improve the functional outcome of patients without observed adverse effects. The pulmonary function and symptoms of these patients were significantly improved in 2 days after MSC transplantation. Among them, two common and one severe patient were recovered and discharged in 10 days after treatment. Compared to the placebo control group, the level of TNF-alpha was significantly decreased and IL-10 increased in MSC treatment group. The gene profile showed MSCs were ACE2- and TMPRSS2- which indicated MSCs are free from COVID-19 infection.  Therefore, the intravenous transplantation of MSCs was safe and effective for treatment in patients with COVID-19 pneumonia, especially for the patients in critically severe condition.

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