Exploring the Immunomodulatory Aspect of Mesenchymal Stem Cells for Treatment of Severe Coronavirus Disease 19

Abstract

Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) is an enveloped, positive sense, single stranded RNA (+ssRNA) virus, belonging to the genus Betacoronavirus and family Coronaviridae. It is primarily transmitted from infected persons to healthy ones through inhalation of virus-laden respiratory droplets. After an average incubation period of 2–14 days, the majority of infected individuals remain asymptomatic and/or mildly symptomatic, whereas the remaining individuals manifest a myriad of clinical symptoms, including fever, sore throat, dry cough, fatigue, chest pain, and breathlessness. SARS-CoV-2 exploits the angiotensin converting enzyme 2 (ACE-2) receptor for cellular invasion, and lungs are amongst the most adversely affected organs in the body. Thereupon, immune responses are elicited, which may devolve into a cytokine storm characterized by enhanced secretion of multitude of inflammatory cytokines/chemokines and growth factors, such as interleukin (IL)-2, IL-6, IL-7, IL-8, IL-9, tumor necrosis factor alpha (TNF-α), granulocyte colony-stimulating factor (GCSF), basic fibroblast growth factor 2 (bFGF2), monocyte chemotactic protein-1 (MCP1), interferon-inducible protein 10 (IP10), macrophage inflammatory protein 1A (MIP1A), platelet-derived growth factor subunit B (PDGFB), and vascular endothelial factor (VEGF)-A. The systemic persistence of inflammatory molecules causes widespread histological injury, leading to functional deterioration of the infected organ(s). Although multiple treatment modalities with varying effectiveness are being employed, nevertheless, there is no curative COVID-19 therapy available to date. In this regard, one plausible supportive therapeutic modality may involve administration of mesenchymal stem cells (MSCs) and/or MSC-derived bioactive factors-based secretome to critically ill COVID-19 patients with the intention of accomplishing better clinical outcome owing to their empirically established beneficial effects. MSCs are well established adult stem cells (ASCs) with respect to their immunomodulatory, anti-inflammatory, anti-oxidative, anti-apoptotic, pro-angiogenic, and pro-regenerative properties. The immunomodulatory capabilities of MSCs are not constitutive but rather are highly dependent on a holistic niche. Following intravenous infusion, MSCs are known to undergo considerable histological trapping in the lungs and, therefore, become well positioned to directly engage with lung infiltrating immune cells, and thereby mitigate excessive inflammation and reverse/regenerate damaged alveolar epithelial cells and associated tissue post SARS-CoV-2 infection. Considering the myriad of abovementioned biologically beneficial properties and emerging translational insights, MSCs may be used as potential supportive therapy to counteract cytokine storms and reduce disease severity, thereby facilitating speedy recovery and health restoration.

Key Role of Mesenchymal Stromal Cell Interaction with Macrophages in Promoting Repair of Lung Injury

“…MSCs are ACE2-negative, and therefore they are resistant to SARS-CoV-2 infection and retain their immunomodulatory activities when encountering the virus [ 185 , 186 ]. This important feature favors MSC therapeutic use in COVID-19 [ 187 ]. Interaction with innate immune cells, especially Mφs, and molecules secreted by MSCs and Mφs, described above, could dampen immune hyper-activation in SARS-CoV-2 infection.…”

Protective Effects of Herba Houttuyniae Aqueous Extract against OVA-Induced Airway Hyperresponsiveness and Inflammation in Asthmatic Mice

“…Moreover, VEGF accelerated M2 macrophage infltration and disrupted the airway epithelial barrier in lung tissues of asthmatic animals [48][49][50][51]. Emerging evidence also displayed that VEGF has associations with thromboembolism and tissue injury/repair in COVID-19 and viral infection, indicating the promotion of secondary airway infammation [52][53][54]. Te results of this study showed that HHAE signifcantly reduced the expression levels of p38 MAPK, PI3K, Akt, and VEGF mRNA and protein in lung tissue of asthmatic mice, suggesting that the mechanism of HHAE alleviating asthma infammation is related to the inhibition of the p38 MAPK/PI3K signaling pathway.…”

Mesenchymal Stem Cell-Derived Extracellular Vesicles: An Emerging Diagnostic and Therapeutic Biomolecules for Neurodegenerative Disabilities

“…MSCs naturally produce a variety of active ingredients with trophic, immunomodulatory, pro-regenerative, anti-inflammatory, pro-angiogenic, and anti-apoptotic properties [ 6 ]. MSCs regulate immune function in a paracrine manner by producing immunomodulatory factors such as transforming growth factor (TGF), hepatic growth factor (HGF), interleukin (IL)6, and IL-10, as well as pro-angiogenic factors like basic fibroblast growth factor (bFGF) and placental growth factor (PGF) [ 7 , 8 ].…”