Internal Medicine: Open Access
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Mesenchymal Stem Cell: Therapeutic Intervention in Covid-19

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Introduction

The announced pandemic of [1] COVID-19 (Coronavirus Disease 2019), broke out with numerous cases at the end of 2019 in Wuhan, China exhibiting serious respiratory dysfunctions. It was initially identified for infections, and was supposed to be a seasonal flu outbreak by considering those patients who have background of work in wholesale market of shrimp and fish. A few days back, after the rejection of Seasonal grippe infection, avian influenza, adenovirus, SARS, and other pathogens. This novel coronavirus shows 5% genetic correlation with SARS and is a subclass of Sarbecovirus [2]. Since SARS-CoV is zoonotic in origin, this has resulted in the tentative mass culling of the masked palm civets. However, further studies later revealed that no widespread infections were found in wild or farmed civets and clinical symptoms of SARS were only overt in the municipalities sold on the markets, suggesting that civets were unlikely to have been the primary/natural reservoir host [3,4]. Now, the virus has been narrowly called SARS-CoV-2, the name was designated by the World Health Organization (WHO) [5].

With the help of several samples, phylogenetic and sequencing analysis were done which reports that it belongs to coronavirus family (Orthocoronavirinae subfamily) [6] in Betacoronavirus-2B lineage and shows 96% identity with the bat SARS-CoV (Bat Cov RaTG13) [7]. The virus, use its S1 and S2 subunits of hetero-trimeric spike proteins to interact with the human cell receptor, Angiotensin-Converting Enzyme 2 (ACE2) [8], to infect a host cell. SARS-CoV-2 infect lungs (Figure 1) by causingangiocentric inflammation, thrombosis and micro-angiopathy, and angiogenesis [9].

Figure 1: Effect of SARS-CoV-2 on lungs.

This pandemic influenced all the clinicians and researchers worldwide to gather from various branches of biomedicines for seeking a plan or therapy/vaccine to handle the pandemic [10]. Most of the current preclinical and clinical data on antiviral therapy are available from other viruses, including SARS-CoV-1 (first reported in 2003), Middle East Respiratory Syndrome Coronavirus (MERS-CoV), (recorded for the first time in 2012) and non-coronavirus (example- outbreak of the Ebola virus). It is not obvious about how efficiently these details can be extrapolated to SARS-CoV-2. In fact, scientific importance of in vitro antiviral behavior defined as semi-maximal Efficacy Concentration [EC50] values appears undefined, given in the absence of pharmacokinetics/pharmacodynamics or surgical evidence. This equalizes the workable concentrations compared to these levels to an effect of treatment [11]. Diagnosis is also challenging as a number of studies from Singapore [12] and Germany [13], inferred about the asymptomatic transmission of SARS-CoV-2 by viral shedding.

From various published literatures one can infer that the Mesenchymal Stem Cells (MSCs) are active against viral infection and these are attributable in the involvement of specific cytokines improved the efficiency [14]. Therefore, MSCs should be presumed to thrive even though they are transplanted to a patient reported for COVID-19. As, there is a discrepancy in the MSCs therapy for the diagnosis of COVID-19, we have integrated the clinical literature and trials to convey valuable knowledge in the review. The review provides a deep insight of the role of MSCs in the disease and representation of action of MSCs in SARS-CoV-2 life cycle illustrated in (Figure 2). It is necessary to alert readers that new data appears approximately every hour considering the Medical conditions, care, options to prevent and outcomes of COVID-19.

Figure 2: Schematic representation of action of MSCs in SARSCoV- 2 life cycle.

Methodology

Morphology of SARS-COV-2

SARS-CoV-2 is a spherical or pleomorphic enveloped particles with club-shaped glycoprotein projections [15]. SARS-CoV-2 was assessed for its size ranging between 70-90 nm, observed under electron microscope which also suggested its wide variety of intracellular organelles [16]. As it shows high sequence similarity with SARS-CoV, the structure of SARS-CoV-2 is speculated to be the same as SARS-CoV [17]. It is found that the envelope, membrane, and spike protein of coronavirus are embedded in host membrane derived lipid bilayer which encapsulates the helical nucleocapsid comprising viral RNA [18] illustrated in (Figure 3). The single stranded RNA is approximately 30 kb long having positive polarity with 5’ cap and 3’ Poly-A tail [19]. Almost all structures of protease [20] and spike [21] of SARSCoV- 2 have been resolved which leads an opportunity to develop or repurpose the drugs for treating COVID-19.

Figure 3: Structure of SARS-CoV-2.

Therapeutic intervention of COVID-19

As per 31 August, 2020; neither any drugs nor any biologics is/are established to be efficient for the prevention/treatment of COVID-19 infection. Many antivirals, parasitic drug combinations, immunotherapies, and vaccines are under trials and their efficacy against COVID-19 is still dilemmatic. The only mode of treatment, widely in use for COVID-19 is repurposing of drugs [22]. Drugs like Chloroquine and Hydroxychloroquine [23], Mefloquine [24], certain flavonoid compounds [25], Lopinavir [26], Remdesivir [27], Quercetin [28] and other reported drugs are currently in use to treat COVID-19 patients.

Mesenchymal stem cells therapy

Amidst the COVID-19 rush for various drugs like Hydroxychloroquine and Remdesivir etc. and various vaccines, the US Food and Drug Administration (FDA) have recently approved the use of MSCs for coronavirus treatment under the discretion of expanded accesses. At present, cell-based therapy and stem cell therapy in particular has been a remarkable medical domain in which potential to cure incurable diseases is foreseen [29]. MSCs have drawn interests owing to the possible source, high rate of proliferation, minimal intrusive treatment and clear of ethical problems. MSC rehabilitation is significantly better as applied to other therapies [30]. They are widely available and can be isolated from different tissues, such as bone marrow and adipose tissues, including the umbilical cord, dental pulp, menstrual blood, buccal fat pad, fetal liver and others. MSCs can expand efficiently to clinical volume in adequate time period and for repeated diagnostic utilization it can be processed. Moreover, MSC therapy have the potential to prevent the storm of cytokines and can advance the endogenous repair by its regenerative and reparative property [31,32] illustrated in (Figure 4). MSCs therapy has been commonly employed in the diagnosis and treatment of type 2 diabetes, autoimmune disorder, spinal cord damage, GVHD and many other disorders, with strong antibody levels [33-36]. Although MSCs do not have clear anti-viral effects, studies have shown that they are immune to viral interaction by the presence of Interferon Gamma Stimulated Genes (ISGs) found in them prior to differentiation. MSCs frequently control our body's adaptive and innate immune systems by destroying T-cells, maturing dendritic cells, decreasing activation and proliferation of B-cells, and hindering NK cell proliferation and cytotoxicity by soluble factors or cellto- cell pathways (Figure 3) [31,32]. Recently, [37] the use of these cells in the therapeutic diagnosis of H5N1 viral infections with related consequences on the lung has also been proposed [38]. Thus their role in regulating immune malfunctioning is widely reported and can be extrapolated as an eminent tool for COVID-19 research and treatment.

Figure 4: Proposed role of Mesenchymal stem cells.

MSCs related clinical trials for COVID-19

There are total 3201 clinical studies registered on ClinicalTrials.gov [39] for treating COIVD-19 out of which only 54 studies are related with MSCs. All 54 clinical studies’ title and their status are tabulated in Table 1. In the related trials, one study is withdrawn and fourteen studies are not recruited yet. However, one study has been completed in china by using umbilical cord derived Mesenchymal Stem Cells (MSCs) but there results are not posted yet.

Results and Discussion

Table 1: MSCs based clinical trials for treating COVID-19.

Being free from vital ethical concerns with low risk of teratoma formation, MSCs gains the status of most commonly used stem cells in cell therapy. Moreover, their regenerative capacity immunomodulatory effect, anti-inflammatory effect as well as handling the cytokines storm have made MSCs a potent candidate for preclinical and human clinical trials for viral treatment. However, certain limitations resides in MSC-based therapies should never be neglected. The heterogeneity nature of MSCs might bring the inconsistency in research results. With recent literature it is found that MSCs may not be immunologically silent as assumed previously [40].

Conclusion

To overcome the residing limitations, use of cell-free therapeutic strategies such as MSC-exosomes should be focused more. There are limited clinical trials and study of MSCs on virus-associated diseases and in the case of SARS CoV-2 these investigations are still not completed. Hence, the efficacy and potency of MSCs the treatment of COVID-19 cannot be concluded at this time. This review highlighted the MSCs therapy application and clinical trials for COVID-19.

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