In late December 2019, the World Health Organization (WHO) noticed few clinical cases reported from Wuhan City of China, suffering from respiratory infections and pneumonia. These cases, which were related to the Wuhan seafood market, were initially misdiagnosed as common flu but later considered having unidentified etiology and eventually lead to immediate closure and sanitization of this market. After further investigations and research, scientists revealed that the causative agent of this disease in these patients was a novel coronavirus (nCoV), similar to the coronavirus causing The impact of COVID-19 rapidly became so diverse and global, that by mid-March 2020 WHO declared the disease as a global public health care emergency and a pandemic. As per the WHO, the total confirmed COVID-19 cases reported globally were 33,842,281 followed by 1,010,634 deaths till 1 October, 2020 [2] . The main pathological features of COVID-19 are fairly similar to those observed in SARS, but, in severe cases, these can lead to Acute respiratory distress syndrome (ARDS), acute lung injury (ALI) with lung inflammation and edema along with hyaline membrane formation. COVID-19 patients have to be given supportive treatment in complicated and severe cases that need clinical interventions such as ventilation, antipyretics, and few repurposed drugs (for example remdesivir). Apart from these, one has to rely on their immune system. Various treatment strategies are being opted by clinicians all across the globe to counterattack this disease however neither a substantial treatment nor a promising vaccine has been developed so far. Although few potential vaccines have been predicted which still requires further investigations and clinical trials before becoming available to the public. With no established antiviral medication or vaccine, COVID-19 accounts for 0.7% to 15.4% mortality rate and also poses other unprecedented concern for the economy as well as health, leading to drawing the interest of various scientists to combat and 8 COVID-19 as well, the hyper-activation of immune response occurs which results in generating a cytokine storms. T-helper-1 (Th1) cells get activated by elevated levels of IL1B, IFNγ, IP10, and MCP1 secreted by NK cells, mast cells and macrophages. Additionally, critically ill patients have been reported with a high level of granulocyte colony-stimulating growth factor (GCSF), Macrophage inflammatory protein (MIP1A), TNFα, IL-2R and IL-6. COVID-19 also induces the 3. Generation of cytokine storm by innate and immune cells: a. Upregulation Ag II due to low level of ACE-2 receptor which mediates activation of NF-kβ and AP-I signaling pathway via AT-1 receptor resultant in vasodilation, edema, and cytokine secretion. b. Nuclear localization of IRF-3 by virus which reduces the production of IFN-γ. c. Activation of toll-like receptor, RAGE and MHC-II via generation of DAMP's from injured pneumocytes and through PAMP's which leads to activation of NF-κβ, IRF-3/7, AP-1 signaling pathway. d. Weak sensitization of mast cells by virus releases a small amount of Ig E and IFN-γ followed by the attraction of NK cells, macrophage, and B-cells which further elevates the secretion of a cytokine storm. 4. Overview of damaged alveolus resulted from cytokine storm and hyperactive immune cells. The figure is made via biorender application: https://biorender.com/) 9 pro-inflammatory release of IL-4 from T-helper-2 (Th2) to suppress inflammation [26] .
Inflammatory cytokine storm in patients contributes to secondary complications such as sepsis, hyper-coagulability, ALI, ARDS and lung fibrosis.
Overall, the escaping of the virus from immune cells, hyperimmune activation of innate and adaptive cells, excessive accumulation of chemokines and cytokines secreted from pulmonary cells as well as modulation of ACE-2 expression may attribute to the pathogenesis of COVID-19, and targeting these physiological processes may be used in combating the disease. Keeping 
In the past decade, owing to enormous potential, self-renewal and differentiation properties, stem cells have already revealed a promising role in treating and combating numerous life-threatening diseases and became a pivot area of modern research. Based on the source of isolation or origin, stem cells can be divided into three categories viz. embryonic, fetal and adult [3] . Although fetal and embryonic stem cells have a higher potential than adult stem cells, the later are more implicated in experimental biology due to their widespread availability and less ethical issues. Bone marrowderived, adipogenic, human dental pulp and umbilical cord blood are among numerous sources of adult stem cells, which plays a crucial role in regenerative medicine. Moreover, these stem cells can be isolated and saved in stem cell banks under ultra-low temperature for many years without Mesenchymal stem cells, named due to their presence in the mesodermal niche, are multipotent.
They are also termed as mesenchymal stromal cells, if they fulfill the minimum criteria of adherent property, presence of CD105, CD73, and CD90, absence of CD45, CD34, CD14 or CD11b, CD79a or CD19, and HLA-DR cell surface markers as well as gives rise to descendant lineages including chondrocytes, osteocytes, adipocytes, and myocytes [30] as characterized by the International Society of Stromal Therapy (ISCT) in 2005 [31] . In general, Mesenchymal stem cells term can be used for plastic adherent fibroblast shaped cells, which fulfills the criteria of stem cells and MSC acronym is used for both mesenchymal stem as well as stromal cell types [32] . However, the name of MSCs is still controversial. Caplan et al. (2017) , recommended changing the Mesenchymal stem cell name to "medicinal signaling cells" as indeed these cells show the property of homing and secrete bioactive factors that possess the immunomodulatory and regenerative potential that act as drugs in situ and has shown site-specific therapeutic outcomes. It has been shown that infused exogenous MSCs signals resident stem cells of the patient to repair the damage via their bioactive factors instead of undergoing their differentiation [33] . For research as well as for clinical purposes, ample amounts of MSCs can be isolated from the embryo, fetus as well as adult stem cell sources, which include bone marrow, umbilical cord blood, adipose tissue, menstrual blood, Wharton's jelly, amniotic fluid and Human Deciduous teeth.
Mesenchymal stem cells could play a pivotal role in combating COVID-19 because of its immunomodulation and regenerative potential as depicted in Figure 2 . From the past many years, the role of MSC's as immunomodulation and its regenerative potential have been relentlessly J o u r n a l P r e -p r o o f investigated. Use of MSCs as a regenerative medicine has been well-established but, needs further investigation for the management and treatment of steroid-resistant graft-versus-host disease (GVHD), systemic lupus erythematosus (SLE), ARDS, chronic obstructive pulmonary disease (COPD), liver cirrhosis, pneumonia and Lung fibrosis, in various in-vitro experiments, animal model systems [34] [35] [36] and human in-vivo studies [8, [37] [38] [39] [40] . Numerous preclinical and clinical studies claimed that MSCs act as an immunosuppressive agent for the treatment of GVHD [41] . MSCs shows potential to escape recognition by CTL or NK cells, inducing allogeneic T-cell tolerance,
attenuate T-cell proliferation via reducing Th1 and Th17 activation, which further compromises the immune response. This is due to lack in the expression of human leukocyte antigen (HLA) class II, co-stimulatory molecules (B71, CD40L, B72) and low-level expression of HLA-I and LFA-3 in these cells [42] . MSC's behave as an immunosuppressive agent even after these cells have been immunosuppressed by host cells via apoptosis. The highly Cytotoxic T-cells induce apoptosis of MSCs, which in turn release indoleamine 2,3-dioxygenase (IDO) by phagocytic cells needed for the clearance of apoptotic MSC bodies. Released IDO by phagocytic cells acts as an immunosuppressents, which sequentially suppresses the graft rejection mechanism [43] . Thus, MSCs help in overcoming the major issue confronted in GVHD, which is the rejection of graft by the cytotoxic effect of immune cells and also shows the potency of homing at the site of inflammation [44] .
J o u r n a l P r e -p r o o f MSCs can elicit a shielding effect for combating COVID-19 by involving multiple pathways as depicted in Figure 3 . MSC's stimulate the immunomodulatory activity by secreting various juxtracrine and paracrine molecules such as transforming growth factor β (TGF-β), IDO, Human leukocyte antigen isoform (HLA-G5), prostaglandin E2 (PGE2) and IL6 [45] . These factors act on modulating signaling pathways such as NO, which inhibit the phosphorylation of STAT-5, conversion of tryptophan into kynurenine by IDO, which subsequently suppresses the T-Cell proliferation. In one of the studies, MSC's immunomodulatory activity was determined by culturing them with immune cells and measuring the cytokine profiles released by these cells. It has been found that MSC's decrease the activity of DC1 pro-inflammatory cytokine profile; increase the antiproliferative cytokine profile of DC2; reduces the IFN-γ released from NK cells and Th1; elevates IL-4 released by Th-2 and elevates proliferation of Treg cells [46] . One of the paracrine factors, PGE2 proved vital activity in MSC's immunosuppression [47] . MSCs modulates immune cells such as CD4+, CD8+, DC cells, macrophages, and NK Cells, which suppresses the cytokine stormgenerated via COVID -19 infection and results in increasing the life expectancy of an infected person [48] .
As MSCs act via secreting paracrine, juxtacrine molecule and micro-vesicles, thus MSCs conditioned media can also be utilized as immunosuppressive therapy for COVID-19. This perception is congruent with the previous study, which showed promising results in treating COPD with MSCs conditioned media, where the presence of secreted micro-vesicles (MVs) was confirmed [49] . MVs are membrane vesicles that exhibit various receptors like MHC-I, tetraspanins, cell-cell adhesion receptors, and the presence of cytoplasmic content such as Hsp, mRNA, microRNA and a set of protein lipids. [50] . Monsel et al. (2015) depicted that MVs reduces the effect of pneumonia induced ALI via enhancing monocytes mediated phagocytosis. This phenomenon helps in clearing bacteria; elevates secretion of keratinocyte growth factor release via mKGF which reduce endotoxin mediated alveolar damage; suppresses cytokine-induced lung injury; polarizes M1 macrophage to J o u r n a l P r e -p r o o f MSCs also play a vital role in targeting ACE-2 mechanisms, which is essential for SARS-CoV-2 pathogenesis. As depicted by various scientists, ACE-2 hampered RAS via deregulated Ag II level, which leads to various complications which consequently were resolved by direct infusion of ACE-2 negative mesenchymal stem cells as recently proven by Leng et al.(2020) , in a pilot study, where results depicted recovery of COVID-19 patients with pneumonia [48] . MSCs have the potential to differentiate into alveolar epithelial type 2 cells (AT-II cells), also known as type II lung pneumocytes [53, 54] . ACE-2 receptors are expressed by AT-II cells, which are subsequently deregulated by the virus entry and initiating the apoptosis of neighboring AT-II cells by modulating the immune system hence generating a positive loop of inflammation between these cells. Although there are controversies whether MSCs directly differentiated in-vivo or signals native stem cells to differentiate, still by knowing that MSCs have differentiation potential into AT-II cells, proven by Huang et al. (2014) , in a pulmonary fibrosis mouse model [55] , keeping this in mind, it can be suggested that MSC's infusion could be used to combat COVID-19. Alternatively, differentiated AT-II like cells could also be administered directly to fasten the response mediated by these cells.
Infused MSCs also induce lung progenitors cell differentiation in bronchopulmonary dysplasia and reduces lung injury from hyperoxic conditions [56] . Apart from immunomodulation, regenerative and homing potential, interestingly, the drawback of MSC population entrapment in the lung during intravenously administered systemic infusion [57] could become an advantage in treating COVID-19 pneumonia, where the main target of the virus is the lungs. MSC's entrapment potential in the lungs would play a vital role in recovering inflamed lung microenvironment, lung fibrosis, cytokine storm, damaged epithelial and endothelial cells via its immunomodulate potential.
MSC's protect themselves from host cells via releasing isoform of human leukocyte antigen HLA-G5, which modulates the immune response. HLA-G5 suppresses NK lytic activity and IFN-γ Secretion; elevates the production of pro-inflammatory cytokine IL-10, which creates an allogenic J o u r n a l P r e -p r o o f microenvironment to inhibit T cell-mediated immunity; activates CD4 + CD25 high FOXP3 + regulatory T cells [58] . As HLA-G5 enhances MSC's counterattack effect against the virus thus, it could be used as a preconditioned factor to enhance MSC's activity. Preconditioning of MSC's with Conditioned media has revealed to enhance the paracrine effect of MSC's in treating lung injury [59] . MSC's could be infused with IFN-β to mild disease patients as the viral entry inhibit the production IFN incongruent to the pathogenesis of SARS-CoV and skip the initial response of cells leading to an increase in viral load and which hamper the immune system [24] . So, if viral replication at the initial phase can be controlled or inhibit, mortality and complications related to the disease can be managed.
To date, the complete depiction of the use of MSCs as an immunomodulator as well as the entire pathology of COVID-19 is still unclear. Reformist work is needed by scientists to understand both.
Thus, MSCs or differentiated AT-II like cells can be exploited as an in-vitro model system to study the pathology of the virus, the production and test the vaccines as these cells are easy to cultivate, accessible from various sources, and carry less ethical issues. As a model system, MSCs could also be used to produce antibodies against the virus and deduce the complete underlying mechanism of its action for treating COVID-19.
Clinical phase trial results of MSC's transplanted in H7N9 influenza induced ARDS or ARSD shows reduce mortality in the treated patients compared to the control groups [9, 60] , which raises hopes that MSCs can be used as a feasible approach of COVID-19 treatment. MSCs from various sources are already under preclinical and clinical approaches by numerous clinicians and researchers to mine out the complete potential of stem cells in treating COVID-19 disease. Sources and types of stem cells used in clinical trials are listed and depicted in Figure 4 [61] . Apart from the umbilical cord as a source, dental stem cells are also reported in various clinical trials. Stem cells from Human Deciduous teeth (SHED) can also serve as a potential source for MSCs [62] . To combat disease, both autologous, and the allogeneic infusion of MSCs are under clinical trial as depicted in Table: 1 [61] . [48] .
In another study [69] , clinical outcomes of a single patient were published reporting that the infused UC-MSCs are clinically effective and safe to administer. A 65-year old critically ill female was enrolled for the study and transfused with 5 x 10 7 UC-MSCs cells intravenously at day 9 of infection with a further followed by two infusion with an interval of three days. After the infusion, the patient was shifted to the normal ward from ICU with a significant decreased in level of C-reaction protein, white blood, and neutrophil, ALT/AST along with increased level of total lymphocyte count. The study also suggested that the infusion of thymosin α1 will greatly enhance the immunomodulation potential of MSCs. A study conducted by commercial Pluristem therapeutics claimed 100% survival of patients treated with allogenic mesenchymal-like cells [70] , while BioWorld commercial shows an 83% survival rate of ventilator-dependent COVID-19 patients when infused with mesoblast cells [71] .
The primary data for safety and efficacy outcomes of MSCs infusion in mild to critical-ill COVID-19 patients shows MSCs as a promising candidate for combating the pandemic disease. However, the clinical outcomes are a result of a pilot study that recommends the enrolment of more patients and further investigation for the use of MSC as a therapeutic medicine for COVID-19. hand, based-on the immune-modulatory, homing, anti-inflammatory and regenerative potential, that is already proven in various diseases such as SARS-CoV, Pneumonia, ALI, ARDS, COPD, GvHD [74, 75] . The regenerative potential of MSCs is still controversial as they may fail to differentiate themselves after infusion. However, they may elicit regenerative potential by signaling the naïve stem cells of the host body [33, 56] .
With scarce therapeutic options, MSCs could act as a forefront treatment for the counterattack of SARS-CoV-2 virus, as these cells (i) Repairs the damage pulmonary epithelial cells via regenerative potential (ii) Differentiate into type II alveolar epithelial-like cells [53] , which gets damaged as a result of hyperimmune response started with SARS-CoV -2 infection (iii) Lack the expression of ACE-2 receptor and TMPRSS2 protease, which have been proven crucial for viral entry in host cells, J o u r n a l P r e -p r o o f thus, eliminating the risk of susceptibility to COVID-19 infection [48] . (iv)Induction of allogeneic tolerance (v) Reduction in pulmonary edema via lipoxin A4 [76] . (vi) Bacterial clearance via the release of an antibacterial peptide [77] . (vii) Reduced alveolar epithelial and arterial endothelial cell apoptosis via modulating signaling of hypoxia-inducible factor (HIF-α) and reactive oxygen species resulting in inhibition of caspase-3 mediated apoptosis [78] .
As discussed in our review and suggested by numerous scientists, autologous and allogeneic infusion of MSCs, which are primarily ACE 2 negative, henceforth resistant to SARS-CoV-2, could be an ideal solution for treating a disease which can be used alone or as a combination with antiviral drugs.
MSCs potential as a COVID-19 treatment is still in the initial phase of implementation and testing by Apart from promising preliminary data of MSCs as a potential candidate for treating the COVID-19, clinical implementation of stem cells as a therapeutics is cost-effective and always a matter of