INTRODUCTION
The world has been facing a dreadful situation due to the spread of the Severe Acute Respiratory Syndrome–Coronavirus-2 (SARS-CoV-2) (1). However, neither confirmed effective antiviral medications nor vaccines are available to deal with this emer-gency (2). Many reports have suggested that it is the cytokine storm in COVID-19 that leads to acute respiratory distress syndrome (ARDS) (3). The cytokine storm in COVID-19 refers to the fact that a variety of cytokines are rapidly produced after viral infections (4). In addition, such a cytokine storm induces hypoxia, and direct viral infection can cause cellular damage. Multiorgan damage and injury have been concomitant with COVID-19, and can be observed more in patients with a more severe form of the disease (5).
Stem cells are specialized cells that can renew themselves by means of cell division and can differentiate into multilineage cells. Mesenchymal stem cell (MSCs) have immunomodulatory features and secrete cytokines and immune receptors that regulate the microenvironment in the host tissue (6). In addition, it has been observed that the crucial role of MSCs in therapy has been mediated by exosomes released by the MSCs. These exo-somes have exhibited immunomodulatory, antiviral, anti-fibrotic, and tissue-repair-related functions in vivo; similar effects have been observed in vitro (6).

COVID-19 AND THE IMMUNE SYSTEM
The dynamic equilibrium maintained by innate and adaptive immunity is essential for impeding the progression of COVID-19 (7). In patients infected with SARS-CoV-2, the plasma levels of IL-1β, IL-1RA, IL-7, IL-8, IL-10, IFN-γ, monocyte chemoattrac-tant peptide (MCP)-1, macrophage inflammatory protein (MIP)-1A, MIP-1B, G-CSF, and TNF-α are significantly higher than in controls. The levels of these factors are also increased in patients who were admitted to ICUs (8). Similarly, reductions in the levels of T cells and NK cells have been observed in COVID-19 patients (9). The loss of such cells can impair the immune system (10). The levels of the helper T cells, cytotoxic suppressive T cells, and regulatory T cells are much lower in patients with COVID-19 than in their healthy and less severe counterparts. The decrease in the regulatory T cells may hamper their ability to inhibit the chronic inflammation (11). Interes-tingly, a remarkable increase is observed in the naïve T cells, where as the memory T cells are reduced in infected patients (10). The reduced expression of memory cells may be a plau-sible explanation for the increased rates of reinfection by SARS-CoV-2.

THE CYTOKINE STORM
SARS-CoV-2 binds to the Angiotensin-converting enzyme 2 (ACE2) receptor and enters the host cell (1). During infection, the innate and adaptive immune systems work together to inactivate the virus. Since leukocytes and neutrophils are present in higher concentrations in COVID-19 individuals, these immune cells may result in the cytokine storm (10). After viral entry, the virus induces pyroptosis and cell death. The dead cells recruit macrophages to the site of injury that phago-cytose them. The phagocytes then express damage-associated molecular patterns (DAMPs), which bind to the toll-like receptors (TLR) and induce nuclear factor kappa B (NF-κb) signalling by means of the MyD88 pathway. NF-κb enters the nucleus and catalyzes the transcription of pro-IL-1β and pro-caspase-1. When additional signals are detected, the pro-IL-1β and procaspase 1 are cleaved into IL-1β and caspase 1 (12). The activated NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3) recruits the apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC) and pro-cas-pase-1 to form the NLRP3 inflammasome (13). In addition, the phagocytosis releases ATP, which binds to the P2X purino-ceptor 7 (P2RX7) and activates the inflammasome (14). The increased calcium levels caused by the viral proteins results in lysosomal damage, thereby releasing cathepsins that activate the inflammasome (15). Further, the binding of SARS-CoV-2 to the ACE2 reduces the available ACE2 receptors on the cell surface. This increases the levels of Angiotensin II (AngII) in the extracellular space, because ACE2 converts AngI and AngII into Ang 1-9 and Ang1-7, respectively. AngII increases the levels of TNF-α and IL-6 in the cell that upregulates NF-κb, activating the inflammasome (12). The continuous activation of the inflammasome results in a cytokine storm, which recruits more immune cells, necrosis, and cell death. This inflamma-some pathway further causes tissue injury in various organs (Fig. 1).

MSCs AND IMMUNOMODULATION
MSCs are predominantly isolated from the bone marrow, adipose tissue, dental pulp, umbilical cord, Wharton’s jelly, placenta, synovial fluid, endometrium, and peripheral blood. These cells exhibit different cell-surface markers and can be used for a variety of treatment options (Table 1). MSCs can undergo in vitro amplification and self-renewal, and have low immunogenicity and immune-modulatory functions; the latter have attracted attention in clinical trials (16). MSCs have been widely used in various cellular therapies, such as pre-clinical studies, as well as in some clinical trials, because of their high safety and efficacy (17, 18). MSCs can exert immune-modu-latory effects in the host cells of both the innate and the adaptive immune system. The direct or indirect interactions of MSCs with the immune cells make the MSCs activate the immunomodulatory responses (19). The immunomodulatory functions of MSCs depend on the environment of the host cells; based on the inflammatory status, the MSCs decide the type of immunoregulatory effect (20). MSCs represent pro-inflammatory immune reactions and anti-inflammatory reactions (21). MSCs regulate the immune system via the transforming growth factor b1 (TGFβ1), which can trigger the proliferation of Tregs, induce IL-6, which prevents the proliferation of neutrophils, and stimulate the prostaglandin E2 (PGE2), which inhibits the antigen presentation by dendritic cells and proliferations of T-effector cells (22, 23). MSCs mediate these kinds of effects by direct contact, where it releases the regulatory cytokines, such as IFN-γ, indoleamine 2,3-dioxygenase, TGFβ, IL-10, and PGE2 (24). Moreover, MSCs can hinder the proliferation and/or func-tions of the CD4+ Th1 and TH17 cells, CD8+ T cells, and the natural killer (NK) cells, mainly by secreting soluble factors, such as TGFβ1 and hepatocyte growth factor (HGF) (16).

MESENCHYMAL STEM CELLS (MSCs) AND MSC SECRETOME
It has currently become apparent that MSCs induce therapeutic characteristics by a paracrine pathway by releasing bioactive substances known as secretomes (25). MSC-secretomes are made of soluble proteins, including cytokines, chemokines, growth factors, and extracellular vesicles (EVs), which include micro-vesicles and exosomes (26). Stem cells release these secretomes by common secretory mechanisms. When the culture medium or secretome are injected into the patients, the neighboring cells assimilate the molecules by paracrine signalling (27). The exosomes themselves contain numerous bioactive molecules, which include microRNAs (miRNA), transfer RNAs (tRNA), long noncoding RNAs (lncRNA), growth factors, proteins, and lipids. The lipid content of the exosomes provide an added advantage by aiding in the infusion of the exosomes with the plasma membrane of the neighboring cells (28). The molecules involved in regulation of cell growth, proliferation, survival, and immune responses are released by exosomes, are elaborately illustrated in Fig. 2. Upon internalization of the mole-cules in the secretome, the neighboring cells modulate various downstream pathways, including immunomodulation, suppression of apoptosis, prevention of fibrosis, and remodelling of the injured tissues (25).

IMMUNOMODULATORY POTENTIAL OF MSC-EXOS
Exosomes are nanoparticles with a diameter of 40-150 nm. To generate and isolate the exosomes, MSCs can be conditioned to increase the release of exosomes by treatment with cyto-kines or by serum starvation or hypoxia (29). The exosomes are then purified and can be subsequently introduced into the body. MSC-Exos can inhibit CD4+ and CD8+ T cells and NK cells (30). They inhibited T cells expressing IL-17 and induced IL-10-expressing regulatory cells that are involved with suppression of inflammation. MSC-Exos also aid in suppressing the differentiation of CD4+ and CD8+ T cells by releasing mole-cules like TGFβ and prevent inflammation in vivo (31). Similarly, treatment with MSC-Exos reduced the proliferation and activa-tion of NK cells (32). MSC-Exos could shift macrophages from the M1 to the M2 phenotype, further suppressing pro-inflam-matory states (33). Moreover, sepsis is an important lethal factor in COVID-19 patients, and treatments with MSC-Exos have increased the rate of survival in mice with sepsis (34). Concomitantly, MSC-Exos also suppressed release of the pro-inflammatory factors TNF-α, IFN-γ, IL-6, IL-17, and IL-1β (35) and promoted release of anti-inflammatory factors, such as IL-4, IL-10 and TGF-β (36). Additionally, MSC-Exos also reduced the number of chemokines in the serum when injected (37). These immunomodulatory effects of MSC-Exos have also been attributed to their anti-inflammatory cargo, such as IDO, HLA-G, PD-L1 and galectin-1 (38, 39). These mechanisms are illustrated in Fig. 3.

MSC-EXOS THERAPY FOR COVID-19
In COVID-19, multiorgan damage has been seen in many-infected individuals. MSC-Exos is known to alleviate lung injury in asthmatic models and ARDS (40, 41). MSC-Exos may also be useful in the treatment of cardiovascular (42) and renal pro-blems (43). Hence, they can be used to treat organ damage associated with COVID-19. Similarly, MSC-EVs have also exhi-bited inhibitory activity on the hemagglutination of avian, swine, and human influenza viruses (44). Likewise, MSC-Exos lowered the death rate in H7N9 patients without any toxic effects during follow-up examinations (45). In addition, these exosomes consist of adhesion molecules that accurately guide them to the injured site. The usage of the exosomes may be preferred to the MSCs, since they can easily cross the blood-brain barrier, are inexpensive, and cannot undergo independent self-renewal, hence preventing adverse consequences, such as tumor formation. In this pandemic situation, MSC-Exos may be considered as a good treatment option to alleviate the effect of SARS-CoV-2 infection.

CURRENT CLINICAL TRIALS OF STEM CELL-BASED THERAPY IN COVID-19
Of late, stem-cell-based studies in the treatment of COVID-19 have been gaining momentum. The efficiency and safety of usage of exosomes that had been obtained from BM-MSCs was recently tested on 24 SARS-CoV-2 patients (46). These patients exhibited moderate to severe ARDS. When the exosomes were introduced into the patients, there were no side effects, and patients improved in clinical status and oxygenation (46). In a similar study, patients treated with MSCs showed a remark-able improvement in pulmonary function, higher levels of peripheral lymphocytes, and a reduction in the cells that trigger the cytokine storm. Interestingly, the MSCs did not exhibit ACE2 or TMPRSS2 expression, showing that they may not be infected with COVID-19 (47). Several clinical trials are in the pipeline for usage of stem cells for the treatment of COVID-19 (Table 2). Wharton’s jelly-derived MSCs (WJ-MSCs), which have been used in various studies based on stem-cell therapy and trials, are in progress for their usage for COVID-19 treatment (48). Moreover, adipose tissue-derived AD-MSCs have been used in a few studies in various doses and protocols for COVID-19 therapy (49). Likewise, a novel trial includes inhalation of MSC-Exos for alleviation of symptoms (50). In addition, MSCs from dental pulp (51) and olfactory mucosa (52) were administered in various doses. MSCs in the clinical trials are predominantly administered intravenously; i.v. injection and, in some studies, MSCs have been given as adjuvant therapy in addition to drugs like oseltamivir, hormones, hydroxychloroquine, and azithromycin (53, 54). These trials reveal promising new routes for the battle against COVID-19 (55-94).

FUTURE DIRECTIONS
Stem cells have been studied extensively for their ability to regenerate and for the treatment of various diseases. Recently, we devised an improved protocol for the isolation of urine-derived stem cells and their further differentiation into immune cells (95). Moreover, our research group promoted the hematopoietic differentiation of hiPSCs using a novel small molecule (96). At the advent of COVID-19, it has become mandatory to discover therapeutic strategies that are easily reproducible and cost effective. Drugs currently available for the treatment of COVID-19 include ones that target viral replication. These drugs include camo-stat mesylate, which is involved in the inhibition of viral fusion to the cell membrane, and favipiravir and remdesivir, which are anti-viral drugs. However, because the cytokine storm is found predominantly in COVID-19 patients, it is essential to consider drugs that inhibit viral replication while treating the cytokine storm. Hence, MSC-Exos may be appropriate therapeutic agents for COVID-19 (97). MSCs can be more advantageous than other anti-inflammatory agents, because they can provide immunomodulatory effects based on the host cells. In addition to these effects, MSCs can prevent fibrosis of tissues, enable reversal of lung dysfunction, and aid in the regeneration of damaged tissue, which can be significantly beneficial for COVID-19-associated organ damage (98, 99). Because the healing properties of the MSCs can be primarily attributed to the secretomes or exosomes, using them may be more effective than using MSCs themselves. Exosomes can be mass-produced, administered systematically with minimaltoxicity, and be able to reach the cell targets more efficiently. In addition to their inherent immunomodulatory potential, the MSC-Exos can also be used as a drug-delivery system (100). MSC-Exos can be modified in vivo to release exosomes that have a higher immunomodulatory potential (101) and can be cultured using various cytokines to exhibit an anti-inflammatory state (102). Although MSC-Exos appear to be promising thera-peutic agents for COVID-19, more experimental research is necessary for them to be used clinically. Moreover, it is es-sential to optimize the protocols for storage and isolation of MSC-Exos for the treatment of COVID-19. It is also imperative to do experiments to understand the underlying mechanisms of COVID-19 in order to optimize MSC-Exo therapy for treatment (97). Further, it is also essential to find the optimum dosage, route of administration, and treatment schedule for MSC-Exos. Hence, since MSCs are more widely studied in these aspects than are MSC-Exos, they are predominantly preferred in clinical trials for COVID-19 (103).

CONCLUDING REMARKS
COVID-19 has invoked frenzy in individuals worldwide. The unceasing increase of infection and death has halted the lives of the citizens of countries everywhere. Hence, it is important to discover novel therapeutic platforms and productive measures without further delay (104). The therapies produced must be easily reproducible and available in large quantities so that enough bioactive molecules will be available for all indivi-duals who have succumbed to COVID-19. MSCs and MSC-Exos can be used for their immunomodulatory effects in indi-viduals with COVID-19.