key: cord-0781753-8t59flj5
authors: Sadeghi, Somaye; Soudi, Sara; Shafiee, Abbas; Hashemi, Seyed Mahmoud
title: Mesenchymal stem cell therapies for COVID-19: Current status and mechanism of action
date: 2020-09-23
journal: Life Sci
DOI: 10.1016/j.lfs.2020.118493
sha: 54abc213d2fbf683a427015ecc02b9c65b02ba7d
doc_id: 781753
cord_uid: 8t59flj5

The outbreak of COVID-19 in December 2019, has become an urgent and serious public health emergency. At present, there is no effective treatment or vaccine for COVID-19. Therefore, there is a crucial unmet need to develop a safe and effective treatment for COVID-19 patients. Mesenchymal stem cells (MSCs) are widely used in basic science and in a variety of clinical trials. MSCs are able to engraft to the damaged tissues after transplantation and promote tissue regeneration, besides MSCs able to secrete immunomodulatory factors that suppress the cytokine storms. Moreover, the contribution of MSCs to prevent cell death and inhibit tissue fibrosis is well established. In the current review article, the potential mechanisms by which MSCs contribute to the treatment of COVID-19 patients are highlighted. Also, current trials that evaluated the potential of MSC-based treatments for COVID-19 are briefly reviewed.

Over the past decade, the world has experienced the prevalence of life-threatening pandemic of coronaviruses, the severe acute respiratory syndrome (SARS) in 2002, and the Middle East respiratory syndrome (MERS) in 2011. In early 2020, the outbreak of the novel coronavirus (2019-nCoV) has led to a global pandemic known as novel coronavirus disease (COVID-19) after originating in Wuhan, China. The 2019-nCoV is highly contagious with a long incubation period and strong infectivity (1). From a pathological perspective, the COVID-19 is highly pathogenic with severe pneumonia associated with rapid virus replication (2). As of April 30, 2020, despite great efforts from scientific and clinical communities, there is no suitable therapy or vaccine for COVID-19 and the therapeutic strategies are generally to manage rather than cure this disease.

Current studies have shown that similar to SARS and avian influenza, cytokine storm is the main immunopathogenesis mechanism of COVID-19 which eventually develop acute respiratory distress syndrome (ARDS) (3) .

Stem cell-based therapies, in particular mesenchymal stem cells (MSCs), have shown great potential in the treatment of a variety of diseases (4, 5) . MSC-based therapy has been used for ARDS due to the ability of MSCs to secrete anti-inflammatory, anti-fibrosis, and anti-apoptosis cytokines, which eventually dampen the cytokine storm (6, 7) . Together, current literature suggests that ARDS might be cured with MSCs. Therefore, in the current review paper, the clinical characteristics of COVID-19 will be shortly highlighted, then the opportunities and challenges in the application of MSCs for the coronavirus induced-ARDS are discussed. glycoproteins assemble in the endoplasmic reticulum (ER) and golgi apparatus and form viral particle buds (8) . The virion-containing vesicles then fuse to the plasma membrane and release the virus (10).

The immune system plays an important role in the pathogenesis of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Formation of an appropriate innate immune response in the early stages of the disease which is followed by an effective adaptive immune response limits the progression of the virus from reaching the alveoli and prevents tissue damage. In this case, the virus causes a mild to moderate respiratory disease and patient recovers without requiring special treatment (10) . But if the adverse immune responses are formed and the virus spreads in the lungs, then severe inflammatory responses and cytokine secretions are induced followed by and extensive cell-mediated immune responses to remove the infected cells ( Figure 1 ). This situation will contribute to the pulmonary edema, dysfunction of air-exchange, as well as ARDS (9, 11) . The virus may also enters the bloodstream, and inflammation spreads throughout the body, causing septic shock and vital organ failure especially those organs with high ACE2 expressions such as liver and kidneys (9) (10) (11) .

Although the protective or destructive immune responses are still being investigation, current evidence support the following immune-related pathogenic factors (10).

Human leukocyte antigens are among the most polymorphic genes that regulate immune responses against self and non-self-antigens. The quantity and quality of the epitopes presented by HLA molecules affect the outcome of cytotoxic or helper T cells activation in infectious disease (12) . The protective immune response will appear against viral infections, if HLA's present conserved viral epitopes instead of mutated or variable parts and enhance lymphocyte clonal expansion (13) . Different studies confirmed the effective role of HLA in the development of adequate immune responses against influenza, human immunodeficiency virus, and Hepatitis C virus infections (13, 14) . Although 

The reduction of lymphocyte to less than 1.0 x 10 9 cell per liter in the peripheral blood is called lymphocytopenia. The changes in the lymphocyte count are among the indicators of both viral and non-viral infections and often used to determine the severity of infection (15, 16) . Lymphopenia is caused by an excessive infiltration of lymphocytes into the infected organs and an imbalance in the proliferation and death of lymphocytes (17) .

Dysregulated or impaired immune responses against infectious agents terminated to strong systemic inflammation and induces apoptotic death of lymphocytes. The previous study demonstrated that an increase in Fas-L expression on plasmacytoid dendritic cells induces apoptosis of CD8+ cytotoxic lymphocytes in lethal H5N1 influenza infection (18) . Monitoring the dynamic changes in the lymphocyte count of blood samples of dead and cured COVID-19 patients confirmed the decisive role of lymphocyte depletion in disease progression (19) . Therefore, by measuring the percentage of peripheral blood lymphocytes, the severity of the disease and the effectiveness of treatments can be determined. Moreover, the proliferation of viruses in lymphocyte can induce lymphocyte apoptosis and contribute to the reduction of lymphocyte levels in the blood (20, 21) . Soluble Fas ligand, inflammatory cytokines, and glucocorticoids are among the indirect inducers of apoptosis in lymphocytes in SARS-CoV-2 infection (20) .

The appropriate function of cytotoxic T lymphocytes is the main mechanism to eliminate virally infected cells and reduce viral dissemination. However, if the lymphocytes become exhausted and fail to reduce the viral load, the patient experience a progressive viral infection, tissue damage, or chronic infection. High viral load, expression of inhibitory receptors, and suppressive cytokines are among the

While the mechanistic effects of antibody protection in COVID-19 patients have not yet been well established, the high level of neutralizing antibodies against S protein was found after the infection in the patient's blood (25) . Recently, it was reported that antibodies through binding to the receptorbinding domain (RBD) of the S protein can block the virus interactions with ACE2 protein (26, 27) .

However, both specific and non-specific antibodies can interact with FC receptors or complement receptors and increase virus entry and proliferation (28, 29) . This pathogenic effect of antibodies has been confirmed in the severe forms of COVID-19 disease. Different experiments demonstrated the direct correlation between increased IgG levels and disease progression in COVID-19 patients (30, 31).

The formation of a non-protective inflammatory response in infections leads to uncontrolled systemic inflammatory responses which are characterized by an increase in the pro-inflammatory cytokines and chemokines secretion that is called cytokine storm (32) . During these process monocytes, macrophages and neutrophils are being activated in the bloodstream and release the pro-inflammatory cytokines that disrupt the endothelium barrier and extravagate to different organs. The activated CD4+ T cells differentiate to Th1 cells and contribute to a delayed inflammatory response, and also contribute to the activation of cytotoxic CD8+ T cells and Th17 cells which could induce excessive inflammatory responses that are associated with increased cytokine secretion such as IL-6, interferongamma (IFN-ᵞ), and granulocyte-macrophage colony-stimulating factor (GM-CSF) (34) . GM-CSF can activate monocytes to further release IL-6 and other factors that lead to the formation of a cytokine storm followed by ARDS which is the leading cause of death in patients with severe COVID-19 pneumonia (33, 34).

The second stage of COVID-19 pathogenesis is the result of an imbalance between inflammatory and anti-inflammatory cytokines from the patient immune system in response to the viral infection (35) . In 

As of April 30, 2020, there is no effective therapy or vaccine for COVID-19 infection and current treatments are mainly supportive approaches including oxygen therapy, fluid management and the use of a broad spectrum of antibiotics to inhibit secondary infection. Moreover, several antiviral agents have been repurposed to be used against 10) . Here, the major treatment approaches for COV-D-19 are briefly highlighted.

Nonsteroidal anti-inflammatory drugs have been proposed for COVID-19 treatments. However, recent studies have shown that corticosteroids which are routinely used for influenza infection are not effective enough for COVID-19 (36) (37) (38) . Moreover, previous studies reported no therapeutic benefits for corticosteroids in SARS and MERS infections, and were associated with complications such as hyperglycemia and avascular necrosis (39) . The effectiveness of corticosteroids in COVID-19 is controversial, a recent study reported that dexamethasone, is able to reduce the mortality rate of COVID-19 patients who receive invasive mechanical ventilation or oxygen (40) .

Monoclonal antibodies against inflammatory mediators have been proposed as potential agents for COVID-19 treatment (39). Some monoclonal antibodies or immunomodulatory agents have been previously tested in clinical trials for the treatment of cytokine storm-related diseases, including anakinra (IL-1 blockade), bevacizumab (anti-vascular endothelial growth factor), eculizumab (antibody inhibiting terminal complement) and blocking the gamma interferon and Janus kinase/STAT signal transduction pathway (39, 41, 42) . Tocilizumab, a FDA approved IL-6 receptor antagonist, previously used to manage the cytokine syndrome and acute lymphocytic leukemia, has J o u r n a l P r e -p r o o f Journal Pre-proof been used in the patients with COVID-19 pneumonia with promising outcomes (38, 39, 43) . At this point, the use of these drugs for COVID-19 requires further investigation (11, 44) .

In addition to active immunity through the vaccine, immunity can be achieved through the direct injection of sera of the patients recovered from COVID-19. It was shown that convalescent plasma of patients recovered from SARS and influenza viruses' infections has therapeutic effects without adverse events (45, 46) . This treatment plan is now included in the treatment program for the patients with new coronavirus and related to the level of neutralizing antibody titer in the extracted serum, nevertheless, its clinical application is also limited (33) . Despite the beneficial effects, this approach has several limitations, antibodies could lead to the excessive stimulation of immune response which may cause cytokine secretion syndrome and life-threatening toxicity. In addition, the antibody concentration in the blood is very low and makes it challenging to provide enough antibody for the treatment (44).

Chloroquine (CQ) and hydroxychloroquine (HCQ), conventional drugs for malaria infection therapy, were used for COVID-19 patients (3, 39) . Several possible mechanisms have been suggested for their actions, one is the inhibition of the virus entry through changing the ACE2 glycosylation (47) .

Besides, through increasing the pH of endosomes and lysosomes in the antigen-presenting cells (APC), and through the suppression of T cells activation and cytokines production by these cells (47) .

Diarrhea and vomiting are common side effects of these two drugs. Moreover, it has been known that having high blood pressure and diabetes worsens in COVID-19 conditions. Therefore, the application of CQ or HCQ with the drug used for high blood pressure and diabetes may result in life-treating complications. Although HCQ has fewer side effects, the prolonged and overdose use of HCQ results in critical side effects (36, 47) . Although some studies have noted the therapeutic effects of HCQ, the evidence of the benefits and limitations of this drug for the treatment of COVID-19 patients is insufficient and very conflicting (48) . 

Currently, numerous clinical trials are launched to investigate potential therapies for COVID-19 patients (39) . In the meantime, MSCs-based therapy has been proposed for COVID-19. MSCs from a variety of sources have been proposed as a potential treatment for many diseases (49) (50) (51) . MSCs would appear to have some attractive therapeutic potential to the COVID-19 owing to their powerful anti-inflammatory and immunoregulatory abilities. MSCs can engraft to the damaged tissues after transplantation and contribute to immune modulation and tissue regeneration (52) (53) (54) (55) .

Mechanistically, MSCs are involved in the down-regulation of acute-phase responses such as the inhibition of abnormally activated T lymphocytes, macrophages, and pro-inflammatory cytokines secretion, thereby could reduce the occurrence of cytokine storm (56) . Moreover, MSCs can inhibit cell apoptosis, and promote endogenous tissue repair and release antimicrobial molecules that can potentially treat the major abnormalities. In contrary to what could be achieved by targeting any intermediaries' single mediator (e.g. monoclonal antibody against TNF, IL-6), MSCs in addition to reducing excessive inflammation, increase the clearance of pathogens (50, (55) (56) (57) . The safety and effectiveness of MSCs have been documented in several clinical trials (50, (58) (59) (60) .

Currently, MSCs have been applied in numerous trials particularly in the context of inflammatorymediated disorders (54) . Therefore, it is expected that MSC-based therapies to be effective in the treatment of COVID-19 patients.

It is suggested that immunological therapy may be effective in COVID-19 patients (6) 

Apoptosis is a host defense mechanism against infectious agents and plays a central role in the hostpathogen interactions. Apoptosis was observed at different stages of viral infections in SARS patients (63) . Lymphopenia due to T-cell depletion and exhaustion of immune cells by apoptosis has been observed in COVID-19 patients (24). Therefore, the effective control of apoptosis in COVID-19 patients is critical. MSCs able to prevent cell apoptosis which could be the result of hypoxia, chemical agents, mechanical damage, or radiation. For example, the anti-apoptotic effects of MSCs have been proved in cardiac ischemic, as well as in neural and pulmonary disorders (4). For example, keratinocyte growth factor (KGF) and hepatocyte growth factor (HGF) released from MSCs protect J o u r n a l P r e -p r o o f alveolar epithelial cells from apoptosis with the increased expression of Bcl-2 and inhibition of HIF1 protein (67) . Moreover, in the hypoxia-related apoptosis, MSCs induced the expression of some factors such as vascular endothelial growth factor (VEGF), HGF and TGF-β1 that can reverse the apoptosis of endothelial cells (45) . Other factors are also involved in the anti-apoptotic effect of MSCs, including insulin-like growth factor-1 (IGF-1) and IL-6 that lead to elevated levels of secreted frizzled-related protein 2 (SFRP2), an important anti-apoptotic mediator in fibroblast-like cells (4).

MSCs contribute to tissue regeneration and repair due to their unique feature in reducing abnormal immune responses, ability to differentiate into the target tissues or secretion of some factors which induce host reparative/regenerative mechanisms (68) . The MSC-secreted factors able to promote tissue repair via supporting the growth and differentiation of local stem/progenitor cells, and through the regulation of extracellular matrix molecules deposition, stimulating the anti-scarring pathways, and inducing the neovascularization (69, 70) .

In the respiratory diseases, not only the elimination of virus but also the repair of the damaged tissues and restoration of lung tissues are required. ARDS is characterized by disruption of the alveolarcapillary membrane barrier, edema, hyperplasia, and pneumocystis with inflammatory cellular infiltration (71) . Therefore, it is necessary to use new drugs that not only inhibit the inflammation but also stimulate the regeneration of damaged alveolar epithelial cells. MSCs can be considered as a promising treatment option in pulmonary disorders due to their immunoregulatory effect and their potential to differentiate into the lung cells (52) . 

The antibacterial properties of MSCs are mediated through, 1) the secretion of soluble mediators to decrease bacterial count and improve the antimicrobial response of immune cells, or 2) the suppression of pro-inflammatory cell migration into the infected tissues.

MSCs through toll-like receptor (TLR) signaling and crosstalk with immune cells restore the balance between pathogens elimination at an early phase of an inflammatory response, and inflammation suppression to improve the homeostasis and initiate tissue repair (75) . Because of the compatibility of these features with the COVID-19 pathogenesis, MSCs-therapy could be considered as a promising approach.

The therapeutic effects of MSCs in reducing mortality, improving organ function, and also reducing the bacterial load by releasing antimicrobial peptides (such as human cathelicidin (LL-37) and lipocalin-2 (LCN-2)) and enhancing monocyte phagocytosis were shown in different lung injury animal models (54, 75) .

Because COVID-19 infection is associated with an increased risk of infection with other respiratory viruses, fungi, and bacterial infection, therefore the antibacterial treatments are essential (76) .

Antibiotic treatment significantly reduces the bacterial load in the body, but unable to induce tissue repair (77) . However, MSCs have multiple protective mechanisms through the secretion of several paracrine factors which not only contribute to bacterial clearance, also modulate the immune response and restore the epithelial integrity and facilitate repair/regenerative processes (77) . Of importance, MSCs can prevent the development of drug-resistant microbes, a problem with conventional antibiotics (74, 76) .

The functional mechanism of MSCs is relying on their paracrine effects through exosome secretion.

Exosomes as a membrane vesicles can be released from a variety of cells and are capable to deliver microRNAs (miRNAs), lipids and proteins to the cells (78) . miRNAs as a class of non-coding RNAs, regulate the gene expression by targeting mRNAs. It has been shown that MSCs are involved in J o u r n a l P r e -p r o o f physiological and pathological processes through miRNAs derived from exosomes (79) . Moreover, the therapeutic effect of miRNAs derived from MSC' exosome have been shown in several diseases including Parkinson's, transmissible spongiform encephalopathy, spinal cord injury and autoimmune diseases (78, 80) . It has recently been reported that miR-199a, miR-145 and miR-221, from UCBMSC-derived exosomes, are involved in inhibiting hepatitis C virus (HCV) RNA replication (78).

Clinical and preclinical researches have focused on the potential role of MSC in reducing the mortality rate, inflammation, and lung injury in ARDS (55, (81) (82) (83) (84) . The safety and efficacy of MSCs in ARDS have been established in numerous clinical trials (61, 72) . MSC therapy seems to be effective in ARDS due to its low immunity, polytropic effects, and the ability to migrate to the injury sites (64) . MSCs able to reduce the levels of C-reactive protein (CRP) modulate the overactivation of cytokine-secreting cells in COVID-19 patients (7).

MSCs reduce the host's damage caused by inflammation while increasing the host's resistance to sepsis and ARDS due to the enhanced host cell phagocytosis, increased bacterial clearance, and antibacterial peptide production (55, 85) . MSCs also express several interferon-stimulated genes (ISGs) that are known to show the anti-viral activities (86) . MSCs contribute to lung tissue regeneration in ALI and ARDS diseases via the secretion of cytoprotective agents (57, 61, 82) .

Angiopoietin and keratinocyte growth factor secreted from MSCs able to restore alveolar epithelial and endothelial cells in ALI and ARDS models (82, 87) . The ability of MSCs to reduce the pathological deviation such as the accumulation of lung collagen and fibrosis, and reducing the levels of matrix metalloproteinases have been demonstrated (88) . Therefore, it could be effective in the pulmonary fibrosis in the COVID-19 (86) . MSCs have become an exciting candidate for COVID-19

induced ARDS due to their immunomodulatory effects, regenerative properties, the controlling the oxidative damage, protection of the endothelium, and the epithelium and their antibacterial effects (88) . Increasing studies related to MSC therapy in the COVID-19 outbreak have promise results and indicate their possibility of effective in this infection (89) (90) (91) (92) . However, these studies are limited and future clinical trial is undeniable (93) . Despite early promising results, the limitations related to MSC 

Recently, one study reported the clinical outcome of a 65-year-old female COVID-19 patient with severe pneumonia, respiratory and multiorgan failure who was treated with allogeneic human umbilical cord blood-derived mesenchymal stem cells (UCBMSCs), for three times (5 × 10 7 cells each time) (94) . After the second dose, the patient was off the ventilator and well tolerance was observed, and the measured parameters returned to the normal levels. Two days after the third injection, the patient was transferred out of the ICU and her test was confirmed negative for coronavirus. Although this study was reported on one case and extensive trials are needed, but indicated that MSCs could be applicable for COVID-19 infection or could be applied in combination with other therapies for COVID-19 (94) .

Another study was investigated the impact of MSCs therapy in 7 patients with COVID-19 pneumonia (one patient with critically serious, 4 patients with serious and 2 patients with common clinical symptoms). Treatment was a single dose of clinical-grade MSCs (1 × 10 6 cells/kg), intravenously (6) .

Patients were monitored for 14 days after MSCs transplantation. On the second day after the injection, pulmonary function and symptoms of patients were improved. The results showed that after MSCs transplantation, the peripheral lymphocytes were increased and CRP and inflammatory cytokines significantly decreased, whereas IL-10 and regulatory DC cells were increased. Although small sample size and short-term follow-up are some of the limitations of this study, the therapeutic potential of MSCs in COVID-19 patients with severe conditions was reported and no complications were noted in the treatment group (6) .

Recently, several MSC-based clinical trials for COVID-19 have begun in numerous countries (Table   1) CAStem is an injectable product composed of immunity-and matrix-regulatory cells (IMRCs), also named as M cells, differentiated from clinical-grade human embryonic stem cells (hESCs). A phase I/II trial will be done to evaluate the safety and efficacy of CAStem for the treatment of severe COVID-19 associated with or without ARDS. CAStem will be cryopreserved and transported to the clinical site using liquid nitrogen vapor shipping vessels (< -150ºC). Before the injection, CAStem will be reconstituted in normal saline. In this study, 3 cohorts with 3 patients/cohort will receive 3, 5, or 1 × 10 7 cells/kg (NCT04331613). Figure 2, represented the various aspects that should be considered in MSCs-based therapy.

The COVID-19 pandemic presents a serious and urgent healthcare crisis. Numerous clinical trials are launched to find out an effective treatment for this highly infective disease. However, no suitable therapy exists to date. Preclinical data suggest that MSCs through multiple protective mechanisms such as anti-inflammatory, antimicrobial, and regenerative properties could be used to treat COVID- 

The authors declare that there is no conflict of interest. 

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