key: cord-1035120-g7c49wr5
authors: Ebrahimi, Mohsen; Rad, Mohammad Taha Saadati; Zebardast, Arghavan; Ayyasi, Mitra; Goodarzi, Golnaz; Tehrani, Sadra Samavarchi
title: The critical role of mesenchymal stromal/stem cell therapy in COVID‐19 patients: An updated review
date: 2021-09-20
journal: Cell Biochem Funct
DOI: 10.1002/cbf.3670
sha: cde3112ae4c2293e6eefa9a54ec6b5d312e1ff87
doc_id: 1035120
cord_uid: g7c49wr5

New coronavirus disease 2019 (COVID‐19), as a pandemic disaster, has drawn the attention of researchers in various fields to discover suitable therapeutic approaches for the management of COVID‐19 patients. Currently, there are many worries about the rapid spread of COVID‐19; there is no approved treatment for this infectious disease, despite many efforts to develop therapeutic procedures for COVID‐19. Emerging evidence shows that mesenchymal stromal/stem cell (MSC) therapy can be a suitable option for the management of COVID‐19. These cells have many biological features (including the potential of differentiation, high safety and effectiveness, secretion of trophic factors and immunoregulatory features) that make them suitable for the treatment of various diseases. However, some studies have questioned the positive role of MSC therapy in the treatment of COVID‐19. Accordingly, in this paper, we will focus on the therapeutic impacts of MSCs and their critical role in cytokine storm of COVID‐19 patients.

Pfizer, Covishield, AstraZeneca, Sputnik V, Janssen, Moderna, Sinopharm and Sinovac-CoronaVac. 12 MSCs, as multipotent stem cells, can be isolated and expanded from a range of tissue sources, such as bone marrow (BM), amniotic membrane, fat tissue, umbilical cord and perinatal tissues (PTs). 13, 14 Therapeutic MSCs were initially isolated from BM in 1994. With growing interest in MSCs in clinical trials, the contribution of adipose tissue (AT) and PT became evident. 15 In a preclinical setting, MSCs demonstrate several biological properties (including the potential of differentiation, high safety and effectiveness, secretion of trophic factors and immunoregulatory features) that make them suitable for the treatment of various diseases. [16] [17] [18] Regarding the potential of MSCs in the modulation of the immune system, these cells could be used as an appropriate treatment for patients with COVID-19. [19] [20] [21] However, based on clinical trials and in vivo studies, MSCs have been widely used to treat a variety of diseases, but translation into clinical practice has proven to be far more challenging.

Despite the fact that in the past 5 years, MSCs from BM, AT and PT with almost equal frequency have been used in clinical trials due to a great diversity in MSC products, the tissue source from which MSCs are derived is very important. 22 Thus, due to variable levels of highly procoagulant tissue factor (TF/CD142), which are expressed by MSC products, the safety and effectiveness of cell therapy in are not clear. 23 In other words, some studies have questioned the beneficial effects of MSCs therapy on COVID-19 and focused on its complications. Hence, in the present review, we will highlight the critical roles of MSCs in cytokine storm of COVID-19 and discuss the different therapeutic effects of MSCs on COVID-19.

COVID-19 is generally known as a coronavirus and, as a member of the subfamily Orthocoronavirinae, belongs to the family of Coronaviridae. 24, 25 This big virus family is severely pathogenic and often considered infectious, as caused the epidemic of severe acute respiratory syndrome coronavirus (SARS-CoV) in 2002 and Middle East respiratory syndrome (MERS) in 2012. 26, 27 In late December 2019, the outbreak of a new coronavirus that caused a respiratory-associated disease was reported in Wuhan, Hubei, China; it was then announced as a global health disaster by the World Health Organization (WHO); nowadays, the disease is widely called COVID-19. 28 A great number of studies first concentrated on raccoon dogs and palm civets as an important reservoir of infection in the case of SARS-CoV. At the beginning of 2020, they were misdiagnosed as seasonal flu; also, the pathogenesis and aetiology of such pneumonia-like symptoms remained unidentified. Based on some studies, epidemiologists discovered that the cluster was related to the human seafood market in Wuhan, which led to the hypothesis of zoonotic disease transmission. According to the phylogenomic analysis of COVID- 19, it has been demonstrated that the novel coronavirus is most closely linked to two SARS-like-CoV sequences, which were obtained in bats between 2015 and 2017, proposing that the bats' coronavirus and COVID-19 share similar ancestry. As a result, COVID-19 is known as SARS-CoV-2, a SARS-like virus.

Moreover, the two bat viruses were isolated in Zhoushan, China; in this regard, it was thought that COVID-19 might have first appeared close to Zhoushan. 29, 30 Coronaviruses consist of alpha-, beta-, gammaand delta-coronavirus subfamilies. Alpha-and beta-coronaviruses can cause infection in mammals, whereas the other two types are more likely to infect birds. 31 COVID-19 shares about 80%, 50% and 96% sequence likeness with SARS-CoV, MERS and bat coronavirus, respectively. 32 Unlike other coronaviruses, this emerging virus is a positive-sense single-stranded RNA (ssRNA) virus. Moreover, its genome size ranges between about 27 000 and 32 000 base pairs (bp). This novel virus is spherical with a diameter of about 125 nm, which is translated into structural proteins (eg, spike, envelope, membrane and nucleocapsid) and nonstructural proteins (eg, replicas [orf1a/b]), nsp2, nsp3 and accessory proteins (orf3a and orf7a/b). [33] [34] [35] The virus can be transmitted through the environment, droplets or aerosols, coughing and sneezing, and direct contact with infected individuals.

The disease quickly spread not just throughout China but also throughout the ancient continent. It did not take long for the disease to spread throughout the globe and become a global pandemic. 36 Less than 3 months after the outbreak began, >100 000 cases and about 4500 deaths were reported worldwide. 37 When dozens of countries were witnessing a growing number of new cases, the pattern of disease spread in China was declining. At the beginning of the public spread of the disease, some countries, such as Iran and Italy, became significantly more affected by the disease. 38 Early clinical manifestations of COVID-19 patients are dry cough, fever, myalgia, sore throat, diarrhoea and difficulty breathing, 39 and the prognosis of infected people was correlated with host features. 40 It was reported that during hospitalization, respiratory failure occurred in approximately 90% of patients. 39 A number of biochemical parameters change during the disease course, including decreased white blood cells (WBC) and lymphocytes, as well as increased aspartate aminotransferase (AST), alanine aminotransferase (ALT), lactate dehydrogenase (LDH) and C-reactive protein (CRP). 41 After about 2 to 5 days, the symptoms manifest. 42 The average interval from the onset of symptoms to death has been considered 14 days, 43 depending on the patient's immune system and age. This average interval is shorter in people >70 years of age than in people <70 years of age. 44 A chest computed tomography (CT) scan can confirm pneumonia, but there are some aberrant characteristics, such as RNAaemia, acute respiratory distress syndrome (ARDS), acute heart damage and incidence of grand-glass opacities, all of which culminated in death. 45 Cytokine storm in the lungs is a hallmark of SARS-CoV-2 pathogenesis. Acute cytokine release of GCSF, IL-2, IL-6, IL-7, IP-10, MCP-1, MIP1A and TNF caused by a virus causes pulmonary edema, airway dysfunction and ARDS.

In the vast majority of cases, SARS-CoV-2 infections vary from asymptomatic to symptoms similar to seasonal flu, and about 14%, 6% and 3% of patients showed severe, critical and fatal outcomes, respectively. 46 Due to lung and multiorgan failure, tissue destruction and virus-induced cytokine storm with a unique pattern, severe patients necessitate intensive care unit (ICU). 47 Secondary clinical manifestations, including cardiomyopathy, acute cardiac damage, acute renal infection, bacterial infection, organ failure and sepsis, occur in about 5% of all cases. 48 Patients with severe COVID-19 are more likely to experience complications such as ARDS, acute lung injury (ALI) and sepsis. [49] [50] [51] ARDS is the most severe type of ALI 52 with neutrophil, monocyte and lymphocyte infiltration in the bloodstream. 53 It is generally divided into categories depending on the clinical circumstances, such as sepsis, transfusion or trauma. 54 Based on evidence, sepsis-induced ARDS is the most prevalent cause. 55 All three ARDS, ALI and sepsis are defined by the release of abnormally high levels of cytokines, which

can cause systemic problems. 56 The frequency and severity of ALI is a key determinant of the prognosis of COVID-19 patients.

In the ICU, over 30% of COVID-19 patients have significant pulmonary edema, dyspnea, hypoxemia or possibly ARDS. 57 A large number of critically ill COVID-19 patients (who have a poor prognosis) are in a systemic procoagulant condition, which puts them at risk for disseminated intravascular coagulation (DIC), thrombosis and thrombotic multiorgan failure (which is one of the major reasons for mortality in these patients). Because of the risk of damage to these patients, systemic intravenous (IV) MSC therapy would be a contraindication. 23 The Chinese Center for Disease Control and Prevention conducted the largest study on COVID-19 patients in China; they analysed data from 72 314 COVID-19 patients and found that 81% of cases were mild with an overall case fatality rate of 2.3%, and 5% of them presented with respiratory failure, septic shock and multiorgan dysfunction with 50% of fatality. 58 

MSCs were reported by Friedenstein et al as fibroblast-colony forming cells derived from rat BM. 59, 60 Besides BM, MSCs can be obtained from AT, 61 dental pulp, 62 umbilical cord blood, 63 fetal lung 64 and placenta. 65 Based on growing evidence, MSCs, as a heterogeneous population of cells, have the capability of differentiation into mesodermal lineages. These cells have several biological properties (including the potential of differentiation, tissue remodelling, secretion growth factors and immune protective cytokines, safety and easy isolation) that make them suitable for stem cell-based therapy. 66 MSCs can home to injured sites and release various factors (such as vascular endothelial growth factor [VEGF], insulin-like growth factor 1 [IGF-1], IL-6, stromal-derived factor 1 [SDF-1], hepatocyte and nerve growth factors), which can promote cell survival. 67, 68 However, due to the occurrence of instant blood mediated inflammatory response (IBMR), which poses a serious threat to graft survival and function, this is not a very efficient process. In addition, the expression of TF (CD142) has been identified as a key trigger of IBMIR. 18, 22, 23, 58 On the other hand, MSCs' therapeutic effects on lung injury are due to their ability to secrete some factors such as nitric oxide (NO), transforming growth factor β (TGF-β), prostaglandin E2, indoleamine 2, 3 dioxygenase (IDO) and keratinocyte growth factor (KGF). 69, 70 Prostaglandin E2 stimulates the conversion of alveolar macrophages from the proinflammatory M1-macrophages to the antiinflammatory phenotype, which can release IL-10 and decrease the severity of inflammation. 71 Besides, prostaglandin E2, NO, IDO and KGF can also suppress T-cell-dependent inflammation. [72] [73] [74] Furthermore, numerous studies have indicated the immunomodulatory properties of MSCs. The immunomodulatory potential of these cells occurs by altering the function of T cells, B cells, natural killer (NK) cells and monocytes/macrophages. 71, [75] [76] [77] In addition, these cells can decrease interferon-γ (IFN-γ), TNF-α and IL-17 production while increasing IL-10 production, resulting in a modulation of the host immune response. 70 There is no effective therapy for COVID-19, but MSC therapies have shown promising outcomes in treating inflammation, sepsis and ARDS (these are the leading mortality cause of COVID-19 patients). Thus, immunomodulatory and regenerative characteristics suggest that MSCs could be used as a cellular therapy for COVID-19 patients with lung injury. 78 

MSCs can release different cytokines by paracrine secretion or interacting directly with immune cells, resulting in immunomodulation. 79 The activation of toll-like receptors (TLRs) in MSCs is induced by Despite several efforts to comprehend the therapeutic effects of MSCs in ARDS, their mechanism has not yet been fully defined. 92 On the other hand, most COVID-19 patients are at high risk for DIC, thromboembolism and thrombotic multiorgan failure. 23 MSC-based products can express variable levels of TF (CD142), leading to blood clotting and thrombotic multiorgan dysfunction. 23 

MSCs have been widely used in cell-based therapies, from basic research to clinical trials. 93 104, 105 In the context of neutrophils and macrophages, MSCs can control these immune cell responses. 71 Macrophages are classified into M1 (which is a classically activated macrophage) and M2 (which is an alternatively activated macrophage). 106 Pathogen phagocytosis and antigen epitope presentation to DCs, as well as promoting T H 1 responses, are performed by M1 macrophages. However, M2 macrophages are considered immunosuppressive cells as they stimulate T H 2 responses. 107 By activating M2 macrophages, inflammatory cytokines are expressed at low levels, while anti-inflammatory IL-10 is produced at high levels. MSCs can promote M2 macrophage activation through paracrine or cell-to-cell connections. 79, 106 Another immunomodulatory function of MSCs is the inhibition of DC maturation via soluble factor production. 106, 108, 109 MSCs can limit DC maturation by inactivating signalling cascades mediated by mitogenactivated protein kinase (MAPK) and nuclear factor-κB (NF-κB) via producing TNF-stimulated gene 6 (TSG-6). 110 It has been reported that prostaglandin E2 (PGE2) released by activated MSCs plays a key function in DC maturation inhibition. 106 Furthermore, it has been discovered that NK cells and MSCs have a highly complicated interaction. 111 NK cells are lymphocytes in the innate immune system. 112 They have several receptors that can transmit by either activating or inhibiting signals. 113 The production of soluble substances by MSCs suppresses the immune response of NK cells. 106 IL-2-induced NK-cell responses can be inhibited by IDO and PGE2. 106, 114 Additionally, MSCs have TLRs, which appear to play an important function. The TLR3 activation in MSCs results in enhanced immunosuppression of NK cells. 115 These types of stem cells release some chemicals that can influence B-cell and T-cell responses positively or negatively. 116 Through the production of PGE2, IDO, TGF and hepatocyte growth factor (HGF), MSCs can effectively limit T-cell proliferation. 106 is not required and can be administered intranasally or through inhalation. Furthermore, since EVs do not self-replicate, they do not pose the risk of uncontrolled cell division that has been raised in the past regarding cell-based treatments. 83, 127 MSCs were found in greater abundance in lung tissue from patients with fibrotic lung disorders. 128 Early application of MSCs to alleviate inflammation and lung tissue remodelling with mild fibrosis was established in animal models. 128 The lung osmotic gradient created by active ion transport across the alveolar epithelium causes alveolar fluid clearance (AFC). 129 AFC decreases in COVID-19 patients with ARDS, linked to increased morbidity and death. 130 Patients who die of ARDS had much decreased fluid clearance. 131 MSC interaction with chloride and sodium ion channels improves AFC and facilitates the clearance of pulmonary edema. 132, 133 Based on Tang et al's findings, following MSC treatment, oxygenation and immunological indicators improved, and inflammatory indicators were reduced. They indicated that clinical data on the therapy of COVID-19 were provided via MSC transplantation. 19 A case-report study was conducted on a COVID-19 patient with worsening conditions and signs of liver injury despite rigorous treatment. After human umbilical cord MSC (hUCMSC) therapy, most laboratory tests and CT scans revealed that the inflammatory symptoms waned. The patient was taken off the ventilator and able to walk 4 days after her second cell injection without any critical side effects. 134 In another study, Leng et al assessed MSC transplantation in seven COVID-19 pneumonia patients. They discovered that 4 days after MSC injection, the functional outcomes of the patients considerably improved with no adverse effects. 91 Similar to these results, in China, a study on the treatment of a severe COVID-19 patient with human umbilical cord Wharton's jelly-derived MSCs (hWJCs) showed that intravascular transplantation of hWJCs for the treatment of COVID-19 pneumonia was found to be safe and effective. 135 The use of MSCs for COVID-19 has become a hot topic among researchers. MSC therapy improved COVID-19 patients' outcomes; it could be a good option for disease treatment, 21 but further preclinical and clinical research is needed to further investigate its mechanism, safety, and efficacy 136 (Table 1 ). In addition, it is effectively used in clinical trials for the treatment of various disorders, such as multiple 

The authors would like to thank Tehran University of Medical Sciences for their kind supports.

The authors declare no potential conflict of interest.

The data used to support the findings of this study are included in the article.

This article does not contain any studies with human participants or animals performed by any of the authors.

ORCID Sadra Samavarchi Tehrani https://orcid.org/0000-0002-1043-2443

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