key: cord-0870645-2k736hvr authors: Shetty, Rohit; Murugeswari, Ponnalagu; Chakrabarty, Koushik; Jayadev, Chaitra; Matalia, Himanshu; Ghosh, Arkasubhra; Das, Debashish title: Stem cell therapy in COVID-19 – current evidence and future potential date: 2020-11-09 journal: Cytotherapy DOI: 10.1016/j.jcyt.2020.11.001 sha: a6f8786eeb2167a718c3852c67904f0e82414eca doc_id: 870645 cord_uid: 2k736hvr The end of 2019 saw the beginning of the COVID-19 pandemic that soared in 2020, affecting 215 countries worldwide with no signs of abating. In an effort to contain the spread of the disease and treat the infected, researchers are racing against several odds to find an effective solution. The unavailability of timely and affordable or definitive treatment has caused significant morbidity and mortality. Acute respiratory distress syndrome (ARDS) caused by an unregulated host inflammatory response towards the viral infection, followed by multi-organ dysfunction or failure, is one of the primary causes of deaths in severe cases of COVID-19 infection. Currently, empirical management of respiratory and hematological manifestations along with anti-viral agents are being used to treat the infection. The quest is on for both a vaccine and more a definitive management protocol to curtail the spread. Researchers and clinicians are also exploring the possibility of using cell therapy for severe cases of COVID-19 with ARDS. Mesenchymal stem cells are known to have immunomodulatory properties and have previously been used to treat viral infections. This review explores the potential of mesenchymal stem cells as cell therapy for ARDS. The latter half of 2019 saw a sudden rise in pneumonia or severe respiratory infection in Wuhan, Hubei Province, China, secondary to a novel coronavirus "SARS-CoV-2". [1] The infectivity of SARS-COV-2 surpassed the pace of finding an effective treatment or preventive option and as of 27 th October 2020, there are 43,341,451 confirmed positive cases, with a mortality rate of 2.6% and recovery rate of 73% (WHO.int). A pathogen"s basic reproduction number (R0) denotes the average number of people who can be infected by an infected individual. Though the R0 of COVID-19 differed between countries, it is higher than 1 suggesting an exponential infectivity potential of the virus, which has led to this pandemic. [2, 3] The R0 of COVID-19 (R0: 2-3) and that of the Spanish influenza is similar but higher than that of H1N1 influenza (R0: 1. 46-1.52) and MERS (0.3-0.8). [4] [5] [6] While a majority of patients with COVID-19 infection are asymptomatic, symptoms can range from mild to severe. [7] [8] [9] Pneumonia, respiratory distress, multiorgan dysfunction, sepsis, septic shock, loss of speech and movement, are signs of severity. [10] Elderly and immune-compromised or those with co-morbidities have a higher risk of developing severe symptoms with a fatal outcome. [11, 12] The virus induced cytokine storm results in COVID specific acute respiratory distress syndrome (CARDS), multi-organ dysfunction syndrome (MOD) syndrome and eventual death. [13] Currently, severely affected patients are being treated with antiviral and antiinflammatory drugs, besides supportive measures such as invasive and non-invasive mechanical ventilation. [14] Acute progressive renal injury, an early marker of MOD, requires renal replacement therapy in advanced disease. [15] Horby et al., found that dexamethasone reduced mortality in patients receiving invasive ventilation but not in those without any respiratory support. [16] While treatment with several anti-virals did not show any improvement, [17, 18] patients receiving remdesivir, a RNA polymerase inhibitor, demonstrated significant clinical improvement. [19] Over 50 inconclusive. [20, 21] Anakinara, an IL1 receptor antagonist, has shown beneficial effects in moderate to severe COVID-19 infections. [22, 23] Tocilizumab and sarilumab, both IL6 receptor antagonists, used in small cohorts have alleviated clinical symptoms without oxygen supplementation. [24] Ongoing trials will clear ambiguity on tocilizumab dosage and mortality post-treatment. Janus kinase signal inducer (JAK) pathway inhibitors, ruxolitiniband baricitinib, are also being investigated. [25, 26] Convalescent plasma therapy also has potential, but safety and efficacy have to be established with larger studies. [27] [28] [29] With an increasing number of infections worldwide, there is a pressing need to find a prevention and treatment for COVID-19. Vaccines are being developed, with one from Oxford University in collaboration with Astra-Zeneca in Phase III trial. [30, 31] Though300 clinical trials for investigating anti-viral drugs and 163 for anti-inflammatory drugs are ongoing, it is imperative to look for newer and alternate modalities to treat COVID-19 patients. Researchers have explored the role of stem cells to suppress the ARDS during the cytokine storm, since mesenchymal stem cells are known to have an immunomodulatory role. [1, 32] Severe Acute Respiratory Syndrome Corona Virus-2 ( SARS-CoV-2), belongs to the Sarbecovirus family with a 5% genetic association with the SARS virus, [33] and was given the nomenclature of COVID-19 by the Director General of WHO in 30 th January2020. [34] The S protein on the virus recognizes the spike protein present on angiotensin-converting enzyme-2 (ACE-2) making it the port-of entry into the host cells. [35] The ACE-2 receptor is present ubiquitously and predominantly in the alveolar cells, making the lungs most vulnerable for the infection. [36] ACE-2 receptors have not been detected in the bone marrow, lymph nodes, thymus, spleen, lymphocytes and macrophages. [37] Transmembrane protease serine 2 (TMPRSS2) also plays a decisive role for viral entry into the host cells. [38] The over drive by the host immunity against the virus also adversely affects the host cells. [39] Pro-inflammatory cytokines such as, IL-7, IL-6, Il-2, TNF, MIP1A, IP10, GSCF and chemokines such as CCL2, CCL3, CCL5, CXCL8, CXCL9, CXCL10 are released during the infection. [40, 41] The inflammatory response of the host can cause dysfunctional air exchange, pulmonary edema, cardiac injury and acute respiratory distress syndrome (ARDS), eventually leading to death. Such an effect is called a "cytokine storm", also reported in graft versus-host disease during a graft failure, and seen in advanced stages of COVID-19 infection, [42] It has been reported to occur in a short median time of 8 days, from the appearance of the first symptom to ARDS. [43] Hence, a trial of multiple treatment modalities and strategies are being used, such as anti-viral therapy, hydroxychloroquine, neutralizing antibodies, convalescent plasma therapy, repurposing anti-viral medications, and blockers of ACE-2 receptor with antibodies. [44, 45] Mesenchymal stem cells are multipotent adult stem cells, with immunomodulatory properties. [46] They are found in the bone marrow, adipose tissue, dental pulp, umbilical cord, placenta, Wharton's jelly, amniotic fluid, skin, foreskin, salivary gland, and cord blood ( Figure 1 ). [47] The versatility of the differentiation potential of MSCs is based on the tissue specific source of the cells. [46] Based on the International Society of Cell Therapy (ISCT), MSCs are characterized by their ability to adhere to plastic surfaces, expression of CD105, CD73 and CD90 and lack of CD45, CD34, CD14, CD11b, CD79, CD 19 and HLA-DR. [48, 49] The multipotency of the MSCs is validated by their ability to differentiate into adipocytes, chondroblasts and osteoblasts. [49] They have been widely used to aid in the regeneration of damaged neurons or muscle fibers, and to suppress immune reactions via anti-inflammatory macrophages and regulatory T cells. [50] MSCs express low levels of MHC Class I, but lack MHC Class II on their surface. [44] They exert an antimicrobial role by dynamically balancing the pro and antiinflammatory responses, secreting antimicrobial peptides (AMPs), and molecules such as indoleamine 2,3-dioxygenase and IL-17, in addition to their autocrine and paracrine functions. [51, 52] Bone marrow derived MSCs have been widely used followed by umbilical cord blood and adipose derived MSCs for "cytokine storm" rescue. The Stromal Vascular Fraction Mesenchymal stem cells have been widely used in the management of both infectious and non-infectious etiologies, owing to their immunomodulatory and regenerative potential. Despite highly active antiretroviral therapy (HAART) and reduction in viral load, some Liver disease is a major complication of chronic HBV infection and orthotopic liver transplantation remains the only therapeutic strategy in end stage disease, with Artificial Liver Support System serving as a temporary measure. Migration of MSCs is stimulated by the pro-inflammatory marker TNF, [85] and by the binding of ligands CD106 with integrin 4/1 (CD49/CD29) and CD62E with CD44 receptors. [86, 87] Trophic factors such as epithelial growth factor (EGF), transforming growth factors (TGF-α and β), basic fibroblast growth factor (FGF-2), hepatocyte growth factor (HGF), insulin-like growth factor-1 (IGF-1), vascular endothelial growth factor (VEGF), stem cell factor (SCF), stem cell derived factor (SDF-1), and immunomodulatory factors such as prostaglandin E2, inducible nitric oxide synthase, indoleamine 2,3-dioxygenase, chemokine CCL2,IL10, and IL6 are some of the molecules released by MSCs. [88, 89] The cytokine secretion profile of dendritic cells and HCV. [114, 115] Interestingly it has been shown that SARS-CoV virus internalization was prevented by the host cell receptor ACE-2 in IFITM expressing cells. [114] In the lungs, ACE-2 receptor is expressed in alveolar type-II cells and endothelial cells and these cells play a role in preventing virus entry, reducing fibrosis, anti-inflammatory and endothelial protective effects. [116] [117] [118] COVID-19 mortality rate is higher in patients who have preexisting systemic diseases such as diabetes, renal disease and hypertension. In these conditions, the ACE-2 receptor plays an important role as it is a major enzyme in the rennin-angiotensin system, which has been localized in the apical The emergence of the COVID-19 pandemic and its sequelae has prompted clinicians and researchers to explore all possible preventive and treatment modalities since the existing strategies are targeting symptoms, rather than the underlying pathology. Antivirals, pulmonary and renal support systems, and immunomodulators are being used to treat the cytokine storm, which causes respiratory depression and multi-organ dysfunction. Until effective vaccines and specific treatment options are available, it is a challenge to limit the disease progression due to its high infectivity. The MSCs serve as a potential therapeutic candidate for combat the cytokine storm owing to their primordial cell lineage with multipotent functions such as immunomodulation and antiinflammatory, and their ability to secrete various growth factors and soluble vesicles. 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The authors also would like to thank Narayana Nethralaya Foundation for its support. Last but not the least the authors would like to thank the Multimedia Team, Narayana Nethralaya Eye Institute for their help inmaking the schematic diagrams. The authors declare no conflicts of interest.