key: cord-0743830-q8pjwl3s authors: Sahu, Kamal Kant; Siddiqui, Ahmad Daniyal; Cerny, Jan title: Mesenchymal Stem Cells in COVID-19: A Journey from Bench to Bedside date: 2020-07-30 journal: Lab Med DOI: 10.1093/labmed/lmaa049 sha: f629df1a45fa0137ca7cd466caefe68c5ee15479 doc_id: 743830 cord_uid: q8pjwl3s The COVID-19 pandemic has led to a major setback in both the health and economic sectors across the globe. The scale of the problem is enormous because we still do not have any specific anti-SARS-CoV-2 antiviral agent or vaccine. The human immune system has never been exposed to this novel virus, so the viral interactions with the human immune system are completely naive. New approaches are being studied at various levels, including animal in vitro models and human-based studies, to contain the COVID-19 pandemic as soon as possible. Many drugs are being tested for repurposing, but so far only remdesivir has shown some positive benefits based on preliminary reports, but these results also need further confirmation via ongoing trials. Otherwise, no other agents have shown an impactful response against COVID-19. Recently, research exploring the therapeutic application of mesenchymal stem cells (MSCs) in critically ill patients suffering from COVID-19 has gained momentum. The patients belonging to this subset are most likely beyond the point where they could benefit from an antiviral therapy because most of their illness at this stage of disease is driven by inflammatory (over)response of the immune system. In this review, we discuss the potential of MSCs as a therapeutic option for patients with COVID-19, based on the encouraging results from the preliminary data showing improved outcomes in the progression of COVID-19 disease. Recently, research exploring the therapeutic application of mesenchymal stem cells (MSCs) in critically ill patients suffering from COVID-19 has gained momentum. The patients belonging to this subset are most likely beyond the point where they could benefit from an antiviral therapy because most of their illness at this stage of disease is driven by inflammatory (over)response of the immune system. In this review, we discuss the potential of MSCs as a therapeutic option for patients with COVID-19, based on the encouraging results from the preliminary data showing improved outcomes in the progression of COVID-19 disease. Keywords: Stem cells, COVID-19, SARS-CoV-2 Virus, pandemic, vaccine, clinical trials As of June 3, 2020, there were 6,551,389 global COVID-19 cases with 386,196 deaths. Although approximately 98% of patients experience mild disease, 2% experience severe disease often requiring critical care support. 1, 2 To date, physicians and intensivists treating patients with COVID-19 have limited treatment options in the absence of an effective antiviral agent or vaccine. [3] [4] [5] Therapeutic options in the form of convalescent plasma therapy, remdesivir, tocilizumab, and repurposing of various drugs are being explored. [6] [7] [8] [9] [10] Recently, a few studies have examined the role of mesenchymal stem cells (MSCs) in critically ill patients with COVID-19. These studies have shown some early promise as therapeutic possibilities for the treatment of severe COVID-19. [11] [12] [13] [14] In multiple and mostly regenerative clinical settings, MSCs have been evaluated to either treat or prevent a disease or condition characterized by tissue damage. Regenerative treatment models have so far suggested the following major methods of repair: 15, 16 anti-inflammatory effect; stem cell homing to damaged networks, with recruitment of other cells; inhibition of apoptosis; and differentiation capability. The molecules and exosomes emitted from stem cells promote tissue healing and regeneration. In addition to the direct effect, stem cells also possess a paracrine function that works by releasing the soluble factors termed stem cell secretomes. 17, 18 This property allows the systemic distribution of the positive immunomodulatory and regenerative effects of MSCs throughout the body, thereby ensuring a systemic effect in addition to local modulation. 18 The role of MSCs in regenerative medicine has been explored in the past. Many studies have shown the beneficial effects of MSC-based therapies. 14, 16, 19 Such therapies have been studied in various neurological disorders, endocrinopathies, and bone and cartilage diseases. Contrary to these results, some studies have showed that MSCs may promote cancer pathogenesis. 20, 21 Therefore, the role of MSCs in regenerative medicine and their therapeutic potential needs more study and clarification. 22 There is thus a constant effort from research bodies and other agencies such as the U.S. Food and Drug Administration (FDA), the International Society for Cellular Therapy, and the International Society for Stem Cell Research to actively monitor stem cell clinic industries across the globe to minimize unapproved and unproven cell-based therapies. 23, 24 With regard to the current pandemic, the main challenge is the novelty of the disease, its unfamiliar pathophysiology, and the lack of an anti-SARS-CoV-2 antiviral agent or vaccine. Realizing the pandemic as a time-sensitive matter, the FDA has been relatively liberal in clearing pathways to study MSCs and natural killer (NK) cells for their potential immune activity in response to COVID-19. 25, 26 Research has shown that MSCs have specific cytokines that drive immunomodulation, which may be useful against SARS-CoV-2. 27 The available literature so far suggests that the hallmark of SARS-CoV-2 infection is a cytokine-induced storm. SARS-CoV-2 induces an acute release of cytokines such as granulocyte colony-stimulating factor, IP10, Monocyte Chemoattractant Protein-1, interleukin (IL)-2/6/7, and tumor necrosis factor (TNF) in large amounts. 28, 29 These cytokines lead to increased vasculature permeability, pulmonary edema, vascular congestion, and impairment of air exchange across the membranes, and in severe cases they may lead to acute respiratory distress syndrome (ARDS) and death. Recently, Huang et al 30 studied the cytokine profile of 41 patients with COVID-19. They found higher plasma levels of proinflammatory cytokines in patients in the intensive care unit (ICU) than in patients who were not. Chen, Wu, et al 31 found markedly lower absolute numbers of T lymphocytes, CD4+ T cells, and CD8+ T cells in patients with severe cases. 31 The patients with high cytokine levels, lower CD4+ T cells, and lower CD8+ T cells became more sick, required ICU care, and had a higher likelihood of developing ARDS. Current efforts with MSC therapeutics are focusing on the capability of MSCs to abort or minimize this cytokine storm, thereby reducing lung damage and promoting the restoration of tissue function through their inherent reparative properties. 32 The MSCs express angiotensin-converting enzyme 2 (ACE-2) and transmembrane protease serine 2 (TMPRSS2) cells and have the potential to induce mature dendritic cells (DCs) to novel Jagged-2 dependent regulatory DCs that possess an immunosuppressive capacity to generate specific immune tolerance and diminish Th2-type inflammation. 33, 34 The MSCs also help in the preferable differentiation of human CD34+ cells to regulatory DCs over classical DCs. 35 Based on these immunomodulatory functions, Leng et al 11 found MSC infusion beneficial in their patients with COVID-19. Similarly, Zhao 36 also suggested that MSCs could help patients who are critically ill with COVID-19. Stem cells derived from various tissues in the body are being evaluated for therapies in numerous degenerative disorders. 16, 37 The common stem cells used in clinical practice originate from bone marrow (BM), adipose tissue (AT), amnion, the umbilical cord (UC), dental pulp, menstrual blood, the buccal fat pad, and fetal liver. 37 The MSCs hold much promise to change the dynamics of incurable diseases for many reasons: (i) easy accessibility, (ii) multipotency, (iii) ease of expansion to required clinical volume, (iv) storage potential for repetitive therapeutic usage, (v) immune evasive property indicating a minimal chance of rejection with allogeneic MSCs, and (vi) easy route of administration (via intravenous [IV] ). For patients with COVID-19, among the various stem cells, UC mesenchymal stem cells (UC-MSCs) have recently gained more attention because of their ready availability, compatibility, potency, and plasticity: 19, [38] [39] [40] [41] i. When compared with BM, UC harvests have a higher concentration of stem cells. ii. The UC-MSCs have a faster doubling time. iii. A higher proliferation rate of UC-MSCs allows for a scalable expansion that may benefit a larger population of critically ill patients. iv. The harvesting tissue for UC-MSCs is a byproduct during delivery and does not require any invasive procedure unlike BM stem cell extraction. v. The UC-MSCs have the advantage of being immune tolerant because of low expression of major histocompatibility complex (MHC) class I and no expression of MHC class II. These characteristics allow the use of even allogeneic MSCs. Similarly, another potential source of MSCs with an advantage over other harvesting sites is AT. Using AT-derived MSCs has the following benefits: 38, 39 i. Easily accessible site for extraction that poses minimum discomfort to the donor. ii. Comparatively easy to isolate MSCs from the harvested AT. iii. Comparatively, a higher fraction of MSCs can be extracted from harvested AT compared with BM. iv. Comparatively, a higher success rate of isolating MSCs from AT than UC. Studies on animal models have shown that pneumocyte type II cells support coronavirus replication better than pneumocyte type I cells and alveolar macrophages. 42, 43 In addition, postmortem histopathology examination of lung tissue from patients with COVID-19 has shown significant lung damage with evidence of diffuse alveolar damage, type II pneumocyte hyperplasia, and intra-alveolar fibrinous exudates. 44 Recent studies have provided ample evidence that stem cells promote lung tissue healing and regeneration by differentiating to pulmonary epithelial cells. Once injected intravenously, a significant amount of MSCs accumulate in the lung and exhibit an immunomodulatory effect, thereby protecting the alveolar epithelial cells, restoring the pulmonary alveolar niche, preventing fibrosis, and improving overall pulmonary function. 45, 46 This phenomenon may benefit critically ill patients with COVID-19 and help them recover from ARDS, pulmonary edema, and diffuse alveolar damage. The COVID-19 pandemic is evolving, and we are still in the learning phase. There is a lack of impactful data on MSC therapeutics for COVID-19. Physicians can extrapolate the potential clinical benefits of MSCs in COVID-19 pneumonia based on studies from previous viral outbreaks with positive outcomes. 47 Chen et al infused MSCs extracted from allogeneic menstrual blood from healthy female donors into 17 patients with H7N9-induced ARDS. They found a significant mortality benefit in the MSC-infused arm (17.6% died) as compared with the control arm (54.5% died). The major limitations of the study were the small sample size, high attrition rate, and not-ideal comparison sample because patients were receiving other drugs as well. Because H7N9 and SARS-CoV-2 share similar complications-ARDS, hypoxic respiratory failure, severe inflammation, overt immune response, and multiorgan dysfunction syndrome-MSCs therapy may be beneficial for patients with COVID-19 pneumonia as well. 27, 28 A recent metaanalysis on MSC use in ARDS (study period 1990 to March 31, 2020) 7 showed an improvement in radiographic shadows, pulmonary function, and biochemical marker levels. This meta-analysis also showed a mortality benefit with the use of MSCs but not to a significant level. With regard to COVID-19, Leng et al 11 common illnesses). Significant clinical benefit was noted in all patients with symptomatic improvement and reduced oxygen requirement after 2 to 4 days of MSC transplantation. Mass cytometry and cytokine analysis of the patients' peripheral blood also showed disappearance of overactivated T cells and NK cells, an increase in anti-inflammatory cytokines like IL-10, and a decrease in proinflammatory cytokines like TNF-alpha. However, the small sample size, the lack of a control arm, patients who were also receiving other drugs, and a patient cohort with only 1 patient with critical serious illness are possible limitations to consider before analyzing the results. The above-discussed studies regarding the use of MSCs in COVID-19 have provided a much-needed clinical platform for further research on MSCs in COVID-19 and other viral disorders. Therapy using MSC in high-risk populations including pregnant women, patients with human immunodeficiency virus, patients with malignancies, and transplant recipients would need further refinement before being executed. [48] [49] [50] [51] [52] In addition, it is too early to suggest that MSCs are safe to use in patients with COVID-19 and requires further confirmation. 53, 54 Current Literature on Ongoing Recently, clinical trials studying various aspects of MSC use in COVID-19 are underway in several clinical phases ( Figure 1 ). China and the United States are the 2 leading countries studying cell-based therapy-related clinical trials, from which some reports have been published as well ( Table 1) . 55 To prove MSC therapy successful, in addition to evaluating its efficacy it is equally important to assess other practical aspects of community use and accessibility. 57, 58 With regard to MSCs in COVID-19, although the experience so far has been encouraging, the key barriers still include the following: [59] [60] [61] i. Data to date are preliminary and based on compassionate use of MSCs, with final results from clinical trials still pending. ii. The downstream effects of MSCs on the lungs are unclear and unknown. For example, we lack an understanding of MSC impact on the expression of ACE-2 and TMPRSS2, which are known facilitators of viral entry into cells and subsequent replication ( Figure 2 ). iii. Similarly, there is a differential expression of ACE-2 receptors in various organ systems. It would be noteworthy to determine whether there would be a difference in the recovery/response of different organs upon MSC infusion. iv. There is concern over the commercialization and subsequent abuse of unproven cell-based therapies by unauthorized stem cell clinics. v. Therapy with MSCs is not a readily available resource, especially in developing countries. vi. High cost, insurance hurdles, and no standardized treatment protocol are issues of concern. The cost of MSC therapy is extremely variable (between $5000 and $50,000) and depends on the type of stem cells, laboratory location (for extraction), patient location (for infusion), and proliferation character of stem cells. To add to the complexity of the situation, in the United States, Medicare does not cover MSC therapy. vii. In addition, MSC therapy is technically complex, requiring highly specialized staff and equipment. Number of studies currently enrolled regarding MSCs in COVID-19 by country (as of April 22, 2020). Pictorial description of the source of stem cells, and impact of mesenchymal stem cells. www.labmedicine.com viii. Scalability because of these technical challenges may lead to a high discrepancy in the supply-demand chain. ix. There could be immediate adverse effects from MSC infusion; transfusion reactions such as allergies, anaphylaxis, serum sickness, delayed hypersensitivity reactions, and secondary bacteremia. On a positive note, Leng et al 11 did not note any acute infusionrelated issues, allergic reactions, or delayed hypersensitivity or secondary infections in their cohort of patients. Researchers have found that MSCs are ACE-2 negative and TMPRSS2 negative and are thereby unlikely to become infected by SARS-CoV-2. During this unprecedented healthcare crisis, researchers and clinicians across the globe are working relentlessly to identify the best strategies and treatment for patients with COVID-19. Although MSCs are a potentially promising therapy, they are still in the early stages of development for COVID-19 treatment. Further data from ongoing clinical trials across the world will help clarify their potential utility in battling the COVID-19 pandemic. 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