Mesenchymal stem cells: a new front emerges in coronavirus disease 2019 treatment

Currently, treating coronavirus disease 2019 (COVID-19) patients, particularly those afflicted with severe pneumonia, is challenging, as no effective pharmacotherapy for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) exists. Severe pneumonia is recognized as a clinical syndrome characterized by hyper-induction of pro-inflammatory cytokine production, which can induce organ damage, followed by edema, dysfunction of air exchange, acute respiratory distress syndrome, acute cardiac injury, secondary infection and increased mortality. Owing to the immunoregulatory and differentiation potential of mesenchymal stem cells (MSCs), we aimed to outline current insights into the clinical application of MSCs in COVID-19 patients. Based on results from preliminary clinical investigations, it can be predicted that MSC therapy for patients infected with SARS-CoV-2 is safe and effective, although multiple clinical trials with a protracted follow-up will be necessary to determine the long-term effects of the treatment on COVID-19 patients.     

Mesenchymal stromal cells as potential immunomodulatory players in severe acute respiratory distress syndrome induced by SARS-CoV-2 infection

Severe acute respiratory syndrome coronavirus-2 and the related coronavirus disease-19 (COVID-19) is a worldwide emerging situation, which was initially reported in December 2019 in Wuhan, China. Currently, more than 7258842 new cases, and more than 411879 deaths have been reported globally. This new highly transmitted coronavirus is responsible for the development of severe acute respiratory distress syndrome. Due to this disorder, a great number of patients are hospitalized in the intensive care unit followed by connection to extracorporeal membrane oxygenation for breath supporting and survival. Severe acute respiratory distress syndrome is mostly accompanied by the secretion of proinflammatory cytokines, including interleukin (IL)-2, IL-6, IL-7, granulocyte colony-stimulating factor (GSCF), interferon-inducible protein 10 (IP10), monocyte chemotactic protein-1 (MCP1), macrophage inflammatory protein 1A (MIP1A), and tumor necrosis factor alpha (TNF-α), an event which is known as “cytokine storm”. Further disease pathology involves a generalized modulation of immune responses, leading to fatal multiorgan failure. Currently, no specific treatment or vaccination against severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has been developed. Mesenchymal stromal cells (MSCs), which are known for their immunosuppressive actions, could be applied as an alternative co-therapy in critically-ill COVID-19 patients. Specifically, MSCs can regulate the immune responses through the conversion of Th1 to Th2, activation of M2 macrophages, and modulation of dendritic cells maturation. These key immunoregulatory properties of MSCs may be exerted either by produced soluble factors or by cell-cell contact interactions. To date, several clinical trials have been registered to assess the safety, efficacy, and therapeutic potential of MSCs in COVID-19. Moreover, MSC treatment may be effective for the reversion of ground-glass opacity of damaged lungs and reduce the tissue fibrosis. Taking into account the multifunctional properties of MSCs, the proposed stem-cell-based therapy may be proven significantly effective in critically-ill COVID-19 patients. The current therapeutic strategy may improve the patient’s overall condition and in parallel may decrease the mortality rate of the current disease.     

The role of CD4+FoxP3+ regulatory T cells in the immunopathogenesis of COVID-19: implications for treatment

The severe cases of Coronavirus Disease 2019 (COVID-19) frequently exhibit excessive inflammatory responses, acute respiratory distress syndrome (ARDS), coagulopathy, and organ damage. The most striking immunopathology of advanced COVID-19 is cytokine release syndrome or “cytokine storm” that is attributable to the deficiencies in immune regulatory mechanisms. CD4⁺FoxP3⁺ regulatory T cells (Tregs) are central regulators of immune responses and play an indispensable role in the maintenance of immune homeostasis. Tregs are likely involved in the attenuation of antiviral defense at the early stage of infection and ameliorating inflammation-induced organ injury at the late stage of COVID-19. In this article, we review and summarize the current understanding of the change of Tregs in patients infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and discuss the potential role of Tregs in the immunopathology of COVID-19. The emerging concept of Treg-targeted therapies, including both adoptive Treg transfer and low dose of IL-2 treatment, is introduced. Furthermore, the potential Treg-boosting effect of therapeutic agents used in the treatment of COVID-19, including dexamethasone, vitamin D, tocilizumab and sarilumab, chloroquine, hydroxychloroquine, azithromycin, adalimumab and tetrandrine, is discussed. The problems in the current study of Treg cells in COVID-19 and future perspectives are also addressed.     

Perspectives on mesenchymal stem/progenitor cells and their derivates as potential therapies for lung damage caused by COVID-19

The new coronavirus, severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), which emerged in December 2019 in Wuhan, China, has reached worldwide pandemic proportions, causing coronavirus disease 2019 (COVID-19). The clinical manifestations of COVID-19 vary from an asymptomatic disease course to clinical symptoms of acute respiratory distress syndrome and severe pneumonia. The lungs are the primary organ affected by SARS-CoV-2, with a very slow turnover for renewal. SARS-CoV-2 enters the lungs via angiotensin-converting enzyme 2 receptors and induces an immune response with the accumulation of immunocompetent cells, causing a cytokine storm, which leads to target organ injury and subsequent dysfunction. To date, there is no effective antiviral therapy for COVID-19 patients, and therapeutic strategies are based on experience treating previously recognized coronaviruses. In search of new treatment modalities of COVID-19, cell-based therapy with mesenchymal stem cells (MSCs) and/or their secretome, such as soluble bioactive factors and extracellular vesicles, is considered supportive therapy for critically ill patients. Multipotent MSCs are able to differentiate into different types of cells of mesenchymal origin, including alveolar epithelial cells, lung epithelial cells, and vascular endothelial cells, which are severely damaged in the course of COVID-19 disease. Moreover, MSCs secrete a variety of bioactive factors that can be applied for respiratory tract regeneration in COVID-19 patients thanks to their trophic, anti-inflammatory, immunomodulatory, anti-apoptotic, pro-regenerative, and proangiogenic properties.     

Dysregulation of the immune response in coronavirus disease 2019

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) can trigger a cytokine storm in the pulmonary tissue by releasing various types of mediators, leading to acute respiratory distress syndrome (ARDS). Increased neutrophil-to-lymphocyte ratio, as well as CD4+ T lymphopenia, is reported in cases with novel coronavirus disease (COVID-19), meanwhile, lymphopenia is a significant finding in the majority of COVID-19 cases with a severe phenotype. Moreover, excessive activation of monocyte/macrophage and cytokine storms are associated with the severity of the disease and the related complications in SARS-CoV-2 infection. Understanding the immune response dysregulation in COVID-19 is essential to develop more effective diagnostic, therapeutic, and prophylactic strategies in this pandemic.     

Clinical progress in MSC-based therapies for the management of severe COVID-19

Considering the high impact that severe Coronavirus disease 2019 (COVID-19) cases still pose on public health and their complex pharmacological management, the search for new therapeutic alternatives is essential. Mesenchymal stromal cells (MSCs) could be promising candidates as they present important immunomodulatory and anti-inflammatory properties that can combat the acute severe respiratory distress syndrome (ARDS) and the cytokine storm occurring in COVID-19, two processes that are mainly driven by an immunological misbalance. In this review, we provide a comprehensive overview of the intricate inflammatory process derived from the immune dysregulation that occurs in COVID-19, discussing the potential that the cytokines and growth factors that constitute the MSC-derived secretome present to treat the disease. Moreover, we revise the latest clinical progress made in the field, discussing the most important findings of the clinical trials conducted to date, which follow 2 different approaches: MSC-based cell therapy or the administration of the secretome by itself, as a cell-free therapy.     

Therapeutic prospects of mesenchymal stem/stromal cells in COVID-19 associated pulmonary diseases: From bench to bedside

The ongoing outbreak of coronavirus disease 2019 (COVID-19) caused by the novel severe acute respiratory syndrome coronavirus 2 has become a sudden public emergency of international concern and seriously threatens millions of people’s life health. Two current studies have indicated a favorable role for mesenchymal stem/stromal cells (MSCs) in clinical remission of COVID-19 associated pulmonary diseases, yet the systematical elaboration of the therapeutics and underlying mechanism is far from satisfaction. In the present review, we summarize the therapeutic potential of MSCs in COVID-19 associated pulmonary diseases such as pneumonia induced acute lung injury, acute respiratory distress syndrome, and pulmonary fibrosis. Furthermore, we review the underlying mechanism of MSCs including direct- and trans-differentiation, autocrine and paracrine anti-inflammatory effects, homing, and neovascularization, as well as constitutive microenvironment. Finally, we discuss the prospects and supervision of MSC-based cytotherapy for COVID-19 management before large-scale application in clinical practice. Collectively, this review supplies overwhelming new references for understanding the landscapes of MSCs in the remission of COVID-19 associated pulmonary diseases.     

Mesenchymal stem/stromal cells as adjuvant therapy in COVID-19-associated acute lung injury and cytokine storm: Importance of cell identification

Theoretically, mesenchymal stem cells (MSCs) are very promising as adjuvant therapy to alleviate coronavirus disease 2019 (COVID-19)-associated acute lung injury and cytokine storm. Several published studies, which used MSCs to alleviate COVID-19-associated acute lung injury and cytokine storm, reported promising results. However, the evidence came from a case report, case series, and clinical trials with a limited number of participants. Therefore, more studies are needed to get robust proof of MSC beneficial effects.     

A cytokine super cyclone in COVID-19 patients with risk factors: the therapeutic potential of BCG immunization

The seventh human coronavirus SARS-CoV2 belongs to the cluster of extremely pathogenic coronaviruses including SARS-CoV and MERS-CoV, which can cause fatal lower respiratory tract infection. Likewise, SARS-CoV2 infection can be fatal as the disease advances to pneumonia, followed by acute respiratory distress syndrome (ARDS). The development of lethal clinical symptons is associated with an exaggerated production of inflammatory cytokines, referred to as the cytokine storm, is a consequence of a hyperactivated immune response aginst the infection. In this article, we discuss the pathogenic consequences of the cytokine storm and its relationship with COVID-19 associated risk factors. The increased pro-inflammatory immune status in patients with risk factors (diabetes, hypertension, cardiovascular disease, COPD) exacerbates the Cytokine-storm of COVID-19 into a ‘Cytokine Super Cyclone’. We also evaluate the antiviral immune responses provided by BCG vaccination and the potential role of ‘trained immunity’ in early protection against SARS-CoV2.     

Secondary hemophagocytic lymphohistiocytosis versus cytokine release syndrome in severe COVID-19 patients

COVID-19 or SARS-CoV-2 infection can lead to severe acute respiratory distress syndrome/pneumonia with features of cytokine storm reminiscent of secondary hemophagocytic lymphohistiocytosis (HLH), which can be diagnosed by the calculated HScore. Recent reports have suggested favorable responses to the interleukin-1 receptor antagonist, anakinra in patients with COVID-19 associated secondary HLH. In our single institution study, we compared 14 COVID-19 cytokine storm patients with 10 secondary HLH patients seen immediately prior to the pandemic (non-COVID-19), to determine whether diagnostic features of secondary HLH were typically seen in COVID-19 patients presenting with cytokine storm. Although most of our COVID-19 patients did not fulfill diagnostic criteria for HLH, we hypothesize that identification of HLH may relate to the severity or timing of cytokine release. Based on our observations, we would suggest distinguishing between cytokine release syndrome and secondary HLH, reserving the latter term for cases fulfilling diagnostic criteria.Impact statementSevere COVID-19 associated pneumonia and acute respiratory distress syndrome has recently been described with life-threatening features of cytokine storm and loosely referred to as hemophagocytic lymphohistiocytosis (HLH) or macrophage activation syndrome (MAS). Although a recent report indicated favorable responses to the interleukin-1 receptor antagonist, anakinra in eight patients with COVID-19 secondary HLH diagnosed using the HScore calculation, others have suggested that the diagnosis of secondary HLH is uncommon and that the use of the HScore has limited value in guiding immunomodulatory therapy for COVID-19. Here, we provide additional perspective on this important controversy based upon comparisons between 14 COVID-19 cytokine storm patients and 10 secondary HLH patients seen immediately prior to the pandemic. We hypothesize that identification of HLH may relate to the severity or timing of cytokine release and suggest distinguishing between cytokine release syndrome and secondary HLH, reserving the latter term for cases fulfilling diagnostic criteria.     

Mesenchymal stem cells and COVID-19: What they do and what they can do

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) or coronavirus disease 2019 (COVID-19) pandemic has exhausted the health systems in many countries with thousands cases diagnosed daily. The currently used treatment guideline is to manage the common symptoms like fever and cough, but doesn’t target the virus itself or halts serious complications arising from this viral infection. Currently, SARS-CoV-2 exhibits many genetic modulations which have been associated with the appearance of highly contagious strains. The number of critical cases of COVID-19 increases markedly, and many of the infected people die as a result of respiratory failure and multiple organ dysfunction. The regenerative potential of mesenchymal stem cells (MSCs) has been extensively studied and confirmed. The impressive immunomodulation and anti-inflammatory activity of MSCs have been recognized as a golden opportunity for the treatment of COVID-19 and its associated complications. Moreover, MSCs regenerative and repairing abilities have been corroborated by many studies with positive outcomes and high recovery rates. Based on that, MSCs infusion could be an effective mechanism in managing and stemming the serious complications and multiple organ failure associated with COVID-19. In the present review, we discuss the commonly reported complications of COVID-19 viral infection and the established and anticipated role of MSCs in managing these complications.     

IL-6: Relevance for immunopathology of SARS-CoV-2

COVID-19 mortality is strongly associated with the development of severe pneumonia and acute respiratory distress syndrome with the worst outcome resulting in cytokine release syndrome and multiorgan failure. It is becoming critically important to identify at the early stage of the infection those patients who are prone to develop the most adverse effects. Elevated systemic interleukin-6 levels in patients with COVID-19 are considered as a relevant parameter in predicting most severe course of disease and the need for intensive care. This review discusses the mechanisms by which IL-6 may possibly contribute to disease exacerbation and the potential of therapeutic approaches based on anti-IL-6 biologics.     

Is COVID-19-associated cytokine storm distinct from non-COVID-19 secondary hemophagocytic lymphohistiocytosis?

Cytokine storm is an umbrella term that describes an inflammatory syndrome characterized by elevated levels of circulating cytokines and hyperactivation of innate and/or adaptive immune cells. One type of cytokine storm is hemophagocytic lymphohistiocytosis (HLH), which can be either primary or secondary. Severe COVID-19-associated pneumonia and acute respiratory distress syndrome (ARDS) can also lead to cytokine storm/cytokine release syndrome (CS/CRS) and, more rarely, meet criteria for the diagnosis of secondary HLH. Here, we review the immunobiology of primary and secondary HLH and examine whether COVID-19-associated CS/CRS can be discriminated from non-COVID-19 secondary HLH. Finally, we review differences in immunobiology between these different entities, which may inform both clinical diagnosis and treatment of patients.     

The NLRP3 inflammasome and COVID-19: Activation,pathogenesis and therapeutic strategies

Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), exhibits a wide spectrum of clinical presentations, ranging from asymptomatic cases to severe pneumonia or even death. In severe COVID-19 cases, an increased level of proinflammatory cytokines has been observed in the bloodstream, forming the so-called “cytokine storm”. Generally, nucleotide-binding oligomerization domain-like receptor containing pyrin domain 3 (NLRP3) inflammasome activation intensely induces cytokine production as an inflammatory response to viral infection. Therefore, the NLRP3 inflammasome can be a potential target for the treatment of COVID-19. Hence, this review first introduces the canonical NLRP3 inflammasome activation pathway. Second, we review the cellular/molecular mechanisms of NLRP3 inflammasome activation by SARS-CoV-2 infection (e.g., viroporins, ion flux and the complement cascade). Furthermore, we describe the involvement of the NLRP3 inflammasome in the pathogenesis of COVID-19 (e.g., cytokine storm, respiratory manifestations, cardiovascular comorbidity and neurological symptoms). Finally, we also propose several promising inhibitors targeting the NLRP3 inflammasome, cytokine products and neutrophils to provide novel therapeutic strategies for COVID-19.     

miRNAs; a novel strategy for the treatment of COVID-19

Coronavirus disease 2019 (COVID-19) is the seventh member of the bat severe acute respiratory syndrome family. COVID-19 can fuse their envelopes with the host cell membranes and deliver their genetic material. COVID-19 attacks the respiratory system and stimulates the host inflammatory responses, enhances the recruitment of immune cells, and promotes angiotensin-converting enzyme 2 activities. Patients with confirmed COVID-19 may have experienced fever, dry cough, headache, dyspnea, acute kidney injury, acute respiratory distress syndrome, and acute heart injury. Several strategies such as oxygen therapy, ventilation, antibiotic or antiviral therapy, and renal replacement therapy are commonly used to decrease COVID-19-associated mortality. However, these approaches may not be good treatment options. Therefore, the search for an alternative-novel therapy is urgently important to prevent the disease progression. Recently, microRNAs (miRNAs) have emerged as a promising strategy for COVID-19. The design of oligonucleotide against the genetic material of COVID-19 might suppress virus RNA translation. Several previous studies have shown that host miRNAs play an antiviral role and improve the treatment of patients with COVID-19. miRNAs by binding to the 3′-untranslated region (UTR) or 5′-UTR of viral RNA play an important role in COVID-19-host interplay and viral replication. miRNAs interact with multiple pathways and reduce inflammatory biomarkers, thrombi formation, and tissue damage to accelerate the patient outcome. The information in this review provides a summary of the current clinical application of miRNAs for the treatments of patients with COVID-19.     

Mechanism for the attenuation of neutrophil and complement hyperactivity by MSC exosomes

Complements and neutrophils are two key players of the innate immune system that are widely implicated as drivers of severe COVID-19 pathogenesis, as evident by the direct correlation of respiratory failure and mortality with elevated levels of terminal complement complex C5b-9 and neutrophils. In this study, we identified a feed-forward loop between complements and neutrophils that could amplify and perpetuate the cytokine storm seen in severe SARS-CoV-2–infected patients. We observed for the first time that the terminal complement activation complex C5b-9 directly triggered neutrophil extracellular trap (NET) release and interleukin (IL)-17 production by neutrophils. This is also the first report that the production of NETs and IL-17 induced by C5b-9 assembly on neutrophils could be abrogated by mesenchymal stem cell (MSC) exosomes. Neutralizing anti-CD59 antibodies abolished this abrogation. Based on our findings, we hypothesize that MSC exosomes could alleviate the immune dysregulation in acute respiratory failure, such as that observed in severe COVID-19 patients, by inhibiting complement activation through exosomal CD59, thereby disrupting the feed-forward loop between complements and neutrophils to inhibit the amplification and perpetuation of inflammation during SARS-CoV-2 infection.     

Mesenchymal stromal cell therapy for acute respiratory distress syndrome due to coronavirus disease 2019

Background aimsThe acute respiratory distress syndrome (ARDS) resulting from coronavirus disease 2019 (COVID-19) is associated with a massive release of inflammatory cytokines and high mortality. Mesenchymal stromal cells (MSCs) have anti-inflammatory properties and have shown activity in treating acute lung injury. Here the authors report a case series of 11 patients with COVID-19-associated ARDS (CARDS) requiring mechanical ventilation who were treated with remestemcel-L, an allogeneic MSC product, under individual patient emergency investigational new drug applications.MethodsPatients were eligible if they were mechanically ventilated for less than 72 h prior to the first infusion. Patients with pre-existing lung disease requiring supplemental oxygen or severe liver or kidney injury were excluded. Each patient received two infusions of remestemcel-L at a dose of 2 million cells/kg per infusion given 48–120 h apart.ResultsRemestemcel-L infusions were well tolerated in all 11 patients. At the end of the 28-day follow-up period, 10 (91%, 95% confidence interval [CI], 59–100%) patients were extubated, nine (82%, 95% CI, 48–97%) patients remained liberated from mechanical ventilation and were discharged from the intensive care unit and two (18%, 95 CI%, 2–52%) patients died. The median time to extubation was 10 days. Eight (73%, 95% CI, 34–100%) patients were discharged from the hospital. C-reactive protein levels significantly declined within 5 days of MSC infusion.ConclusionsThe authors demonstrate in this case series that remestemcel-L infusions to treat moderate to severe CARDS were safe and well tolerated and resulted in improved clinical outcomes.     

An Impaired Inflammatory and Innate Immune Response in COVID-19

The recent appearance of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has affected millions of people around the world and caused a global pandemic of coronavirus disease 2019 (COVID-19). It has been suggested that uncontrolled, exaggerated inflammation contributes to the adverse outcomes of COVID-19. In this review, we summarize our current understanding of the innate immune response elicited by SARS-CoV-2 infection and the hyperinflammation that contributes to disease severity and death. We also discuss the immunological determinants behind COVID-19 severity and propose a rationale for the underlying mechanisms.     

SARS-CoV-2 infection and oxidative stress: Pathophysiological insight into thrombosis and therapeutic opportunities

The current coronavirus disease 2019 (COVID-19) pandemic has presented unprecedented challenges to global health. Although the majority of COVID-19 patients exhibit mild-to-no symptoms, many patients develop severe disease and need immediate hospitalization, with most severe infections associated with a dysregulated immune response attributed to a cytokine storm. Epidemiological studies suggest that overall COVID-19 severity and morbidity correlate with underlying comorbidities, including diabetes, obesity, cardiovascular diseases, and immunosuppressive conditions. Patients with such comorbidities exhibit elevated levels of reactive oxygen species (ROS) and oxidative stress caused by an increased accumulation of angiotensin II and by activation of the NADPH oxidase pathway. Moreover, accumulating evidence suggests that oxidative stress coupled with the cytokine storm contribute to COVID-19 pathogenesis and immunopathogenesis by causing endotheliitis and endothelial cell dysfunction and by activating the blood clotting cascade that results in blood coagulation and microvascular thrombosis. In this review, we survey the mechanisms of how severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) induces oxidative stress and the consequences of this stress on patient health. We further shed light on aspects of the host immunity that are crucial to prevent the disease during the early phase of infection. A better understanding of the disease pathophysiology as well as preventive measures aimed at lowering ROS levels may pave the way to mitigate SARS-CoV-2-induced complications and decrease mortality.