Opportunities and challenges of COVID-19 therapy using mesenchymal stem cells and their exosomes

BACKGROUND: Corona Virus Disease 2019 (COVID-19) is a highly contagious, rapidly variable, and dangerous infectious disease. However, no specific and effective treatment for COVID-19 is available until now. The safety and efficacy of mesenchymal stem cells and their exosomes have been well verified in numerous clinical trials. Their immunomodulatory and tissue regeneration capabilities may support them as a prospective therapy for COVID-19 application in the clinic. OBJECTIVE: To focus on the development, pathogenesis and the current treatment status of COVID-19, efficacy and possible immunomodulatory mechanisms of mesenchymal stem cells and their exosomes for COVID-19 so as to provide new insights into the clinical treatment for the disease in the future. METHODS: Articles were searched on PubMed and CNKI with the key words of "SARS-CoV-2, COVID-19, cytokine storm, acute respiratory distress syndrome, mesenchymal stem cells, exosomes, immune regulation, tissue repair” in Chinese and English. Finally, 64 articles were collected for this review. RESULTS AND CONCLUSION: Acute respiratory distress syndrome and acute lung injury caused by cytokine storm are the primary precipitating factors of death in individuals with COVID-19. Mesenchymal stem cells and their exosomes can effectively treat the symptoms of acute respiratory distress syndrome and repair the damaged lung tissue in COVID-19 patients by reducing the cytokine storm and promoting the regeneration of alveolar epithelial cells through the interaction with immune cells and their paracrine effects. All of these investigations confirmed that mesenchymal stem cells and their exosomes can fight the COVID-19 infection, and this might be a promising, safe and effective strategy. However, more preclinical studies and randomized, controlled clinical trials are needed to conduct the biodistribution, metabolic fate, and the potential treatment risks of mesenchymal stem cells and their derived exosomes in vivo to fully exploit their clinical efficacy. © 2023, Publishing House of Chinese Journal of Tissue Engineering Research. All rights reserved.

Cytokine Release Syndrome and Treatment in COVID-19

The emergent outbreak of coronavirus disease 2019 (COVID-19) is a global health problem and has been recognized as a pandemic. Although COVID-19 leads to mild flu-like symptoms in most patients, the disease may cause frequently fatal, severe complications, such as acute respiratory distress syndrome and cytokine release syndrome. In these patients, defects in lymphocytic cytolytic activity trigger the proinflammatory cytokine cascade, and then "cytokine storm” begins. As a result, it leads to uncontrolled active macrophage entry into the tissues and hemophagocytosis. Here, the responses of host cells, cytokine release syndrome and the therapeutic approaches to alleviate the cytokine storm in COVID-19 will be reviewed.

Sleep as a likely immunomodulation agent: novel approach in the treatment of COVID-19

The potential advantages of sleep concerning suppressing cytokine storms and inflammation in coronavirus disease 2019 (COVID-19) based on its immunopathogenesis are summarized in the current study. COVID-19 as a global pandemic in the past months has afflicted many people. Clinical properties, pathology, and the pathogenesis of acute respiratory disorder caused by coronaviruses or other pathogens are evidence implying the probable contribution of oxidation, excessive inflammation, and excessive immune response, particularly cytokine storm, to the pathology of COVID-19. According to findings by experimental and clinical research on animals and in humans, sleep loss impairs immune function. Sleep loss strongly influences peripheral levels of the immune response's inflammatory mediators, which is accomplished by the generation of various hormones and mediators during sleep. There are a large number of studies supporting the presence of reciprocal regulation between low-intensity inflammatory response and sleep. By improving sleep quality and at the same time adjusting the circadian rhythm, it may be possible to prevent infections and boost immunity. As a result, sufficient (or even more) sleep duration may lower susceptibility to COVID-19 infection as well as increase antibody levels. © 2023 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group.

The Impact of the Association between Periodontitis and Coronavirus Disease Infection on Oral and Systemic Complications. Review

Several risk factors have been associated with severe coronavirus disease and include factors such as advanced age and sex (male) and comorbidities such as obesity and the presence of underlying diseases (eg, hypertension, cardiovascular disease, cerebrovascular disease, chronic kidney disease, and diabetes). These predisposing conditions share several standard features that could explain why they are associated with worse disease outcomes. Persistent and uncontrolled inflammation is a key manifestation of several diseases, such as periodontitis, cardiovascular diseases, neurodegenerative diseases, diabetes, and coronavirus disease infection. The oral cavity is a reservoir for respiratory pathogens, especially among patients with poor oral hygiene and periodontitis, and dysregulated inflammatory and immune response. In fact, periodontal pockets in the elderly have been associated with increased risk of mortality from pneumonia, and periodontitis patients are more likely to develop hospital -acquired, pneumonia than healthy ones are.Conclusions;Periodontitis shares several common features with coronavirus disease including similarities in comorbidities and effects on systemic inflammation. However, further research would be needed to confirm these hypotheses.

Can BCG Vaccine Be a Potential Tool for COVID-19?

SARS-CoV-2 has affected essentially all countries worldwide and caused millions of people to become infected and die. Therefore, it is extremely valuable to investigate new approaches to stop the most scarring ongoing pandemic. BCG vaccine has been proposed that it could reduce the rate of new COVID cases and limit the severity of infection since TB and COVID-19 have similar dominant effects, such as cytokine storm and improper immune response. This review aimed to focus on the latest literature data on trained immunity as well as the possible cross protection effect of BCG vaccine against COVID-19. The first immune response to BCG vaccines has started with the stimulation of adaptive immune response and establishment of the immunological memory of antigen-specific T and B cells to target infectious agents. In the past years, innate immune response was thought to be not having the talent to adapt and "learn” from previous exposure to a pathogen. Trained immunity is conceivable as 'de facto' innate immune system memory. Some researches argue that there is a strong relationship between BCG immunization and COVID-19 although some are against this argument. Based on the data obtained from different research studies and ongoing clinical trials, there is still no evidence that BCG vaccine is effective against COVID-19. Besides assumptions, knowns and unknowns, the clinical efficiency of BCG vaccine against SARS-CoV-2 should be validated by accurate scientific clinical reports in different age groups to understand the potential benefits of BCG vaccine to limit COVID-19 incidence and mortality.

Utility of the HScore for Predicting COVID-19 Severity.

BACKGROUND: Cytokine release syndrome is a life-threatening condition known to cause fever and multiple organ dysfunction and is suspected to be related to the severity of coronavirus disease 2019 (COVID-19). We sought to examine the utility of the HScore and non-cytokine markers of inflammation for predicting COVID-19 outcomes. We hypothesized that cytokine storm, assessed by a modified HScore, would be linked to more severe COVID-19 symptoms and higher mortality. METHODS:  A retrospective review of records from a large, private hospital system was conducted on patients with hemophagocytic lymphohistiocytosis (HLH) (2014-2019) and compared to a large cohort of COVID-19-positive patients (2020). Patients with a sufficient number of elements in their record for a modified HScore calculation (n=4663), were further subdivided into population 1 (POP1, n=67; HLH, n=493 COVID-19), which had eight HScore elements, and population 2 (POP2) with six available HScore elements (POP2, n=102; HLH, n=4561 COVID-19). RESULTS: Modified HScore predicted COVID-19 severity in POP1 and POP2 as measured by higher odds of being on a ventilator (POP2 OR: 1.46, CI: 1.42-1.5), ICU admission (POP2 OR: 1.38, CI: 1.34-1.42), a longer length of stay (p<0.0001), and higher mortality (POP2 OR: 1.34, CI: 1.31-1.39). C-reactive protein (CRP) and white blood cell (WBC) count were the most consistent non-cytokine predictors of COVID-19 severity. CONCLUSION:  Cytokine storm, evaluated using a modified HScore, appeared to play a role in the severity of COVID-19 infection, and selected non-cytokine markers of inflammation were predictive of disease severity.

Beneficial Effects of L-Arginine in Patients Hospitalized for COVID-19: New Insights from a Randomized Clinical Trial.

We have recently demonstrated in a double-blind randomized trial the beneficial effects of L-Arginine in patients hospitalized for COVID-19. We hypothesize that one of the mechanisms underlying the favorable effects of L-Arginine is its action on inflammatory cytokines. To verify our hypothesis, we measured longitudinal plasma levels of pro-inflammatory and anti-inflammatory cytokines implied in the pathophysiology of COVID-19 in patients randomized to receive oral L-Arginine or placebo. The study was successfully completed by 169 patients. Patients in the L-Arginine arm had a reduced respiratory support evaluated at 10 and 20 days; moreover, the time to hospital discharge was significantly shorter in the L-Arginine group. The assessment of circulating cytokines revealed that L-Arginine significantly reduced the circulating levels of pro-inflammatory IL-2, IL-6, and IFN-γ and increased the levels of the anti-inflammatory IL-10. Taken together, these findings indicate that adding L-Arginine to standard therapy in COVID-19 patients markedly reduces the need of respiratory support and the duration of in-hospital stay; moreover, L-Arginine significantly regulates circulating levels of pro-inflammatory and anti-inflammatory cytokines.

The effect of Fingolimod on patients with moderate to severe COVID-19.

Hyper-inflammation, cytokine storm, and recruitment of immune cells lead to uncontrollable endothelial cell damage in patients with coronavirus disease 2019 (COVID-19). Sphingosine 1-phosphate (S1P) signaling is needed for endothelial integrity and its decreased serum level is a predictor of clinical severity in COVID-19. In this clinical trial, the effect of Fingolimod, an agonist of S1P, was evaluated on patients with COVID-19. Forty patients with moderate to severe COVID-19 were enrolled and divided into two groups including (1) the control group (n = 21) receiving the national standard regimen for COVID-19 patients and (2) the intervention group (n = 19) that prescribed daily Fingolimod (0.5 mg) for 3 days besides receiving the standard national regimen for COVID-19. The hospitalization period, re-admission rate, intensive care unit (ICU) administration, need for mechanical ventilation, and mortality rate were assessed as primary outcomes in both groups. The results showed that re-admission was significantly decreased in COVID-19 patients who received Fingolimod compared to the controls (p = .04). In addition, the hemoglobin levels of the COVID-19 patients in the intervention group were increased compared to the controls (p = .018). However, no significant differences were found regarding the intubation or mortality rate between the groups (p > .05). Fingolimod could significantly reduce the re-admission rate after hospitalization with COVID-19. Fingolimod may not enhance patients' outcomes with moderate COVID-19. It is necessary to examine these findings in a larger cohort of patients with severe to critical COVID-19.

Effects of Tocilizumab on Inflammation and Iron Metabolism in Critically Ill Patients with COVID-19.

COVID-19 produces cytokine-mediated persistent inflammation and is associated with elevated iron stores and low circulating iron. It is believed that central to the pathophysiological mechanism is interleukin 6 and hepcidin. A state of iron overload, termed hyperferritinemia, and inflammatory anemia take place. Both conditions are linked to a worse result in critically ill patients. Blocking the interleukin 6-hepcidin pathway with Tocilizumab could present favorable outcomes. The aim of this study was to evaluate if Tocilizumab influences survival, the occurrence of sepsis, anemia and transfusions in critically ill patients suffering from COVID-19. This prospective observational study focused on levels of interleukin 6, hepcidin and blood iron parameters in patients treated with Tocilizumab. Data were compared before and after therapy as well as between treated and control groups. Results indicate that there is no difference in terms of survival nor in the rate of anemia or sepsis occurrence. Hepcidin was elevated and anemia ensued after treatment, which could indicate alternative pathways. In conclusion, when the classic interleukin 6-hepcidin pathway is blocked, inflammation seems to use alternative routes. Further understanding of these pathways is required and new pharmacological therapies need to be developed to treat persistent inflammation.

Hyperinflammatory Response in COVID-19: A Systematic Review.

COVID-19 is a multisystemic disease caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The immunopathogenic conditions of the hyperinflammatory response that cause systemic inflammation are extremely linked to its severity. This research sought to review the immunopathological elements that contribute to its progression. This is a systematic review using the PUBMED, LILACS, MEDLINE, and SCIELO databases using articles between May 2020 and July 2022 with the following search terms in conjunction with "AND": "SARS-CoV-2"; "COVID-19"; "ARDS" and "Cytokine Storm". The quality appraisal and risk of bias were assessed by the JBI checklists and the Cochrane Collaboration's RoB 2.0 and ROBINS-I tools, respectively, and the risk of bias for in vitro studies by a pre-defined standard in the literature. The search resulted in 39 articles. The main actors in this response denote SARS-CoV-2 Spike proteins, cellular proteases, leukocytes, cytokines, and proteolytic cascades. The "cytokine storm" itself brings several complications to the host through cytokines such as IL-6 and chemokines (such as CCL2), which influence tissue inflammation through apoptosis and pyroptosis. The hyperinflammatory response causes several unfavorable outcomes in patients, and systemic inflammation caused largely by the dysregulation of the immune response should be controlled for their recovery.

Clinical Consequences for Individuals Treated with Tocilizumab for Serious COVID-19 Infection.

There seem to currently be no therapeutic medications found for the severe coronavirus infection in 2019 (COVID-19). In light of this, it has been hypothesized that the immunomodulatory treatment known as tocilizumab can lessen the inflammatory response that occurs in the respiratory system, speed up the process of clinical benefit, lower the risk of death, and avert the need for ventilators. This randomized controlled trial (RCT) studied patients with a proven infection of SARS-CoV-2 and hyperinflammatory reactions. The inclusion criteria included fever (body temperature > 38 °C), pulmonary infiltrates, or supplemental oxygen. The patients received either conventional treatment with one dose of either tocilizumab (8 mg per kilogram of body weight) or conventional treatment only. The subjects were randomized to receive either treatment with a 1:1 ratio. A time-to-event test was conducted to determine the time to intubation or death. There was an insignificant difference between the investigated groups regarding the time to death, time to mechanical ventilation, and percentage of deaths. The conventional group's median (IQR) hospital length of stay was 4 (3-6) days, whereas the tocilizumab therapy group was 7 (4.75-10) days. There was a substantial difference in the mechanical ventilation rates in both groups, which were 17 (34%) and 28 (56%), respectively. In hospitalized patients with severe illness and COVID-19, tocilizumab was ineffective in preventing intubation or death. Trials must be larger, however, in order to exclude the potential benefits or harms.

Role of Neutrophil Extracellular Traps in COVID-19 Progression: An Insight for Effective Treatment.

The coronavirus disease 2019 (COVID-19), caused by SARS-CoV-2, has resulted in a pandemic with over 270 million confirmed cases and 5.3 million deaths worldwide. In some cases, the infection leads to acute respiratory distress syndrome (ARDS), which is triggered by a cytokine storm and multiple organ failure. Clinical hematological, biochemical, coagulation, and inflammatory markers, such as interleukins, are associated with COVID-19 disease progression. In this regard, neutrophilia, neutrophil-to-lymphocyte ratio (NLR), and neutrophil-to-albumin ratio (NAR), have emerged as promising biomarkers of disease severity and progression. In the pathophysiology of ARDS, the inflammatory environment induces neutrophil influx and activation in the lungs, promoting the release of cytokines, proteases, reactive oxygen species (ROS), and, eventually, neutrophil extracellular traps (NETs). NETs components, such as DNA, histones, myeloperoxidase, and elastase, may exert cytotoxic activity and alveolar damage. Thus, NETs have also been described as potential biomarkers of COVID-19 prognosis. Several studies have demonstrated that NETs are induced in COVID-19 patients, and that the highest levels of NETs are found in critical ones, therefore highlighting a correlation between NETs and severity of the disease. Knowledge of NETs signaling pathways, and the targeting of points of NETs release, could help to develop an effective treatment for COVID-19, and specifically for severe cases, which would help to manage the pandemic.

Inosine: a broad-spectrum anti-inflammatory against SARS-CoV-2 infection-induced acute lung injury via suppressing TBK1 phosphorylation.

SARS-CoV-2-induced cytokine storms constitute the primary cause of COVID-19 progression, severity, criticality, and death. Glucocorticoid and anti-cytokine therapies have been frequently administered to treat COVID-19 but have had limited clinical efficacy in severe and critical cases. Nevertheless, the weaknesses of these treatment modalities have prompted the development of anti-inflammatory therapy against this infection. We found that the broad-spectrum anti-inflammatory agent inosine downregulated proinflammatory IL-6, upregulated anti-inflammatory IL-10, and ameliorated acute inflammatory lung injury caused by multiple infectious agents. Inosine significantly improved survival in mice infected with SARS-CoV-2. It indirectly impeded TANK-binding kinase 1 (TBK1) phosphorylation by binding stimulator of interferon genes (STING) and glycogen synthase kinase-3ß (GSK3ß), inhibited the activation and nuclear translocation of the downstream transcription factors IRF3 and NF-κB, and downregulated IL-6 in the sera and lung tissues of mice infected with lipopolysaccharide (LPS), H1N1, or SARS-CoV-2. Thus, inosine administration is feasible for clinical anti-inflammatory therapy against severe and critical COVID-19. Moreover, targeting TBK1 is a promising strategy for inhibiting cytokine storms and mitigating acute inflammatory lung injury induced by SARS-CoV-2 and other infectious agents.

Interleukin 6: A biomarker for COVID-19 progression.

COVID-19 was discovered in China for the first time in December 2019 and was declared a pandemic by the World Health Organization on March 11, 2020. Due to its rapid geographic expansion over the last three years, it has now become a global health issue. The infection is caused by SARS-CoV-2, which is obtained from a zoonotic source and transmitted directly or through contact. Following exposure, the immune system becomes hyperactive resulting in the production of pro-inflammatory cytokines, particularly interleukin-6 (IL-6), a naturally occurring pleiotropic cytokine that plays a significant role in respiratory failure and multi-organ dysfunction. This massive inflammatory phenomenon is reminiscent of cytokine release syndrome (CRS) or "cytokine storm", which may be at the root of many severe complications. In fact, serum IL-6 levels are significantly high in patients with severe Covid-19 disease. The goal of treatment is to change the cytokine's concentration or activity. Interleukin-6 production could be inhibited, reducing inflammation and so serving as a therapeutic target. anti-interleukin-6 receptor monoclonal antibodies have been proven to reduce the severity of COVID-19 in clinical trials aimed at clarifying the function of immunoregulation. As a result, the Il-6 assay is a reliable predictor of morbidity and mortality at the time of infection diagnosis. The aim of our study is to highlight the role of interleukin 6 as biomarker of the COVID- 19 progression.

Diminution of STING Expression in the Blood of Patients with Severe or Critical COVID-19 Pneumonia.

INTRODUCTION: Cytokine storm and critical COVID-19 pneumonia are caused in at least 10% of patients by inborn errors of or auto-Abs to type I IFNs. The pathogenesis of life-threatening COVID-19 pneumonia in other patients remains unknown. METHODS: This study was conducted at Masih Daneshvari Hospital, Tehran, Iran. In the period of study, 75 confirmed cases of COVID-19 with presentations ranging from mild upper respiratory tract infection to lower respiratory tract infection, including moderate, severe, and critical disease, were recruited. Expression of STING mRNA was measured in peripheral blood mononuclear cells (PBMCs) and compared between patients with different severity and outcome. RESULTS: There was a significant negative correlation between age and STING expression level (p value = 0.010). Patients with "severe to critical" illness had a 20-fold lower STING expression level compared to the "mild to moderate" group (p value = 0.001). Also, the results showed lower expressions of STING in the patients admitted to the ICU (p value = 0.015). Patients who finally died had lower expression of STING at the time of sampling (p value = 0.041). CONCLUSION: STING mRNA expression in PBMCs was significantly lower in older COVID-19 cases, the patients with more severe illness, who needed intensive care, and who eventually died.

Repurposing of drugs targeting the cytokine storm induced by SARS-CoV-2.

A cytokine storm is one of the leading causes of acute respiratory distress syndrome (ARDS) and sepsis-associated multiple organ failure in many respiratory viral infections, including severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The coronavirus disease 2019 (COVID-19) pandemic has caused millions of deaths worldwide, resulting in an urgent need for effective therapeutic interventions. Repurposing immunosuppressive drugs that target cytokines with immunomodulatory properties is a promising approach to counteract SARS-CoV-2-induced ARDS at the infective and post-infective stages. In this minireview, we examine drugs targeting IL-1ß, IL-4/IL-13, IL-6 and TNF-α tested in COVID-19 patients.

The role of serum circulating microbial toxins in severity and cytokine storm of COVID positive patients.

The emergence of Coronavirus disease 2019 (Covid-19) is a global problem nowadays, causing health difficulty with increasing mortality rates, which doesn't have a verified treatment. SARS-CoV-2 infection has various pathological and epidemiological characteristics, one of them is increased amounts of cytokine production, which in order activate an abnormal unrestricted response called "cytokine storm". This event contributes to severe acute respiratory distress syndrome (ARDS), which results in respiratory failure and pneumonia and is the great cause of death associated with Covid-19. Endotoxemia and the release of bacterial lipopolysaccharides (endotoxins) from the lumen into the bloodstream enhance proinflammatory cytokines. SARS-CoV-2 can straightly interplay with endotoxins via its S protein, leading to the extremely elevating release of cytokines and consequently increase the harshness of Covid-19. In this review, we will discuss the possible role of viral-bacterial interaction that occurs through the transfer of bacterial products such as lipopolysaccharide (LPS) from the intestine into the bloodstream, exacerbating the severity of Covid-19 and cytokine storms.

A storm in a teacup -- A biomimetic lung microphysiological system in conjunction with a deep-learning algorithm to monitor lung pathological and inflammatory reactions.

Creating a biomimetic in vitro lung model to recapitulate the infection and inflammatory reactions has been an important but challenging task for biomedical researchers. The 2D based cell culture models - culturing of lung epithelium - have long existed but lack multiple key physiological conditions, such as the involvement of different types of immune cells and the creation of connected lung models to study viral or bacterial infection between different individuals. Pioneers in organ-on-a-chip research have developed lung alveoli-on-a-chip and connected two lung chips with direct tubing and flow. Although this model provides a powerful tool for lung alveolar disease modeling, it still lacks interactions among immune cells, such as macrophages and monocytes, and the mimic of air flow and aerosol transmission between lung-chips is missing. Here, we report the development of an improved human lung physiological system (Lung-MPS) with both alveolar and pulmonary bronchial chambers that permits the integration of multiple immune cells into the system. We observed amplified inflammatory signals through the dynamic interactions among macrophages, epithelium, endothelium, and circulating monocytes. Furthermore, an integrated microdroplet/aerosol transmission system was fabricated and employed to study the propagation of pseudovirus particles containing microdroplets in integrated Lung-MPSs. Finally, a deep-learning algorithm was developed to characterize the activation of cells in this Lung-MPS. This Lung-MPS could provide an improved and more biomimetic sensory system for the study of COVID-19 and other high-risk infectious lung diseases.

Opportunities and challenges of COVID-19 therapy using mesenchymal stem cells and their exosomes

BACKGROUND: Corona Virus Disease 2019 (COVID-19) is a highly contagious, rapidly variable, and dangerous infectious disease. However, no specific and effective treatment for COVID-19 is available until now. The safety and efficacy of mesenchymal stem cells and their exosomes have been well verified in numerous clinical trials. Their immunomodulatory and tissue regeneration capabilities may support them as a prospective therapy for COVID-19 application in the clinic. OBJECTIVE: To focus on the development, pathogenesis and the current treatment status of COVID-19, efficacy and possible immunomodulatory mechanisms of mesenchymal stem cells and their exosomes for COVID-19 so as to provide new insights into the clinical treatment for the disease in the future. METHODS: Articles were searched on PubMed and CNKI with the key words of "SARS-CoV-2, COVID-19, cytokine storm, acute respiratory distress syndrome, mesenchymal stem cells, exosomes, immune regulation, tissue repair” in Chinese and English. Finally, 64 articles were collected for this review. RESULTS AND CONCLUSION: Acute respiratory distress syndrome and acute lung injury caused by cytokine storm are the primary precipitating factors of death in individuals with COVID-19. Mesenchymal stem cells and their exosomes can effectively treat the symptoms of acute respiratory distress syndrome and repair the damaged lung tissue in COVID-19 patients by reducing the cytokine storm and promoting the regeneration of alveolar epithelial cells through the interaction with immune cells and their paracrine effects. All of these investigations confirmed that mesenchymal stem cells and their exosomes can fight the COVID-19 infection, and this might be a promising, safe and effective strategy. However, more preclinical studies and randomized, controlled clinical trials are needed to conduct the biodistribution, metabolic fate, and the potential treatment risks of mesenchymal stem cells and their derived exosomes in vivo to fully exploit their clinical efficacy. (English) [ FROM AUTHOR]