Specific Clinical and Immunological Changes Following Mesenchymal Stem Cell Transplantation in COVID-19-induced Acute Respiratory Distress Syndrome Patients: A Phase-I Clinical Trial.

Acute respiratory distress syndrome (ARDS) is a systemic inflammation resulting from immune system overactivity. ARDS is also a fatal complication of COVID-19. Mesenchymal stem cells (MSCs) have immune modulatory properties. This study evaluated the safety and efficacy of three times transplantation of umbilical cord-derived MSCs (UC-MSCs) in terms of specific immunological and clinical changes in mild-to-moderate COVID-19-induced ARDS patients. In this single-center, open-label, phase 1 clinical trial, 20 patients diagnosed with COVID-19 and mild-to-moderate ARDS were included and were divided into two groups: a control group receiving standard care and an intervention group receiving UC-MSC in addition to standard care. Three consecutive intravenous transplants of UC-MSC (1×  cells/kg body weight per each transplant) were performed in the intervention group on days 1, 3, and 5. The biological assay was investigated four times (days 0, 5, 10, and 17). UC-MSCs improved the patients' clinical and paraclinical parameters, including leukocytosis, lymphopenia, thrombocytopenia, and liver enzyme abnormalities compared to the control group. They also decreased pro-inflammatory lymphocytes (TH1 and TH17) and increased anti-inflammatory T lymphocytes. Cell therapy also reduced the mean fluorescence intensity (MFI) in overactivated CD8+ T cells.  These findings show that three UC-MSC injections could regulate a hyperactivated immune system in COVID-19-induced ARDS patients by decreasing the inflammatory T lymphocyte subset and can improve the patient's hematological condition and liver function. However, more studies are needed in this area.

Mesenchymal stromal cell therapy for COVID-19-induced ARDS patients: a successful phase 1, control-placebo group, clinical trial.

BACKGROUND: Acute respiratory distress syndrome (ARDS) is the devastating complication of the new COVID-19 pandemic, directly correlated with releasing large amounts of inflammatory cytokines. Due to their immunoregulatory features, mesenchymal stromal cells (MSCs) provide a promising approach against this disease. In this regard, this study was designed as a single-center, open-label, phase 1 clinical trial with a control group to examine the safety and explore the possible potency of three injections of umbilical cord-derived MSCs (UC-MSCs) in mild-moderate COVID-19-induced ARDS patients. METHODS: Twenty confirmed COVID-19 patients with mild-to-moderate ARDS degree entered the study and were divided into two groups: control group (standard care) and intervention group (standard care + UC-MSCs). The patients received three intravenous infusions of UC-MSCs (1 × [Formula: see text] cells/kg BW per injection) every other day. Respiratory markers, CRP levels and specific serum cytokines were assessed four times (days of 0, 5, 10 and 17) during the 17-day follow-up period. RESULTS: During the study, there were no serious adverse effects after cell transplantations. Besides, significant improvement in SPO2/FIO2 ratio and serum CRP levels was observed. On the other hand, a significant decrease (P < 0.05) in serum cytokine levels of IL-6, IFN-g, TNF-α, IL-17 A and a significant increase in serum cytokine levels of TGF-B, IL-1B and IL-10 were observed. Also, no significant changes were observed in CT scan images of patients during the study period. CONCLUSION: Our obtained results demonstrated that multiple intravenous transplantations of allogenic UC-MSCs in non-severe COVID-19-induced ARDS patients are a safe procedure. In addition, this intervention is a hopeful approach to decline cytokine storm and recover respiratory functions. Indeed, more clinical trials with larger sample sizes are required to confirm these results. Trial registration This clinical trial was registered with the Iranian Registry of Clinical Trials (ID: IRCT20160809029275N1 at 2020.05.30).

Regenerative therapy by using mesenchymal stem cells-derived exosomes in COVID-19 treatment. The potential role and underlying mechanisms.

COVID-19 disease caused by the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), started in December 2019 in Wuhan, China, and quickly became the global pandemic. The high spread rate, relatively high mortality rate, and the lack of specific medicine have led researchers and clinicians worldwide to find new treatment strategies. Unfortunately, evidence shows that the virus-specific receptor Angiotensin-Converting Enzyme 2 (ACE-2) is present on the surface of most cells in the body, leading to immune system dysfunction and multi-organ failure in critically ill patients. In this context, the use of Mesenchymal Stem Cells (MSCs) and their secret has opened new therapeutic horizons for patients due to the lack of ACE2 receptor expression. MSCs exert their beneficial therapeutic actions, particularly anti-inflammatory and immunomodulatory properties, mainly through paracrine effects which are mediated by exosomes. Exosomes are bilayer nanovesicles that carry a unique cargo of proteins, lipids and functional nucleic acids based on their cell origin. This review article aims to investigate the possible role of exosomes and the underlying mechanism involved in treating COVID-19 disease based on recent findings.

Regenerative therapy by using Mesenchymal Stem Cells-derived exosomes in COVID-19 treatment. The potential role and underlying mechanisms

COVID-19 disease caused by the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), started in December 2019 in Wuhan, China, and quickly became the global pandemic. The high spread rate, relatively high mortality rate, and the lack of specific medicine have led researchers and clinicians worldwide to find new treatment strategies. Unfortunately, evidence shows that the virus-specific receptor Angiotensin-Converting Enzyme 2 (ACE-2) is present on the surface of most cells in the body, leading to immune system dysfunction and multi-organ failure in critically ill patients. In this context, the use of Mesenchymal Stem Cells (MSCs) and their secret has opened new therapeutic horizons for patients due to the lack of ACE2 receptor expression. MSCs exert their beneficial therapeutic actions, particularly anti-inflammatory and immunomodulatory properties, mainly through paracrine effects which are mediated by exosomes. Exosomes are bilayer nanovesicles that carry a unique cargo of proteins, lipids and functional nucleic acids based on their cell origin. This review article aims to investigate the possible role of exosomes and the underlying mechanism involved in treating COVID-19 disease based on recent findings.

Are mesenchymal stem cells able to manage cytokine storm in COVID-19 patients? A review of recent studies.

The Covid-19 disease has recently become one of the biggest challenges globally, and there is still no specific medication. Findings showed the immune system in severe Covid-19 patients loses regulatory control of pro-inflammatory cytokines, especially IL-6 production, called the "Cytokine storm" process. This process can cause injury to vital organs, including lungs, kidneys, liver, and ultimately death if not inhibited. While many treatments have been proposed to reduce cytokine storm, but the safety and effectiveness of each of them are still in doubt. Mesenchymal stem cells (MSCs) are multipotent cells with self-renewal potential capable of suppressing overactive immune responses and leading to tissue restoration and repair. These immuno-modulatory properties of MSCs and their derivatives (like exosomes) can improve the condition of Covid-19 patients with serious infectious symptoms caused by adaptive immune system dysfunction. Many clinical trials have been conducted in this field using various MSCs around the world. Some of these have been published and summarized in the present article, while many have not yet been completed. Based on these available data, MSCs can reduce inflammatory cytokines, increase oxygen saturation, regenerate lung tissue and improve clinical symptoms in Covid-19 patients. The review article aims to collect available clinical data in more detail and investigate the role of MSCs in reducing cytokine storms as well as improving clinical parameters of Covid-19 patients for use in future clinical studies.