Mesenchymal Stem Cells: Case Report of an Adjuvant Ambulatory Therapy for a COVID-19 High-Risk and steroid-hypersensitive Patient.

INTRODUCTION: Due to the rapid progression of COVID-19 to severe and critical stages, thousands of patients have required the use of intensive care unit (ICU) treatment, placing an excessive strain on health systems. Immunomodulatory effects of Wharton's Jelly Mesenchymal Stem Cells (WJ-MSCs) have shown promising results on the treatment of patients with COVID-19. However, the effect of promptly applied cell therapy on ambulatory patient prognosis has not been described. This case report presents the clinical outcome of a multimorbid, steroid-hypersensitive, COVID-19 patient treated with WJ-MSCs transplantation. CASE PRESENTATION: A 67-year-old woman with Type 2 diabetes, overweight (82 kg, 168 cm, BMI = 29.053), hypertension (60/190 mmHg) and steroid-hypersensitivity, tested positive for COVID-19 after presenting typical symptoms such as fatigue, chest pain, myalgia, nasal congestion, dysgeusia, anosmia and oxygen saturation (SpO2) 94% - 96%, with normal body temperature (36°C). The patient received pharmacologic treatment but, when symptoms worsened, WJ-MSCs were transplanted to modulate the suspected onset of the cytokine release syndrome. Significant improvement of symptoms and clinical parameters (inflammatory markers and CT score) were observed, and the patient fully recovered within a short period of time. CONCLUSION: The present case report exhibits the favorable outcome of using Wharton's Jelly Mesenchymal Stem Cells (WJ-MSCs) as an ambulatory and adjuvant therapy for COVID-19. Prompt WJ-MSCs infusion can be a safe ambulatory adjuvant therapy in COVID-19 infection care, preventing disease progression to critical stages and avoiding hospital overcrowding.

Efficacy and safety of human umbilical cord-derived mesenchymal stem cells for COVID-19 pneumonia: a meta-analysis of randomized controlled trials.

BACKGROUND: Elevated levels of inflammatory factors are associated with poor prognosis in coronavirus disease-19 (COVID-19). However, mesenchymal stem cells (MSCs) have immunomodulatory functions. Accordingly, this meta-analysis aimed to determine the efficacy and safety of MSC-based therapy in patients with COVID-19 pneumonia. METHODS: Online global databases were used to find relevant studies. Two independent researchers then selected and evaluated the studies for suitability while the Cochrane risk of bias tool determined the quality of all articles and Cochran's Q test and I2 index assessed the degree of heterogeneity in the principal studies. Statistical analysis was performed using Review Manager software, and the effect of each study on the overall estimate was evaluated by sensitivity analysis. RESULTS: Seven studies were included in the meta-analysis, and all MSCs used in the trials were acquired from the umbilical cord. The results of these studies (n = 328) indicated that patients with COVID-19 pneumonia who received MSCs had a 0.58 risk of death compared with controls (95% CI = 0.38, 0.87; P = 0.53; I2 = 0%). In terms of inflammatory biomarkers, MSCs reduced the levels of C-reactive protein (n = 88; MD = - 32.49; 95% CI = - 48.43, - 16.56; P = 0.46; I2 = 0%) and interferon-gamma (n = 44; SMD = - 1.23; 95% CI = - 1.89, - 0.57; P = 0.37; I2 = 0%) in severe COVID-19 patients but had no significant effect on interleukin-6 (n = 185; MD = - 0.75; 95% CI = - 7.76, 6.27; P = 0.57; I2 = 0%). A summary of the data revealed no significant differences in adverse events (n = 287) or serious adverse events (n = 229) between the MSC and control groups. CONCLUSIONS: Infusion of umbilical cord-derived MSCs is an effective strategy for treating patients with COVID-19 pneumonia, with no noticeable adverse effects.

The Anti-Viral Activity of Stem Cells: A Rational Explanation for their Use in Clinical Application.

It is well established the importance of stem cells (SCs) in tissue growth, regeneration and repair, given their ability to self-renew and differentiate into mature cells. Stem cells are present in all individuals and are potentially active to the end of life. However, less is known about their unique function within the immune system as immune regulators and their important task in viral protection. Antiviral resistance is a common mechanism in all cells though stem cells utilize an antiviral RNA interference (RNAi) mechanism, while adult cells react by using the interferondependent repression pathway via interferon-associated protein-based response to induce an antiviral response. Therefore, the idea behind this review is to highlight the mechanisms of viral evasion of host defense, which would then allow us to highlight the rationale use of autologous stem cells and their biochemical and immunological ability to reset the subverted immune responses. Recently, scientists have highlighted their use in the field of immune-therapy, establishing the possibilities of using them outside the conventional protocol with the advancement in manipulating these cells in such a way that specific body activity can be restored. This paper describes the remarkable SCs profile and discusses some ideas regarding their promising use in vivo.

COVID 19 and Stem Cell Therapy: Treatment and Challenges

COVID-19, an extremely contagious disease is showing high rate of infection and fatality, posing a major problem to the population. COVID-19 develops hypoxic respiratory failure. COVID and ARDS both lead to failure of multiple organs. According to WHO, as of 10 June 2022, 532,201,219 confirmed cases of COVID-19 and 6,305,358 deaths have been reported globally. Primary available protection against this SARS-CoV-2 is population-based vaccination which has reduced the infection risk. Yet, SARS-CoV-2 virus continues to be a mystery, as many aspects such as transmission, infection and therapy, are still being studied. Various mutations have been incurred in the Coronavirus due to which potential efficacy of COVID vaccines has reduced. Therefore, the development of supplementary antiCovid19 strategy is still a top priority globally. As a new emergent therapeutic method for COVID-19, stem cell therapy and its derived organoid models have attracted a lot of attention. Stem cells, specifically mesenchymal stem cells (MSCs), have potent tissue healing, anti-inflammatory and immunomodulatory characteristics that might be used to treat COVID-19 patients with damaged organs like lungs and ARDS and compromised immune system. In present review, we have discussed rationality of MSC treatment for COVID-19 as well as the prospects and challenges of utilizing MSCs as a treatment approach in COVID-19. © 2023 World Research Association. All rights reserved.

A Flash on Cell Therapy Strategies in Clinical Trials against SARS-CoV-2

Background: Since December 2019, an outbreak of a novel coronavirus infection has been reported, drawing immediate attention from the World Health Organization. SARS-CoV-2, as the cause of COVID-19 with extra potency of transmission, has led to global concern. Currently, more than a thousand clinical trials have focused on achieving a protective or preventive approach against the virus, among which cell-based therapies seem to be significantly applicable. Objective(s): We aimed to summarize cell-based therapy against COVID-19 and compare the applicable methods and possible outcomes. Method(s): The current clinical trials based on cell-based therapies are summarized according to the cell sorting applications. The possible approaches, advantages, and opinions are discussed. Results and Conclusion(s): Cell-based therapy has already brought some hope. It needs to meet the following features: 1) The long-term protection data after treatment must be provided by stem cell investigators. 2) A design of multivalent antigens based on immunoinformatic prediction is suggest-ed to engineer T-cell and dendritic cell-based therapies in order to deliver the most immunogenic conserved epitopes. 3) According to the sophisticated procedure, the preparation of the cells must be supported by authorities in order to decrease the cost and the time of the whole process.Copyright © 2022 Bentham Science Publishers.

The Emergence of Novel Coronavirus Disease, Global Treatment Update and its Containment Strategies in Overpopulated Countries: A Review

The ongoing pandemic of the novel coronavirus SARS-CoV-2 (COVID-19) has created a major challenge for the public health worldwide. The reported cases indicate that the outbreak is more widespread than initially assumed. Around 18 million people have been infected with 689,000 reported deaths (August 2020;the number is increasing daily);with a high mutation rate, this virus poses an even more serious threat worldwide. The actual source of COVID-19 is still un-clear;even if the initial reports link it to the Chinese seafood wet market in Wuhan, other animals such as birds, snakes, and many small mammals including bats are also linked with this novel coro-navirus. The structure of the COVID-19 shows distinctive proteins among which spike proteins have a pivotal role in host cell attachment and virus-cell membrane fusion in order to facilitate virus infection. Currently, no specific antiviral treatment or vaccine is available. Various drug can-didates, including SARS-CoV and MERS-CoV protease inhibitors, neuraminidase inhibitors, RNA synthesis inhibitors, ACE2 inhibitors and lungs supportive therapy, are under trials. Cell-based therapy also appeared with remarkable treatment possibilities. In this article, we endeavored to succinctly cover the current and available treatment options, including pharmaceuticals, cell-based therapy, and traditional medicine. We also focused on the extent of damages by this novel coron-avirus in India, Pakistan, and Bangladesh;the strategies adopted and the research activities initiat-ed so far by these densely populated countries (neighboring China) are explained in this review.Copyright © 2021 Bentham Science Publishers.

Total Stromal Fraction (TSF)-Fortified Adipose Tissue-Derived Stem Cells Source: An Emerging Regenerative Realm Against COVID-19 In-duced Pulmonary Compromise

The inception of the COVID-19 pandemic has jeopardized humanity with markedly dam-pening of worldwide resources. The viral infection may present with varying signs and symptoms, imitating pneumonia and seasonal flu. With a gradual course, this may progress and result in the deadliest state of acute respiratory distress syndrome (ARDS) and acute lung injury (ALI). More-over, following recovery from the severe brunt of COVID-19 infection, interstitial portions of alve-oli have been found to undergo residual scarring and further to have compromised air exchange. Such alterations in the lung microenvironment and associated systemic manifestations have been recognized to occur due to the extensive release of cytokines. The mortality rate increases with advancing age and in individuals with underlying co-morbidity. Presently, there is no availability of specific antiviral therapy or any other definitive modality to counter this progressive worsening. However, we believe principles and advancing cell-based therapy may prove fruitful in subjugating such reported worsening in these patients. This article reviews eminent knowledge and relevant ad-vancements about the amelioration of lung damage due to COVID-19 infection using adipose tis-sue-derived-total stromal fraction (TSF).Copyright © 2022 Bentham Science Publishers.

Emerging role of mesenchymal stem/stromal cells (MSCs) and MSCs-derived exosomes in bone- and joint-associated musculoskeletal disorders: a new frontier.

Exosomes are membranous vesicles with a 30 to 150 nm diameter secreted by mesenchymal stem/stromal cells (MSCs) and other cells, such as immune cells and cancer cells. Exosomes convey proteins, bioactive lipids, and genetic components to recipient cells, such as microRNAs (miRNAs). Consequently, they have been implicated in regulating intercellular communication mediators under physiological and pathological circumstances. Exosomes therapy as a cell-free approach bypasses many concerns regarding the therapeutic application of stem/stromal cells, including undesirable proliferation, heterogeneity, and immunogenic effects. Indeed, exosomes have become a promising strategy to treat human diseases, particularly bone- and joint-associated musculoskeletal disorders, because of their characteristics, such as potentiated stability in circulation, biocompatibility, low immunogenicity, and toxicity. In this light, a diversity of studies have indicated that inhibiting inflammation, inducing angiogenesis, provoking osteoblast and chondrocyte proliferation and migration, and negative regulation of matrix-degrading enzymes result in bone and cartilage recovery upon administration of MSCs-derived exosomes. Notwithstanding, insufficient quantity of isolated exosomes, lack of reliable potency test, and exosomes heterogeneity hurdle their application in clinics. Herein, we will deliver an outline respecting the advantages of MSCs-derived exosomes-based therapy in common bone- and joint-associated musculoskeletal disorders. Moreover, we will have a glimpse the underlying mechanism behind the MSCs-elicited therapeutic merits in these conditions.

Systematic review and meta-analysis of randomized controlled trials of mesenchymal stromal cells to treat coronavirus disease 2019: is it too late?

BACKGROUND AIMS: Evidence regarding the extent that mesenchymal stromal cells (MSCs) may improve clinical outcomes in patients with coronavirus disease 2019 (COVID-19) has been limited by marked inter-study heterogeneity, inconsistent product characterization and appreciable risk of bias (RoB). Given the evolution of treatment options and trajectory of the pandemic, an updated analysis of high-quality evidence from randomized controlled trials is needed for a timely and conclusive understanding of the effectiveness of MSCs. METHODS: A systematic literature search through March 30, 2022, identified all English language, full-text randomized controlled trials examining the use of MSCs in the treatment of COVID-19. RESULTS: Eight studies were identified (316 patients, 165 administered MSCs and 151 controls). Controls evolved significantly over time with a broad range of comparison treatments. All studies reported mortality at study endpoint. Random effects meta-analysis revealed that MSCs decreased relative risk of death (risk ratio, 0.63, 95% confidence interval, 0.42-0.94, P = 0.02, I2 = 14%) with no significant difference in absolute risk of death. MSCs decreased length of hospital stay and C-reactive protein levels and increased odds of clinical improvement at study endpoint compared with controls. Rates of adverse events and severe adverse events were similar between MSC and control groups. Only two (25%) studies reported all four International Society for Cell & Gene Therapy criteria for MSC characterization. Included studies had low (n = 7) or some (n = 1) concerns regarding RoB. CONCLUSIONS: MSCs may reduce risk of death in patients with severe or critical COVID-19 and improve secondary clinical outcomes. Variable outcome reporting, inconsistent product characterization and variable control group treatments remain barriers to higher-quality evidence and may constrain clinical usage. A master protocol is proposed and appears necessary for accelerated translation of higher-quality evidence for future applications of MSC therapy.

Impact of Remdesivir on the kidney and Potential Protective Capacity of Granulocyte-Colony Stimulating Factor Versus Bone Marrow Mesenchymal Stem Cells in Adult Male Albino Rats

Background: Remdesivir is a novel broad spectrum antiviral drug previously used to treat Ebola. It is a pro-drug nucleoside with antiviral activity that is opposed to SARS-CoV-2 and coronavirus. Aim: Current research was planned to evaluate and compare the potential ameliorative impact of the hematopoietic-stem-cell mobilized by the granulocyte colony-stimulating factor (G-CSF) versus BM-MSC on the effect of novel antiviral remdesivir on the kidney. Materials and Methods: Rats divided into four groups: control group, Remdesivir treated group (20 mg/kg/day IV on the first day followed by 10 mg/kg/day for 6 days), Remdesivir + BM-MSCs group (3x106 cells/ml of PKH26 labelled MSC) and Remedesivir+ Filgrastim group (70 μg/kg/day/5 days). At the end of the experiment, animals were anaesthetized and sacrificed. Both animal kidneys were excised for histological, immunohistochemistry, and electron microscopy studies. Biochemical and morphometric assessments had been performed. Results: Remdesivir caused distortion and degeneration of both the glomeruli and the renal tubules associated with Bowman's space widening. It greatly increased the deposition of collagen and enhanced the expression of caspase 3, IL-6, and TGF-β1. Ultrastructure changes were observed in the form of thickening of glomerular basement membrane, dilated basal plasma membrane infoldings of tubular epithelium and mitochondrial degeneration. Biochemically, decreased antioxidant enzymes, reduced glutathione (GSH), superoxide dismutase (SOD), and catalase (CAT) with increased serum urea and creatinine were also recorded. Both BM-MSCs and G-CSF improved histological structure and function of the kidney. Conclusion: Prescribing drugs such as remdesivir should be carried out with severe care. BM-MSCs and G-CSF are an efficient and ideal option to protect patients from irreversible kidney damage. © 2022. All rights served.

The promising approach of MSCs therapy for COVID-19 treatment.

Several ongoing investigations have been founded on the development of an optimized therapeutic strategy for the COVID-19 virus as an undeniable acute challenge for human life. Cell-based therapy and particularly, mesenchymal stem cells (MSCs) therapy has obtained desired outcomes in decreasing the mortality rate of severe acute respiratory syndrome coronavirus 2 (SARS-COV-2), mainly owing to its immunoregulatory impact that prevents the overactivation of the immune system. Also, these cells with their multipotent nature, are capable of repairing the damaged tissue of the lung which leads to reducing the probability of acute respiratory distress syndrome (ARDS). Although this cell-based method is not quite cost-effective for developing countries, regarding its promising results in order to treat SARS-COV-2, more economical evaluation as well as clinical trials should be performed for improving this therapeutic approach. Here in this article, the functional mechanism of MSCs therapy for the treatment of COVID-19 and the clinical trials based on this method will be reviewed. Moreover, its economic efficiency will be discussed.

COVID 19 and Stem Cell Therapy: Treatment and Challenges

COVID-19, an extremely contagious disease is showing high rate of infection and fatality, posing a major problem to the population. COVID-19 develops hypoxic respiratory failure. COVID and ARDS both lead to failure of multiple organs. According to WHO, as of 10 June 2022, 532,201,219 confirmed cases of COVID-19 and 6,305,358 deaths have been reported globally. Primary available protection against this SARS-CoV-2 is population-based vaccination which has reduced the infection risk. Yet, SARS-CoV-2 virus continues to be a mystery, as many aspects such as transmission, infection and therapy, are still being studied. Various mutations have been incurred in the Coronavirus due to which potential efficacy of COVID vaccines has reduced. Therefore, the development of supplementary antiCovid19 strategy is still a top priority globally. As a new emergent therapeutic method for COVID-19, stem cell therapy and its derived organoid models have attracted a lot of attention. Stem cells, specifically mesenchymal stem cells (MSCs), have potent tissue healing, anti-inflammatory and immunomodulatory characteristics that might be used to treat COVID-19 patients with damaged organs like lungs and ARDS and compromised immune system. In present review, we have discussed rationality of MSC treatment for COVID-19 as well as the prospects and challenges of utilizing MSCs as a treatment approach in COVID-19.

Mesenchymal Stem Cell-Derived Extracellular Vesicles for Therapeutic Use and in Bioengineering Applications.

Extracellular vesicles (EVs) are small lipid bilayer-delimited particles that are naturally released from cells into body fluids, and therefore can travel and convey regulatory functions in the distal parts of the body. EVs can transmit paracrine signaling by carrying over cytokines, chemokines, growth factors, interleukins (ILs), transcription factors, and nucleic acids such as DNA, mRNAs, microRNAs, piRNAs, lncRNAs, sn/snoRNAs, mtRNAs and circRNAs; these EVs travel to predecided destinations to perform their functions. While mesenchymal stem cells (MSCs) have been shown to improve healing and facilitate treatments of various diseases, the allogenic use of these cells is often accompanied by serious adverse effects after transplantation. MSC-produced EVs are less immunogenic and can serve as an alternative to cellular therapies by transmitting signaling or delivering biomaterials to diseased areas of the body. This review article is focused on understanding the properties of EVs derived from different types of MSCs and MSC-EV-based therapeutic options. The potential of modern technologies such as 3D bioprinting to advance EV-based therapies is also discussed.

Mesenchymal stromal cells as treatment for acute respiratory distress syndrome. Case Reports following hematopoietic cell transplantation and a review.

Acute respiratory distress syndrome (ARDS) is a life-threatening lung disease. It may occur during the pancytopenia phase following allogeneic hematopoietic cell transplantation (HCT). ARDS is rare following HCT. Mesenchymal stromal cells (MSCs) have strong anti-inflammatory effect and first home to the lung following intravenous infusion. MSCs are safe to infuse and have almost no side effects. During the Covid-19 pandemic many patients died from ARDS. Subsequently MSCs were evaluated as a therapy for Covid-19 induced ARDS. We report three patients, who were treated with MSCs for ARDS following HCT. Two were treated with MSCs derived from the bone marrow (BM). The third patient was treated with MSCs obtained from the placenta, so-called decidua stromal cells (DSCs). In the first patient, the pulmonary infiltrates cleared after infusion of BM-MSCs, but he died from multiorgan failure. The second patient treated with BM-MSCs died of aspergillus infection. The patient treated with DSCs had a dramatic response and survived. He is alive after 7 years with a Karnofsky score of 100%. We also reviewed experimental and clinical studies using MSCs or DSCs for ARDS. Several positive reports are using MSCs for sepsis and ARDS in experimental animals. In man, two prospective randomized placebo-controlled studies used adipose and BM-MSCs, respectively. No difference in outcome was seen compared to placebo. Some pilot studies used MSCs for Covid-19 ARDS. Positive results were achieved using umbilical cord and DSCs however, optimal source of MSCs remains to be elucidated using randomized trials.

Infection of Bone Marrow-Derived Mesenchymal Stem Cells with Virulent Newcastle Disease Virus Maximizes Cytokine Production: A Step Toward vNDV Immunotherapy

Newcastle Disease (ND) vaccines are being used for more than 7 decades, the disease is still a major challenge for poultry industry both locally and internationally. ND frequently emerges in highly vaccinated flocks causing high economic losses without specific treatment. Mesenchymal stem cells (MSCs) are a group of pluripotent cells with multiple biotechnology applications, including but not limited to tissue genesis, tissue repair, hematopoiesis, and immune modulation. Therapeutic strategies based on the usage of stem cells includes the cells either themselves or their secretions (secretome), which has recently shown ability to inhibit SARS-CoV2 replication in-vitro. In this study, MSCs were prepared from the bone marrow of native Egyptian Fayoumi chicken. The MSC with the surface marker CD105 (CD105+) were magnetically separated and infected with virulent Newcastle disease virus (vNDV). The virusinduced multiple changes at the cellular and ultrastructural level in the infected cells, and it was able to maximize the production of interferon-gamma (IFNγ) and interleukin 2 (IL2), interleukin 6 (IL6) and interleukin 12 (IL12). In conclusion, our data represent a preliminary step in vNDV immunotherapy where MSCs media could be used for the treatment of vNDV in infected flocks © 2022 by the authors. Licensee ResearchersLinks Ltd, England, UK

Integration of FDOSM and FWZIC Under Homogeneous Fermatean Fuzzy Environment: A Prioritization of COVID-19 Patients for Mesenchymal Stem Cell Transfusion

Mesenchymal stem cell (MSC) transfusion has shown promising results in treating COVID-19 cases despite the limited availability of these MSCs. The task of prioritizing COVID-19 patients for MSC transfusion based on multiple criteria is considered a multi-attribute decision-analysis (MADA) problem. Although literature reviews have assessed the prioritization of COVID-19 patients for MSCs, issues arising from imprecise, unclear and ambiguous information remain unresolved. Compared with the existing MADA methods, the robustness of the fuzzy decision by opinion score method (FDOSM) and fuzzy-weighted zero inconsistency (FWZIC) is proven. This study adopts and integrates FDOSM and FWZIC in a homogeneous Fermatean fuzzy environment for criterion weighting followed by the prioritization of the most eligible COVID-19 patients for MSC transfusion. The research methodology had two phases. The decision matrices of three COVID-19 emergency levels (moderate, severe, and critical) were adopted based on an augmented dataset of 60 patients and discussed in the first phase. The second phase was divided into two subsections. The first section developed Fermatean FWZIC (F-FWZIC) to weigh criteria across each emergency level of COVID-19 patients. These weights were fed to the second section on adopting Fermatean FDOSM (F-FDOSM) for the purpose of prioritizing COVID-19 patients who are the most eligible to receive MSCs. Three methods were used in evaluating the proposed works, and the results included systematic ranking, sensitivity analysis, and benchmarking checklist.

Cellular therapies in ARDS

Acute respiratory distress syndrome (ARDS) is a critical illness characterized by a severe hypoxemic respiratory failure, caused by an inflammatory response which results in diffuse lung damage. Despite decades of research, the treatment of ARDS remains supportive. However, in recent years, cell-based therapies have been the subject of intensive ongoing research efforts, showing relevant therapeutic potential in preclinical ARDS models. Among all the different cells that have been identified as suitable candidates for use, mesenchymal stromal cells (MSCs) have been the most attractive candidates and have generated significant interest. MSCs are multipotent adult stem/stromal cells that can modulate the immune response and enhance repair of damaged tissue in multiple in vivo models. Their promising effect seems to be not primarily mediated by MSCs differentiation and engraftment but more by the paracrine release of different soluble mediators and cellular components such as extracellular vesicles (EVs). Preclinical experiments have provided encouraging evidence for the therapeutic potential of MSCs, leading to the launch of several phase I and II clinical trials that have shown safety of MSCs in ARDS, which became very common nowadays due to the Coronavirus disease (COVID-19) pandemic. However, some translational challenges have yet to be solved, such as the reproducibility of cell harvest, storage, reconstitution, and administration of cells/cell-products, before the therapeutic potential of stem cells therapies can be realized. ©2022 The Author(s). Published by MRE Press.

Efficacy of umbilical cord mesenchymal stromal cells for COVID-19: A systematic review and meta-analysis.

Objectives: A major challenge for COVID-19 therapy is dysregulated immune response associated with the disease. Umbilical cord mesenchymal stromal cells (UC-MSCs) may be a promising candidate for COVID-19 treatment owing to their immunomodulatory and anti-inflammatory functions. Therefore, this study aimed to evaluate the effectiveness of UC-MSCs inpatients with COVID-19. Method: Medline, Embase, PubMed, Cochrane Library, and Web of Science databases were searched to collect clinical trials concerning UC-MSCs for the treatment of COVID-19. After literature screening, quality assessment, and data extraction, a systematic review and meta-analysis of the included study were performed. Results: This systematic review and meta-analysis were prospectively registered on PROSPERO, and the registration number is CRD42022304061. After screening, 10 studies involving 293 patients with COVID-19 were eventually included. Our meta-analysis results showed that UC-MSCs can reduce mortality (relative risk [RR] =0.60, 95% confidence interval [CI]: [0.38, 0.95], P=0.03) in COVID-19 patients. No significant correlation was observed between adverse events and UC-MSC treatment (RR=0.85, 95% CI: [0.65, 1.10], P=0.22; RR=1.00, 95%CI: [0.64, 1.58], P=1.00). In addition, treatment with UC-MSCs was found to suppress inflammation and improve pulmonary symptoms. Conclusions: UC-MSCs hold promise as a safe and effective treatment for COVID-19. Systematic Review Registartion: PROSPERO, identifier CRD42022304061.

Translating MSC Therapy in the Age of Obesity.

Mesenchymal stromal cell (MSC) therapy has seen increased attention as a possible option to treat a number of inflammatory conditions including COVID-19 acute respiratory distress syndrome (ARDS). As rates of obesity and metabolic disease continue to rise worldwide, increasing proportions of patients treated with MSC therapy will be living with obesity. The obese environment poses critical challenges for immunomodulatory therapies that should be accounted for during development and testing of MSCs. In this review, we look to cancer immunotherapy as a model for the challenges MSCs may face in obese environments. We then outline current evidence that obesity alters MSC immunomodulatory function, drastically modifies the host immune system, and therefore reshapes interactions between MSCs and immune cells. Finally, we argue that obese environments may alter essential features of allogeneic MSCs and offer potential strategies for licensing of MSCs to enhance their efficacy in the obese microenvironment. Our aim is to combine insights from basic research in MSC biology and clinical trials to inform new strategies to ensure MSC therapy is effective for a broad range of patients.

Immunomodulatory Mechanisms of Mesenchymal Stem Cells and Their Potential Clinical Applications.

Mesenchymal stem cells (MSCs) are multipotent stem cells with the capacity of self-renewal, homing, and low immunogenicity. These distinct biological characteristics have already shown immense potential in regenerative medicine. MSCs also possess immunomodulatory properties that can maintain immune homeostasis when the immune response is over-activated or under-activated. The secretome of MSCs consists of cytokines, chemokines, signaling molecules, and growth factors, which effectively contribute to the regulation of immune and inflammatory responses. The immunomodulatory effects of MSCs can also be achieved through direct cell contact with microenvironmental factors and immune cells. Furthermore, preconditioned and engineered MSCs can specifically improve the immunomodulation effects in diverse clinical applications. These multifunctional properties of MSCs enable them to be used as a prospective therapeutic strategy to treat immune disorders, including autoimmune diseases and incurable inflammatory diseases. Here we review the recent exploration of immunomodulatory mechanisms of MSCs and briefly discuss the promotion of the genetically engineered MSCs. Additionally, we review the potential clinical applications of MSC-mediated immunomodulation in four types of immune diseases, including systemic lupus erythematosus, Crohn's disease, graft-versus-host disease, and COVID-19.