SARS-CoV- 2 continues to evolve, producing novel Omicron subvariants through recombinant lineages that acquire new mutations, undermining existing antiviral strategies. The viral fitness and adaptive potential of SARS-CoV- 2 present significant challenges to emergency treatments, particularly monoclonal antibodies, which demonstrate reduced efficacy with the emergence of each new variant. Consequently, immunocompromised individuals, who are more susceptible to severe manifestations of COVID- 19 and face heightened risks of critical complications and mortality, remain vulnerable in the absence of effective emergency treatments. To develop translational approaches that can benefit this at-risk population and establish broader therapeutic strategies applicable across variants, we previously designed and engineered in silico miniACE2 decoys (designated BP2, BP9, and BP11). These decoys demonstrated promising efficacy in neutralizing Omicron subvariants. In this study, we leveraged the therapeutic potential of mesenchymal stromal cells (MSCs) for tissue repair and immunomodulation in lung injuries and used these cells as a platform for the secretion of BP2. Our innovative assays, which were conducted with the BP2 protein secreted into the culture supernatant of BP2-MSCs, demonstrated the potential for neutralizing SARS-CoV- 2, including Omicron subvariants. The development of these advanced therapeutic platforms holds significant promise for scalability to effectively mitigate the impact of severe COVID- 19, contributing to broader and more resilient treatment strategies against the evolving landscape of SARS-CoV- 2 variants.

Mesenchymal stem/stromal cells (MSCs) offer promising therapeutic potential in cell-based therapies for various diseases. However, the safety of genetically modified MSCs remains poorly understood. This study aimed to evaluate the general toxicity and safety of Wharton's Jelly-Derived MSCs (WJ-MSCs) engineered to express the antimicrobial peptide SE-33 in an animal model. Genetically modified WJ-MSCs expressing SE-33 were administered to C57BL/6 mice at both therapeutic and excessive doses, either once or repeatedly. Animal monitoring included mortality, clinical signs, and behavioral observations. The toxicity assessment involved histopathological, hematological, and biochemical analyses of major organs and tissues, while immunotoxicity and immunogenicity were examined through humoral and cellular immune responses, macrophage phagocytic activity, and lymphocyte blast transformation. Antimicrobial efficacy was evaluated in a Staphylococcus aureus-induced pneumonia model by monitoring animal mortality and assessing bacterial load and inflammatory processes in the lungs. Mice receiving genetically modified WJ-MSCs exhibited no acute or chronic toxicity, behavioral abnormalities, or pathological changes, regardless of the dose or administration frequency. No significant immunotoxicity or alterations in immune responses were observed, and there were no notable changes in hematological or biochemical serum parameters. Infected animals treated with WJ-MSC-SE33 showed a significant reduction in bacterial load and lung inflammation and improved survival compared to control groups, demonstrating efficacy over native WJ-MSCs. Our findings suggest that WJ-MSCs expressing SE-33 are well tolerated, displaying a favorable safety profile comparable to native WJ-MSCs and potent antimicrobial activity, significantly reducing bacterial load, inflammation, and mortality in an S. aureus pneumonia model. These data support the safety profile of WJ-MSCs expressing SE-33 as a promising candidate for cell-based therapies for bacterial infections, particularly those complicated by antibiotic resistance.

The Coronavirus Disease 2019 (COVID-19), caused by virus SARS-CoV-2, is characterized by massive inflammation and immune system imbalance. Despite the implementation of vaccination protocols, the accessibility of treatment remains uneven. Furthermore, the persistent threat of new variants underscores the urgent need for expanded research into therapeutic options for SARS-CoV-2. Mesenchymal stem cells (MSCs) are known for their immunomodulatory potential through the release of molecules into the extracellular space, either as soluble elements or carried by extracellular vesicles (EVs). The aim of this study was to evaluate the anti-inflammatory potential of EVs obtained from human adipose tissue (ASC-EVs) against SARS-CoV-2 infection. ASC-EVs were purified by size-exclusion chromatography, and co-culture assays confirmed that ASC-EVs were internalized by human lung cells and could colocalize with SARS-CoV-2 into early and late endosomes. To determine the functionality of ASC-EVs, lung cells were infected with SARS-CoV-2 in the presence of increasing concentrations of ASC-EVs, and the release of cytokines, chemokines and viruses were measured. While SARS-CoV-2 replication was significantly reduced only at the highest concentrations tested, multiplex analysis highlighted that lower concentrations of ASC-EV sufficed to prevent the production of immune modulators. Importantly, ASC-EVs did not contain detectable inflammatory cytokines, nor did they trigger inflammatory mediators, nor affect cellular viability. In conclusion, this work suggests that ASC-EVs have the potential to attenuate inflammation by decreasing the production of pro-inflammatory cytokines in lung cells following SARS-CoV-2 infection.

Sjögren's syndrome (SS) is a systemic autoimmune disease, with major symptoms including dry mouth and dry eyes, for which there is no effective treatment. Recent studies have demonstrated that mesenchymal stem cells (MSCs) are effective in the treatment of SS, but the efficacy of allogeneic MSCs is affected by variability among different cell donors, and they are easily cleared by the immune system of the recipient. Autologous MSCs are one of the ideal options for the treatment of SS; however, their function decreases with age. Regenerative fibroblast (rFib) is a type of new MSC obtained through chemical reprogramming technology from skin fibroblasts. In this study, we report the safety and efficacy of intravenous infusion of autologous rFib in a volunteer with SS.

In March 2021, the volunteer was diagnosed with SS due to positive anti-SSB antibodies, lymphocyte infiltration in the lip gland, dry eyes, and a large area of purpura in both lower limbs. From May 2021 to November 2022, she received allogeneic Umbilical cord mesenchymal stem cells (UCMSC) therapy (5.0 × 107 UCMSCs per time, totaling 10 infusions), but her condition did not improve. In May 2023, the rFib for the volunteer was prepared, meeting the quality standard of T/CSCB0003-2021 Human Mesenchymal Stem Cells. Between October 2023 and June 2024, the volunteer received a total of 12 intravenous transfusions of autologous rFib. After the treatments, the volunteer experienced no recurrence of purpura in both lower limbs. Symptoms of dry mouth, dry eyes, and fatigue were relieved. ESR, B lymphocytes, rheumatoid factor IgM, and IgA declined, while the proportion of NK cells increased, and most of the cytokines returned to normal levels. In vitro experiments showed that rFib could significantly inhibit the proliferation of T lymphocytes after PHA stimulation. No adverse effects were associated with the use of rFib in the volunteer during the clinical trial.

The results of this clinical trial indicate that intravenous injections of autologous rFib are both safe and effective for treating SS. Autologous rFib may be more suitable for treating autoimmune diseases than allogeneic MSCs.

Diabetes is one of the major diseases and concerns of public health systems that affects over 200 million patients worldwide. It is estimated that 90% of these patients suffer from diabetes type 2, while 10% present diabetes type 1. This type of diabetes and certain types of diabetes type 2, are characterized by dysregulation of blood glycemic levels due to the total or partial depletion of insulin-secreting pancreatic β-cells. Different approaches have been proposed for long-term treatment of insulin-dependent patients; amongst them, cell-based approaches have been the subject of basic and clinical research since they allow blood glucose level sensing and in situ insulin secretion. The current gold standard for insulin-dependent patients is on-demand exogenous insulin application; cell-based therapies aim to remove this burden from the patient and caregivers. In recent years, protocols to isolate and implant pancreatic islets from diseased donors have been developed and tested in clinical trials. Nevertheless, the shortage of donors, along with the need of immunosuppressive companion therapies, have pushed researchers to focus their attention and efforts to overcome these disadvantages and develop alternative strategies. This review discusses current tested clinical approaches and future potential alternatives for diabetes type 1, and some diabetes type 2, insulin-dependent patients. Additionally, advantages and disadvantages of these discussed methods.

Advances in stem cell technology offer new possibilities for patients with untreated diseases and disorders. Stem cell-based therapy, which includes multipotent mesenchymal stem cells (MSCs), has recently become important in regenerative therapies. MSCs are multipotent progenitor cells that possess the ability to undergo in vitro self-renewal and differentiate into various mesenchymal lineages. MSCs have demonstrated promise in several areas, such as tissue regeneration, immunological modulation, anti-inflammatory qualities, and wound healing. Additionally, the development of specific guidelines and quality control methods that ultimately result in the therapeutic application of MSCs has been made easier by recent advancements in the study of MSC biology. This review discusses the latest clinical uses of MSCs obtained from the umbilical cord (UC), bone marrow (BM), or adipose tissue (AT) in treating various human diseases such as pulmonary dysfunctions, neurological disorders, endocrine/metabolic diseases, skin burns, cardiovascular conditions, and reproductive disorders. Additionally, this review offers comprehensive information regarding the clinical application of targeted therapies utilizing MSCs. It also presents and examines the concept of MSC tissue origin and its potential impact on the function of MSCs in downstream applications. The ultimate aim of this research is to facilitate translational research into clinical applications in regenerative therapies.

Hepatocellular carcinoma (HCC) ranks as the most prevalent of primary liver cancers and stands as the third leading cause of cancer-related deaths. Early-stage HCC can be effectively managed with available treatment modalities ranging from invasive techniques, such as liver resection and thermoablation, to systemic therapies primarily employing tyrosine kinase inhibitors. Unfortunately, these interventions take a significant toll on the body, either through physical trauma or the adverse effects of pharmacotherapy. Consequently, there is an understandable drive to develop novel HCC therapies. Adipose-derived stem cells (ADSCs) are a promising therapeutic tool. Their facile extraction process, coupled with the distinctive immunomodulatory capabilities of their secretome, make them an intriguing subject for investigation in both oncology and regenerative medicine. The factors they produce are both enzymes affecting the extracellular matrix (specifically, metalloproteinases and their inhibitors) as well as cytokines and growth factors affecting cell proliferation and invasiveness. So far, the interactions observed with various cancer cell types have not led to clear conclusions. The evidence shows both inhibitory and stimulatory effects on tumor growth. Notably, these effects appear to be dependent on the tumor type, prompting speculation regarding their potential inhibitory impact on HCC. This review briefly synthesizes findings from preclinical and clinical studies examining the effects of ADSCs on cancers, with a specific focus on HCC, and emphasizes the need for further research.

Efficacy of mesenchymal stem cells (MSCs) for treatment of acute respiratory distress syndrome (ARDS) suggests bioactive bone marrow MSC extracellular vesicles (BM-MSC EVs) may be effective. A patient with severe COVID-19 associated ARDS who was presumed to expire was treated with a BM-MSC EV preparation (14 doses over two months) as a rescue treatment for refractory COVID ARDS. Near complete reversal of lung inflammation and fibrosis (per computed tomography), near complete restoration of mobility, hospital discharge (3 months) with resumption of normal activities of daily living (one year) and return to work occurred. No adverse events occurred despite repeated dosing of investigational product, highlighting safety of this potential therapy for ARDS.

COVID-19 is a new infectious disease caused by the severe acute respiratory syndrome coronavirus 2 (SARS CoV-2). Since the outbreak in December 2019, it has caused an unprecedented world pandemic, leading to a global human health crisis. Although SARS CoV-2 mainly affects the lungs, causing interstitial pneumonia and severe acute respiratory distress syndrome, a number of patients often have extensive clinical manifestations, such as gastrointestinal symptoms, cardiovascular damage and renal dysfunction.

This review article discusses the pathogenic mechanisms of cardiovascular damage in COVID-19 patients and provides some useful suggestions for future clinical diagnosis, treatment and prevention.

An English-language literature search was conducted in PubMed and Web of Science databases up to 12th April, 2024 for the terms "COVID-19", "SARS CoV-2", "cardiovascular damage", "myocardial injury", "myocarditis", "hypertension", "arrhythmia", "heart failure" and "coronary heart disease", especially update articles in 2023 and 2024. Salient medical literatures regarding the cardiovascular damage of COVID-19 were selected, extracted and synthesized.

The most common cardiovascular damage was myocarditis and pericarditis, hypertension, arrhythmia, myocardial injury and heart failure, coronary heart disease, stress cardiomyopathy, ischemic stroke, blood coagulation abnormalities, and dyslipidemia. Two important pathogenic mechanisms of the cardiovascular damage may be direct viral cytotoxicity as well as indirect hyperimmune responses of the body to SARS CoV-2 infection.

Cardiovascular damage in COVID-19 patients is common and portends a worse prognosis. Although the underlying pathophysiological mechanisms of cardiovascular damage related to COVID-19 are not completely clear, two important pathogenic mechanisms of cardiovascular damage may be the direct damage of the SARSCoV-2 infection and the indirect hyperimmune responses.

Fibrosis is a pathological process, that could result in permanent scarring and impairment of the physiological function of the affected organ; this condition which is categorized under the term organ failure could affect various organs in different situations. The involvement of the major organs, such as the lungs, liver, kidney, heart, and skin, is associated with a high rate of morbidity and mortality across the world. Fibrotic disorders encompass a broad range of complications and could be traced to various illnesses and impairments; these could range from simple skin scars with beauty issues to severe rheumatologic or inflammatory disorders such as systemic sclerosis as well as idiopathic pulmonary fibrosis. Besides, the overactivation of immune responses during any inflammatory condition causing tissue damage could contribute to the pathogenic fibrotic events accompanying the healing response; for instance, the inflammation resulting from tissue engraftment could cause the formation of fibrotic scars in the grafted tissue, even in cases where the immune system deals with hard to clear infections, fibrotic scars could follow and cause severe adverse effects. A good example of such a complication is post-Covid19 lung fibrosis which could impair the life of the affected individuals with extensive lung involvement. However, effective therapies that halt or slow down the progression of fibrosis are missing in the current clinical settings. Considering the immunomodulatory and regenerative potential of distinct stem cell types, their application as an anti-fibrotic agent, capable of attenuating tissue fibrosis has been investigated by many researchers. Although the majority of the studies addressing the anti-fibrotic effects of stem cells indicated their potent capabilities, the underlying mechanisms, and pathways by which these cells could impact fibrotic processes remain poorly understood. Here, we first, review the properties of various stem cell types utilized so far as anti-fibrotic treatments and discuss the challenges and limitations associated with their applications in clinical settings; then, we will summarize the general and organ-specific mechanisms and pathways contributing to tissue fibrosis; finally, we will describe the mechanisms and pathways considered to be employed by distinct stem cell types for exerting anti-fibrotic events.

Exosomes (exos) are primarily responsible for the process of mesenchymal stem cells (MSCs) treatment for acute lung injury (ALI), but the mechanism remains unclear, particularly in altered microenvironment. Therefore, this study aimed to investigate the potential mechanism of exos derived from human umbilical cord mesenchymal stem cells (hucMSCs) primed with interferon-gamma (IFN-γ) on ALI and to propose a promising and cell-free strategy. This study extracted exos from hucMSCs supernatant primed and unprimed with IFN-γ marked with IFN-γ-exos and CON-exos, which were identified and traced. IFN-γ-exos administration to ALI models suppressed the NF-κB signaling pathway compared to CON-exos, which were quantified through western blot and immunohistochemical staining. Reverse transcription-quantitative polymerase chain reaction validated miR-199b-5p expression in the IFN-γ-exos and CON-exos treatment groups. Data analysis, a dual-luciferase reporter assay, and cell transfection were conducted to investigate the target binding between miR-199b-5p and Aftiphilin (AFTPH), with AFTPH expression analyzed via cell immunofluorescence and western blot. Co-immunoprecipitation was conducted for the interaction between AFTPH and NF-κB p65. The result revealed that miR-199b-5p was down-regulated in the IFN-γ-exos treatment group, which had a target binding site with AFTPH, and an interaction with NF-κB p65. Consequently, IFN-γ-exos inhibited the NF-κB signaling pathway in ALI in vitro and in vivo through the miR-199b-5p/AFTPH axis. Our results demonstrated new directions of novel and targeted treatment for ALI.

Coronavirus disease 2019 (COVID-19) has a clinical manifestation of hypoxic respiratory failure and acute respiratory distress syndrome. However, COVID-19 still lacks of effective clinical treatments so far. As a promising potential treatment against COVID-19, stem cell therapy raised recently and had attracted much attention. Here we review the mechanisms of mesenchymal stem cell-based treatments against COVID-19, and provide potential cues for the effective control of COVID-19 in the future.

Literature is obtained from databases PubMed and Web of Science. Key words were chosen for COVID- 19, acute respiratory syndrome coronavirus 2, mesenchymal stem cells, stem cell therapy, and therapeutic mechanism. Then we summarize and critically analyze the relevant articles retrieved.

Mesenchymal stem cell therapy is a potential effective treatment against COVID-19. Its therapeutic efficacy is mainly reflected in reducing severe pulmonary inflammation, reducing lung injury, improving pulmonary function, protecting and repairing lung tissue of the patients. Possible therapeutic mechanisms might include immunoregulation, anti-inflammatory effect, tissue regeneration, anti-apoptosis effect, antiviral, and antibacterial effect, MSC - EVs, and so on.

Mesenchymal stem cells can effectively treat COVID-19 through immunoregulation, anti-inflammatory, tissue regeneration, anti-apoptosis, anti-virus and antibacterial, MSC - EVs, and other ways. Systematically elucidating the mechanisms of mesenchymal stem cell-based treatments for COVID-19 will provide novel insights into the follow-up research and development of new therapeutic strategies in next step.

Lung endothelial barrier injury plays an important role in the pathophysiology of acute lung injury/acute respiratory distress syndrome (ALI/ARDS). Mesenchymal stem cells (MSCs) therapy has shown promise in ARDS treatment and restoration of the impaired barrier function. It has been reported that Wnt5a shows protective effects on endothelial cells. Therefore, the study aimed to investigate whether overexpression of Wnt5a could promote the protective effects of MSCs on Lipopolysaccharide (LPS)-induced endothelial cell injury.

To evaluate the protective effects of MSCs overexpressing Wnt5a, we assessed the migration, proliferation, apoptosis, and angiogenic ability of endothelial cells. We assessed the transcription of protective cellular factors using qPCR and determined the molecular mechanism using Western blot analysis.

Overexpression of Wnt5a upregulated the transcription of protective cellular factors in MSCs. Co-culture of MSCWnt5a promoted endothelial migration, proliferation and angiogenesis, and inhibited endothelial cell apoptosis through the PI3K/AKT pathway.

Overexpression of Wnt5a promoted the therapeutic effect of MSCs on endothelial cell injury through the PI3K/AKT signaling. Our study provides a novel approach for utilizing genetically modified MSCs in the transplantation therapy for ARDS.

Cytokine storms, which result from an abrupt, acute surge in the circulating levels of different pro-inflammatory cytokines, are one of the complications associated with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. This study aimed to assess the effect of exosomes on the release of pro-inflammatory cytokines in patients with coronavirus disease 2019 (COVID-19) and compare it with a control group. The cytokines evaluated in this study were TNF-α, IL-6, IL-17, and IFN-γ. The study compared the levels of these pro-inflammatory cytokines in the peripheral blood mononuclear cells (PBMCs) of five COVID-19 patients in the intensive care unit, who were subjected to both inactivated SARS-CoV-2 and exosome therapy, with those of five healthy controls. The cytokine levels were quantified using the ELISA method. The collected data was analyzed in SPSS Version 26.0 and GraphPad Prism Version 9. According to the study findings, when PBMCs were exposed to inactivated SARS-CoV-2, pro-inflammatory cytokines increased in both patients and healthy controls. Notably, the cytokine levels were significantly elevated in the COVID-19 patients compared to the control group P-values were < 0.001, 0.001, 0.008, and 0.008 for TNF-α, IL-6, IL-17, and IFN-γ, respectively. Conversely, when both groups were exposed to exosomes, there was a marked reduction in the levels of pro-inflammatory cytokines. This suggests that exosome administration can effectively mitigate the hyperinflammation induced by COVID-19 by suppressing the production of pro-inflammatory cytokines in patients. These findings underscore the potential safety and efficacy of exosomes as a therapeutic strategy for COVID-19.

As severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants continue to wreak havoc worldwide, the "Cytokine Storm" (CS, also known as the inflammatory storm) or Cytokine Release Syndrome has reemerged in the public consciousness. CS is a significant contributor to the deterioration of infected individuals. Therefore, CS control is of great significance for the treatment of critically ill patients and the reduction of mortality rates. With the occurrence of variants, concerns regarding the efficacy of vaccines and antiviral drugs with a broad spectrum have grown. We should make an effort to modernize treatment strategies to address the challenges posed by mutations. Thus, in addition to the requirement for additional clinical data to monitor the long-term effects of vaccines and broad-spectrum antiviral drugs, we can use CS as an entry point and therapeutic target to alleviate the severity of the disease in patients. To effectively combat the mutation, new technologies for neutralizing or controlling CS must be developed. In recent years, nanotechnology has been widely applied in the biomedical field, opening up a plethora of opportunities for CS. Here, we put forward the view of cytokine storm as a therapeutic target can be used to treat critically ill patients by expounding the relationship between coronavirus disease 2019 (COVID-19) and CS and the mechanisms associated with CS. We pay special attention to the representative strategies of nanomaterials in current neutral and CS research, as well as their potential chemical design and principles. We hope that the nanostrategies described in this review provide attractive treatment options for severe and critical COVID-19 caused by CS.

During the COVID-19 pandemic, elderly patients with underlying condition, such as tumors, had poor prognoses after progressing to severe pneumonia and often had poor response to standard treatment. Mesenchymal stem cells (MSCs) may be a promising treatment for patients with severe pneumonia, but MSCs are rarely used for patients with carcinoma. Here, we reported a 67-year-old female patient with lung adenocarcinoma who underwent osimertinib and radiotherapy and suffered from radiation pneumonitis. Unfortunately, she contracted COVID-19 and that rapidly progressed to severe pneumonia. She responded poorly to frontline treatment and was in danger. Subsequently, she received a salvage treatment with four doses of MSCs, and her symptoms surprisingly improved quickly. After a lung CT scan that presented with a significantly improved infection, she was discharged eventually. Her primary disease was stable after 6 months of follow-up, and no tumor recurrence or progression was observed. MSCs may be an effective treatment for hyperactive inflammation due to their ability related to immunomodulation and tissue repair. Our case suggests a potential value of MSCs for severe pneumonia that is unresponsive to conventional therapy after a COVID-19 infection. However, unless the situation is urgent, it needs to be considered with caution for patients with tumors. The safety in tumor patients still needs to be observed.

Human umbilical cord mesenchymal stem cells (HUC-MSCs) are pluripotent stem cells with anti-inflammatory and immunomodulatory properties used in the treatment of acute lung injury (ALI). However, the treatment of ALI using exosomes derived from HUC-MSCs (HUC-MSC-exos) primed with interferon-gamma (IFN-γ-exos) has not been described. This study investigated the effects of IFN-γ-exos on ALI.

IFN-γ primed and unprimed HUC-MSC-exos (IFN-γ-exos and CON-exos, respectively) were extracted, identified, and traced. A549 cells and mice subjected to lipopolysaccharide (LPS)-induced inflammation were treated with IFN-γ-exos or CON-exos. Viability; interleukin (IL)-1β, IL-6, tumor necrosis factor (TNF)-α, and reactive oxygen species (ROS) levels; NF-κB p65, and NLRP3 expression and histology and lung injury scores were measured in cell, supernatant or lung tissue.

Indoleamine 2,3-dioxygenase (IDO) mRNA expression was elevated in HUC-MSCs primed with 5 ng/mL IFN-γ (P<0.001), and IFN-γ-exos and CON-exos were successfully extracted. LPS-induced inflammation resulted in decreased cell viability in A549 cells, and increased IL-1β, IL-6, TNF-α and ROS levels and NF-κB p65 and NLRP3 expression in A549 cells and mice(P<0.05 to P<0.001). Treatment with IFN-γ-exos and CON-exos increased cell viability and decreased the concentrations of IL-1β, and ROS, expression of NF-κB p65 and NLRP3, and the lung injury score, and these effects were more obvious for IFN-γ-exos(P<0.05 to P<0.001).

IFN-γ-exos reduced oxidative stress and inflammatory responses in LPS-induced A549 cells and mice. The result demonstrated the therapeutic potential of IFN-γ-exos in LPS-induced ALI.

One of the main concerns related to SARS-CoV-2 infection is the symptoms that could be developed by survivors, known as long COVID, a syndrome characterized by persistent symptoms beyond the acute phase of the infection. This syndrome has emerged as a complex and debilitating condition with a diverse range of manifestations affecting multiple organ systems. It is increasingly recognized for affecting the Central Nervous System, in which one of the most prevalent manifestations is cognitive impairment. The search for effective therapeutic interventions has led to growing interest in Mesenchymal Stem Cell (MSC)-based therapies due to their immunomodulatory, anti-inflammatory, and tissue regenerative properties. This review provides a comprehensive analysis of the current understanding and potential applications of MSC-based interventions in the context of post-acute neurological COVID-19 syndrome, exploring the underlying mechanisms by which MSCs exert their effects on neuroinflammation, neuroprotection, and neural tissue repair. Moreover, we discuss the challenges and considerations specific to employing MSC-based therapies, including optimal delivery methods, and functional treatment enhancements.

While The World Health Organization (WHO) has announced that COVID-19 is no longer a public health emergency of international concern(PHEIC), the risk of reinfection and new emerging variants still makes it crucial to study and work towards the prevention of COVID-19. Stem cell and stem cell-like derivatives have shown some promising results in clinical trials and preclinical studies as an alternative treatment option for the pulmonary illnesses caused by the COVID-19 and can be used as a potential vaccine. In this review, we will systematically summarize the pathophysiological process and potential mechanisms underlying stem cell-based therapy in COVID-19, and the registered COVID-19 clinical trials, and engineered extracellular vesicle as a potential vaccine for preventing COVID-19.

The study of diseases, specifically their aetiologies, their step-by-step progressions (pathogenesis), and their impact on normal structure and function, is the focus of pathology, a branch of science and medicine. In therapeutic fields, it is critical to decrease significantly elevated levels of proinflammatory cytokines. The immunomodulatory drugs such as dexamethasone have been used in several of inflammatory diseases such as Covid-19. The use of dexamethasone alone or in combination with other drugs or method such as mesenchymal stem cell (MSC) is one of the most up-to-date discussions about Covid-19. In this review, we first examined the effects of dexamethasone as monotherapy on inflammatory cytokines and then examined studies that used combination therapy of dexamethasone and other drugs such as Baricitinib, Tofacitinib and tocilizumab. Also, therapeutic aspects of MSCs are examined in this review.

An unprecedented global social and economic impact as well as a significant number of fatalities have been brought on by the coronavirus disease 2019 (COVID-19), produced by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Acute SARS-CoV-2 infection can, in certain situations, cause immunological abnormalities, leading to an anomalous innate and adaptive immune response. While most patients only experience mild symptoms and recover without the need for mechanical ventilation, a substantial percentage of those who are affected develop severe respiratory illness, which can be fatal. The absence of effective therapies when disease progresses to a very severe condition coupled with the incomplete understanding of COVID-19's pathogenesis triggers the need to develop innovative therapeutic approaches for patients at high risk of mortality. As a result, we investigate the potential contribution of promising combinatorial cell therapy to prevent death in critical patients.

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.

Acute respiratory distress syndrome (ARDS) is a critical complication in severe COVID-19 patients. The intravenous infusion (IVF) of umbilical cord- (UC-) mesenchymal stem cells (MSCs), validated to substantially reduce the release of several inflammatory cytokines in vivo, was also shown to exhibit benefits in improving hypoxemia among severe COVID-19 patients. A single dose of IVF-UC-MSCs therapy for severe COVID-19 patients was shown to alleviate the initial ARDS severity, but have 50%-67% case-fatality rates. In Taiwan, few adult patients with severe COVID-19-induced ARDS receiving compassionate adjuvant treatment consisting of either a single dose (1-10 × 106 cells/kg body weight (kg BW)) or three doses (5 × 106 cells/kg BW in each dose) of IVF-UC-MSCs had good outcomes. However, the optimal dosage and rounds of IVF-UC-MSCs administration for the treatment of severe COVID-19 patients with ARDS are undetermined.

We reviewed the 2020-2022 PubMed literature database concerning the clinical efficacy of IVF-UC-MSCs among severe COVID-19 patients.

The data of COVID-19 case series in the PubMed literature revealed a notable heterogeneity in the therapeutic dosage (a single dose: 1-10 × 106 cells/kg BW; and three doses: 50-200 × 106 cells/kg BW in each dose) and the post-ARDS days of IVF-UC-MSCs administration (a single dose: 1-12; and multiple doses: 5-14) for the treatment of severe COVID-19-associated ARDS. The survival rates among these severe COVID-19 patients ranged from 50% to 76%. However, an overall rate of 93.1% of significant improvement in hypoxemia was observed for the COVID-19 survivors receiving IVF-UC-MSCs at the initial ARDS stage.

According to our analysis, the ideal treatment dosage of IVF-UC-MSCs for severe COVID-19-induced ARDS is likely 5 × 106 cells/kg BW for three cycles within 5 days of ARDS onset in severe COVID-19 patients.

Many clinical trials have reported the use of mesenchymal stromal cells (MSCs) following the indication of severe SARS-CoV-2 infection. However, in the COVID19 pandemic context, academic laboratories had to adapt a production process to obtain MSCs in a very short time. Production processes, especially freezing/thawing cycles, or culture medium have impacts on MSC properties. We evaluated the impact of an intermediate cryopreservation state during MSC culture to increase production yields.

Seven Wharton's jelly (WJ)-MSC batches generated from seven different umbilical cords with only one cryopreservation step and 13 WJ-MSC batches produced with intermediate freezing were formed according to good manufacturing practices. The identity (phenotype and clonogenic capacities), safety (karyotype, telomerase activity, sterility, and donor qualification), and functionality (viability, mixed lymphocyte reaction) were analyzed.

No significant differences between MSC production processes were observed, except for the clonogenic capacity, which was decreased, although it always remained above our specifications.

Intermediate cryopreservation allows an increase in the production yield and has little impact on the basic characteristics of MSCs.

Acute respiratory distress syndrome (ARDS), chronic obstructive pulmonary disease (COPD) and COVID-19 have as a common characteristic the inflammatory lesion of the lung epithelium. The therapeutic options are associated with opportunistic infections, a hyperglycemic state, and adrenal involvement. Therefore, the search for new treatment strategies that reduce inflammation, and promote re-epithelialization of damaged tissue is very important. This work describes the relevant pathophysiological characteristics of these diseases and evaluates recent findings on the immunomodulatory, anti-inflammatory and regenerative effect of mesenchymal stem cells (MSC) and their therapeutic use. In Pubmed we selected the most relevant studies on the subject, published between 2003 and 2022 following the PRISMA guide. We conclude that MSCs are an important therapeutic option for regenerative treatment in COPD, ARDS, and COVID-19, because of their ability to differentiate into type II pneumocytes and maintain the size and function of lung tissue by replacing dead or damaged cells.

Coronavirus disease 2019 (COVID-19), the pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which counts more than 650 million cases and more than 6.6 million of deaths worldwide, affects the respiratory system with typical symptoms such as fever, cough, sore throat, acute respiratory distress syndrome (ARDS), and fatigue. Other nonpulmonary manifestations are related with abnormal inflammatory response, the "cytokine storm", that could lead to a multiorgan disease and to death. Evolution of effective vaccines against SARS-CoV-2 provided multiple options to prevent the infection, but the treatment of the severe forms remains difficult to manage. The cytokine storm is usually counteracted with standard medical care and anti-inflammatory drugs, but researchers moved forward their studies on new strategies based on cell therapy approaches. The perinatal tissues, such as placental membranes, amniotic fluid, and umbilical cord derivatives, are enriched in mesenchymal stromal cells (MSCs) that exert a well-known anti-inflammatory role, immune response modulation, and tissue repair. In this review, we focused on umbilical-cord-derived MSCs (UC-MSCs) used in in vitro and in vivo studies in order to evaluate the weakening of the severe symptoms, and on recent clinical trials from different databases, supporting the favorable potential of UC-MSCs as therapeutic strategy.

Rationale: Trauma, surgery, and infection can cause severe inflammation. Both dysregulated inflammation intensity and duration can lead to significant tissue injuries, organ dysfunction, mortality, and morbidity. Anti-inflammatory drugs such as steroids and immunosuppressants can dampen inflammation intensity, but they derail inflammation resolution, compromise normal immunity, and have significant adverse effects. The natural inflammation regulator mesenchymal stromal cells (MSCs) have high therapeutic potential because of their unique capabilities to mitigate inflammation intensity, enhance normal immunity, and accelerate inflammation resolution and tissue healing. Furthermore, clinical studies have shown that MSCs are safe and effective. However, they are not potent enough, alone, to completely resolve severe inflammation and injuries. One approach to boost the potency of MSCs is to combine them with synergistic agents. We hypothesized that alpha-1 antitrypsin (A1AT), a plasma protein used clinically and has an excellent safety profile, was a promising candidate for synergism. Methods: This investigation examined the efficacy and synergy of MSCs and A1AT to mitigate inflammation and promote resolution, using in vitro inflammatory assay and in vivo mouse acute lung injury model. The in vitro assay measured cytokine releases, inflammatory pathways, reactive oxygen species (ROS), and neutrophil extracellular traps (NETs) production by neutrophils and phagocytosis in different immune cell lines. The in vivo model monitored inflammation resolution, tissue healing, and animal survival. Results: We found that the combination of MSCs and A1AT was much more effective than each component alone in i) modulating cytokine releases and inflammatory pathways, ii) inhibiting ROS and NETs production by neutrophils, iii) enhancing phagocytosis and, iv) promoting inflammation resolution, tissue healing, and animal survival. Conclusion: These results support the combined use of MSCs, and A1AT is a promising approach for managing severe, acute inflammation.

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.

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.

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.

Infusion of umbilical cord-derived MSCs is an effective strategy for treating patients with COVID-19 pneumonia, with no noticeable adverse effects.

COVID-19 is an infectious disease caused by the novel coronavirus (SARS-CoV-2) that first appeared in late 2019 and has since spread across the world. It is characterized by symptoms such as fever, cough, and shortness of breath and can lead to death in severe cases. To help contain the virus, measures such as social distancing, handwashing, and other public health measures have been implemented. Vaccine and drug candidates, such as those developed by Pfizer/BioNTech, AstraZeneca, Moderna, Novavax, and Johnson & Johnson, have been developed and are being distributed worldwide. Clinical trials for drug treatments such as remdesivir, dexamethasone, and monoclonal antibodies are underway and have shown promising results. Recently, exosomes have gained attention as a possible mediator of the COVID-19 infection. Exosomes, small vesicles with a size of around 30-200 nm, released from cells, contain viral particles and other molecules that can activate the immune system and/or facilitate viral entry into target cells. Apparently, the role of exosomes in eliciting various immune responses and causing tissue injury in COVID-19 pathogenesis has been discussed. In addition, the potential of exosomes as theranostic and therapeutic agents for the treatment of COVID-19 has been elaborated.

The past several decades have witnessed the emergence and re-emergence of many infectious viral agents, flaviviruses, influenza, filoviruses, alphaviruses, and coronaviruses since the advent of human deficiency virus (HIV). Some of them even become serious threats to public health and have raised major global health concerns. Several different medicinal compounds such as anti-viral, anti-malarial, and anti-inflammatory agents, are under investigation for the treatment of these viral diseases. These therapies are effective improving recovery rates and overall survival of patients but are unable to heal lung damage caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Therefore, there is a critical need to identify effective treatments to combat this unmet clinical need. Due to its antioxidant and immunomodulatory properties, stem cell therapy is considered a novel approach to regenerate damaged lungs and reduce inflammation. Stem cell therapy uses a heterogeneous subset of regenerative cells that can be harvested from various adult tissue types and is gaining popularity due to its prodigious regenerative potential as well as immunomodulatory and anti-inflammatory properties. These cells retain expression of cluster of differentiation markers (CD markers), interferon-stimulated gene (ISG), reduce expression of pro-inflammatory cytokines and, show a rapid proliferation rate, which makes them an attractive tool for cellular therapies and to treat various inflammatory and viral-induced injuries. By examining various clinical studies, this review demonstrates positive considerations for the implications of stem cell therapy and presents a necessary approach for treating virally induced infections in patients.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the pathogen responsible for the coronavirus disease 2019 (COVID-19) outbreaks that resulted in a catastrophic threat to global health, with more than 500 million cases detected and 5.5 million deaths worldwide. Patients with a COVID-19 infection presented with clinical manifestations ranging from asymptomatic to severe symptoms, resulting in acute lung injury, acute respiratory distress syndrome, and even death. Immune dysregulation through delayed innate immune response or impairment of the adaptive immune response is the key contributor to the pathophysiology of COVID-19 and SARS-CoV-2-induced cytokine storm. Symptomatic and supportive therapy is the fundamental strategy in treating COVID-19 infection, including antivirals, steroid-based therapies, and cell-based immunotherapies. Various studies reported substantial effects of immune-based therapies for patients with COVID-19 to modulate the over-activated immune system while simultaneously refining the body's ability to destroy the virus. However, challenges may arise from the complexity of the disease through the genetic variance of the virus itself and patient heterogeneity, causing increased transmissibility and heightened immune system evasion that rapidly change the intervention and prevention measures for SARS-CoV-2. Cell-based therapy, utilizing stem cells, dendritic cells, natural killer cells, and T cells, among others, are being extensively explored as other potential immunological approaches for preventing and treating SARS-CoV-2-affected patients the similar process was effectively proven in SARS-CoV-1 and MERS-CoV infections. This review provides detailed insights into the innate and adaptive immune response-mediated cell-based immunotherapies in COVID-19 patients. The immune response linking towards engineered autologous or allogenic immune cells for either treatment or preventive therapies is subsequently highlighted in an individual study or in combination with several existing treatments. Up-to-date data on completed and ongoing clinical trials of cell-based agents for preventing or treating COVID-19 are also outlined to provide a guide that can help in treatment decisions and future trials.

The use of induced mesenchymal stem/stromal cells (iMSCs) derived from human induced pluripotent stem cells (hiPSCs) in regenerative medicine involves the risk of teratoma formation due to hiPSCs contamination in iMSCs. Therefore, eradicating the remaining undifferentiated hiPSCs is crucial for the effectiveness of the strategy. The present study demonstrates the Brequinar (BRQ)-induced inhibition of dihydroorotate dehydrogenase (DHODH), a key enzyme in de novo pyrimidine biosynthesis, selectively induces apoptosis, cell cycle arrest, and differentiation; furthermore, it promotes transcriptional changes and prevents the growth of 3-dimensional hiPSC aggregates. Contrastingly, BRQ-treated iMSCs showed no changes in survival, differentiation potential, or gene expression. The results suggest that BRQ is a potential agent for the effective purification of iMSCs from a mixed population of iMSCs and hiPSCs, which is a crucial step in successful iMSC-based therapy.

The current coronavirus pandemic (COVID-19), caused by SARS-CoV-2, has had devastating effects on the global health and economic system. The cellular and molecular mediators of both the innate and adaptive immune systems are critical in controlling SARS-CoV-2 infections. However, dysregulated inflammatory responses and imbalanced adaptive immunity may contribute to tissue destruction and pathogenesis of the disease. Important mechanisms in severe forms of COVID-19 include overproduction of inflammatory cytokines, impairment of type I IFN response, overactivation of neutrophils and macrophages, decreased frequencies of DC cells, NK cells and ILCs, complement activation, lymphopenia, Th1 and Treg hypoactivation, Th2 and Th17 hyperactivation, as well as decreased clonal diversity and dysregulated B lymphocyte function. Given the relationship between disease severity and an imbalanced immune system, scientists have been led to manipulate the immune system as a therapeutic approach. For example, anti-cytokine, cell, and IVIG therapies have received attention in the treatment of severe COVID-19. In this review, the role of immunity in the development and progression of COVID-19 is discussed, focusing on molecular and cellular aspects of the immune system in mild vs. severe forms of the disease. Moreover, some immune- based therapeutic approaches to COVID-19 are being investigated. Understanding key processes involved in the disease progression is critical in developing therapeutic agents and optimizing related strategies.

In coronavirus disease 2019 (COVID-19) patients, elevated levels of inflammatory cytokines from over stimulation of immune cells have become a concern due to the potential outburst of cytokine storm that damages the tissues and organs, especially the lungs. This leads to the manifestation of COVID-19 symptoms, such as pneumonia, acute respiratory distress syndrome (ARDS), multiple organ failure, and eventually death. Mesenchymal stromal/stem cells (MSCs) are currently one of hopeful approaches in treating COVID-19 considering its anti-inflammatory and immunomodulatory functions. On that account, the number of clinical trials concerning the use of MSCs for COVID-19 has been increasing. However, the number of systematic reviews and meta-analysis that specifically discuss its potential as treatment for the disease is still lacking. Therefore, this review will assess the safety and efficacy of MSC administration in COVID-19 patients.

To pool evidence on the safety and efficacy of MSCs in treating COVID-19 by observing MSC-related adverse effects as well as evaluating its effects in reducing inflammatory response and improving pulmonary function.

Following literature search across six databases and one trial register, full-text retrieval, and screening against eligibility criteria, only eight studies were included for data extraction. All eight studies evaluated the use of umbilical cord-derived mesenchymal stromal/stem cell (UC-MSC), infused intravenously. Of these eight studies, six studies were included in meta-analysis on the incidence of mortality, adverse events (AEs), and serious adverse events (SAEs), and the levels of C-reactive protein (CRP) and interleukin (IL)-6. Meta-analysis on pulmonary function was not performed due to insufficient data.

MSC-treated group showed significantly lower risk of mortality than the control group (p = 0.03). No statistical significance was observed on the incidence of AEs (p = 0.78) and SAEs (p = 0.44), and the levels of CRP (p = 0.06) and IL-6 (p = 0.09).

MSCs were safe for use, with lower risk of mortality and no association with AEs. Regarding efficacy, descriptive analysis showed indications of improvement on the inflammatory reaction, lung clearance, and oxygenation status despite the lack of statistical significance in meta-analysis of CRP and IL-6. Nevertheless, more studies are needed for affirmation.

This systematic review and meta-analysis was registered on the PROSPERO database (no. CRD42022307730).

According to the World Health Organization (WHO), in the second half of 2022, there are about 606 million confirmed cases of COVID-19 and almost 6,500,000 deaths around the world. A pandemic was declared by the WHO in March 2020 when the new coronavirus spread around the world. The short time between the first cases in Wuhan and the declaration of a pandemic initiated the search for ways to stop the spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) or to attempt to cure the disease COVID-19. More than ever, research groups are developing vaccines, drugs, and immunobiological compounds, and they are even trying to repurpose drugs in an increasing number of clinical trials. There are great expectations regarding the vaccine's effectiveness for the prevention of COVID-19. However, producing sufficient doses of vaccines for the entire population and SARS-CoV-2 variants are challenges for pharmaceutical industries. On the contrary, efforts have been made to create different vaccines with different approaches so that they can be used by the entire population. Here, we summarize about 8162 clinical trials, showing a greater number of drug clinical trials in Europe and the United States and less clinical trials in low-income countries. Promising results about the use of new drugs and drug repositioning, monoclonal antibodies, convalescent plasma, and mesenchymal stem cells to control viral infection/replication or the hyper-inflammatory response to the new coronavirus bring hope to treat the disease.

Insights into the use of cellular therapeutics, extracellular vesicles (EVs), and tissue engineering strategies for regenerative medicine applications are continually emerging with a focus on personalized, patient-specific treatments. Multiple pre-clinical and clinical trials have demonstrated the strong potential of cellular therapies, such as stem cells, immune cells, and EVs, to modulate inflammatory immune responses and promote neoangiogenic regeneration in diseased organs, damaged grafts, and inflammatory diseases, including COVID-19. Over 5,000 registered clinical trials on ClinicalTrials.gov involve stem cell therapies across various organs such as lung, kidney, heart, and liver, among other applications. A vast majority of stem cell clinical trials have been focused on these therapies' safety and effectiveness. Advances in our understanding of stem cell heterogeneity, dosage specificity, and ex vivo manipulation of stem cell activity have shed light on the potential benefits of cellular therapies and supported expansion into clinical indications such as optimizing organ preservation before transplantation. Standardization of manufacturing protocols of tissue-engineered grafts is a critical first step towards the ultimate goal of whole organ engineering. Although various challenges and uncertainties are present in applying cellular and tissue engineering therapies, these fields' prospect remains promising for customized patient-specific treatments. Here we will review novel regenerative medicine applications involving cellular therapies, EVs, and tissue-engineered constructs currently investigated in the clinic to mitigate diseases and possible use of cellular therapeutics for solid organ transplantation. We will discuss how these strategies may help advance the therapeutic potential of regenerative and transplant medicine.

Purpose: This study assessed the safety, feasibility, and tolerability of mesenchymal stem cells for patients diagnosed with COVID (Coronavirus disease 2019-induced ARDS (acute respiratory distress syndrome)). Materials and Methods: Critically ill adult COVID-19 patients who were admitted to Wonju Severance Christian Hospital were enrolled in this study. One patient received human bone marrow-derived mesenchymal stem cell (hBMSC) transplantation and received a total dose of 9 × 10⁷ allogeneic hBMSCs via intravenous infusion. The main outcome of this study was to assess the safety, adverse events, and efficacy following transplantation of hBMSCs in COVID-19- induced ARDS patients. Efficacy was assessed radiologically based on pneumonia improvement, changes in PaO₂/FiO₂, and O₂ saturation. Results: A 73-year-old man visited Wonju Severance Christian Hospital presenting with fever and fatigue. A throat swab was performed for real-time polymerase chain reaction to confirm COVID-19, and the result was positive. The patient developed ARDS on Day 5. MSC transplantation was performed on that day and administered on Day 29. Early adverse events, including allergic reactions, were not observed following MSC transplantation. Subsequently, clinical symptoms, signs, and laboratory findings, including PaO₂/FiO₂ and O₂ saturation, improved. Conclusion: The results of this case report suggest that intravenous injection of MSC derived from the bone marrow is safe and acceptable and can lead to favorable outcomes for critically ill COVID-19 patients.