In clinical trials, mesenchymal stromal/stem cells (MSCs) have consistently demonstrated safety. However, demonstration of efficacy has been inconsistent and many MSC trials have failed to meet their efficacy endpoint. This disappointing reality is reflected by the limited number MSC therapies approved by regulatory agencies, despite the large number of MSC trials registered on clinicaltrials.gov. Notably, there has been a recent approval of an MSC therapy for pediatric graft-vs.-host disease in the United States, marking the first MSC therapy approved by the U.S. Food and Drug Administration. This review provides a background of the history and potential therapeutic value of MSCs, an overview of MSC products with regulatory approval, and a summary of registered MSC trials. It concludes with a discussion on current and ongoing challenges and questions surrounding MSC therapy that remains to be resolved before becoming available for routine clinical use outside of clinical trials.

Patients ineligible for lung transplant with end-stage Interstitial Lung Disease (ILD) on Extra-Corporeal Membrane Oxygenation (ECMO) face an appalling prognosis with limited therapeutic options. Due to the beneficial effect of Mesenchymal Stromal Cells (MSC) on inflammatory, immunological and infectious diseases, cell therapy has been proposed as an option, but administration is hampered by the ECMO.

Cryopreserved Wharton-jelly derived MSC (WJ-MSC) were conveniently diluted and directly applied consecutively on each lobule (5,1 ml = 107 cells) at a continuous slow rate infused over one hour via flexible bronchoscopy (Consecutive IntraBronchial Administration method, CIBA method).

Intrabronchial administration of MSC to a patient on ECMO was well tolerated by the patient even though it did not reverse the patient's ILD. This manuscript presents preliminary evidence from ongoing clinical trials program on Cell Therapy of Inflammatory, Immune and Infectious Diseases and, to our knowledge, is the first report of intrabronchial administration of MSC in a paediatric ECMO patient with ILD. Even more, MSC administered by this method do not reach the systemic circulation and do get blocked on ECMO membrane.

Direct intrabronchial administration of MSC in a patient on ECMO is feasible and safe, and may be a new avenue to be assayed in ECMO patients with inflammatory, immunological and infectious diseases of the lung.

Graft-versus-host disease (GvHD) is a prevalent complication following allogeneic hematopoietic stem cell transplantation (HSCT) and is characterized by relatively high morbidity and mortality rates. GvHD can result in extensive systemic damage in patients following allogeneic HSCT (allo-HSCT), with the skin, gastrointestinal tract, and liver frequently being the primary target organs affected. The severe manifestations of acute intestinal GvHD often indicate a poor prognosis for patients after allo-HSCT. Endoscopy and histopathological evaluation remain employed to diagnose GvHD, and auxiliary examinations exclude differential diagnoses. Currently, reliable serum biomarkers for the diagnosis and differential diagnosis of GvHD are scarce. As an essential part of standard transplant protocols, early application of immunosuppressive drugs effectively prevents GvHD. Among them, steroids represent first-line therapeutic agents, and the JAK2 inhibitor ruxolitinib represents the second-line therapeutic agent. Currently, no efficacious treatment modality exists for steroid-resistant aGvHD. Therefore, the diagnosis and treatment of GvHD still face significant medical demands. Extracellular vesicles (EVs) are nanometer to micrometer-scale biomembrane vesicles containing various bioactive components, such as proteins, nucleotides, and metabolites. Distinctive changes in serum-derived EV components occur in patients after allo-HSCT; Hence, EVs are expected to be potential biomarkers for diagnosing and treating GvHD. Furthermore, cell-free therapeutics characterized by EVs derived from mesenchymal stem cells (MSCs) have manifested remarkable therapeutic efficacy in preclinical models and preclinical trials of GvHD. Customized engineered EVs with fewer toxic and side effects for the combined treatment of GvHD hold broad prospects for clinical translation. This review article examines the potential value of translating EVs into clinical applications for the diagnosis and treatment of GvHD. It summarizes the latest advancements and prospects of engineered EVs applying GvHD.

Human mesenchymal stromal cells (MSCs) possess regenerative potential due to pluripotency and paracrine functions. However, their stemness and immunomodulatory capabilities are sub-optimal in conventional two-dimensional (2D) culture.

To enhance the efficiency and therapeutic efficacy of MSCs, an in vivo-like 3D culture condition was applied.

MSCs were cultured on polystyrene (2D) or in a gellan gum-based 3D system. In vitro, prostaglandin-endoperoxide synthase 2, indoleamine-2,3-dioxygenase, heme oxygenase 1, and prostaglandin E synthase gene expression was quantified by quantitative real-time polymerase chain reaction. MSCs were incubated with lipopolysaccharide (LPS)-treated mouse splenocytes, and prostaglandin E2 and tumor necrosis factor-alpha levels were measured by enzyme linked immunosorbent assay. In vivo, LPS was injected into the lateral ventricle of mouse brain, and MSCs were administered intravenously the next day. Animals were sacrificed and analyzed on days 2 and 6.

Gellan gum polymer-based 3D culture significantly increased expression of octamer-binding transcription factor 4 and Nanog homeobox stemness markers in human MSCs compared to 2D culture. This 3D environment also heightened expression of cyclooxygenase-2 and heme-oxygenase 1, enzymes known for immunomodulatory functions, including production of prostaglandins and heme degradation, respectively. MSCs in 3D culture secreted more prostaglandin E2 and effectively suppressed tumor necrosis factor-alpha release from LPS-stimulated splenocytes and surpassed the efficiency of MSCs cultured in 2D. In a murine neuroinflammation model, intravenous injection of 3D-cultured MSCs significantly reduced ionized calcium-binding adaptor molecule 1 and glial fibrillary acidic protein expression, mitigating chronic inflammation more effectively than 2D-cultured MSCs.

The microenvironment established in 3D culture serves as an in vivo mimetic, enhancing the immunomodulatory function of MSCs. This suggests that engineered MSCs hold significant promise a potent tool for cell therapy.

Cryopreservation of immune cells is considered as a key enabling technology for adoptive cellular immunotherapy. However, current immune cell cryopreservation technologies face the challenges with poor biocompatibility of cryoprotection materials, low efficiency, and impaired post-thaw function, limiting their clinical translation. This review briefly introduces the adoptive cellular immunotherapy and the approved immune cell-based products, which involve T cells, natural killer cells and etc. The cryodamage mechanisms to these immune cells during cryopreservation process are described, including ice formation related mechanical and osmotic injuries, cryoprotectant induced toxic injuries, and other biochemical injuries. Meanwhile, the recent advances in the cryopreservation medium and freeze-thaw protocol for several representative immune cell type are summarized. Furthermore, the remaining challenges regarding on the cryoprotection materials, freeze-thaw protocol, and post-thaw functionality evaluation of current cryopreservation technologies are discussed. Finally, the future perspectives are proposed toward advancing highly efficient cryopreservation of immune cells.

Multipotent mesenchymal stromal/stem cells (MSCs) refer to a population of stem cells that exhibit distinct progenitor cell characteristics including the potential for differentiation into a wide range of cell types. MSCs have become a promising candidate for cell therapy and tissue regeneration due to their unique properties, such as their ability to differentiate into multiple cell types, their capacity for expansion, self-renewal, and immune-regulatory effects. However, reports have brought attention to thrombosis-related complications associated with MSCs therapy in the last decade. As tissue factor (TF) is a powerful coagulation activator expressed by MSCs that stimulates the extrinsic coagulation pathway, we investigated the thrombotic properties of human umbilical cord MSCs (HUCMSCs) after knocking out the TF gene. MSCs populations that obtained from umbilical cord were cultured and expanded in the appropriate medium cell culture. The identity of the MSCs was verified through flow cytometry, and their ability to differentiate into osteogenic and adipogenic lineages. Two gRNAs for Exons 1 and 2 of the TF gene have been designed and cloned into px458 vector's backbone (pSpCas9 (BB)-2A-GFP). Following transfecting of gRNAs into HUCMSCs and successfully knocking out the TF gene using GAP-PCR, the impact of normal and knockout HUCMSCs on coagulation was assessed through prothrombin time (PT), D-dimer level, clotting time (CT), and turbidity assay. Furthermore, the impact of TF knockout (TFKO) on MMP19 expression was assessed. Our results revealed that the PT was prolonged and D-dimer level was decreased in TFKO group compared to normal HUCMSCs. These findings suggest that TF gene plays a crucial role in regulating coagulation in HUCMSCs. Also, a significant reduction in MMP19 expression was observed within the TFKO group.

Advanced bioinformatics analysis, such as systems biology (SysBio) and artificial intelligence (AI) approaches, including machine learning (ML) and deep learning (DL), is increasingly present in stem cell (SC) research. An approximate timeline on these developments and their global impact is still lacking. We conducted a scoping review on the contribution of SysBio and AI analysis to SC research and therapy development based on literature published in PubMed between 2000 and 2024. We identified an 8 to 10-fold increase in research output related to all 3 search terms between 2000 and 2021, with a 10-fold increase in AI-related production since 2010. Use of SysBio and AI still predominates in preclinical basic research with increasing use in clinically oriented translational medicine since 2010. SysBio- and AI-related research was found all over the globe, with SysBio output led by the (US, n = 1487), (UK, n = 1094), Germany (n = 355), The Netherlands (n = 339), Russia (n = 215), and France (n = 149), while for AI-related research the US (n = 853) and UK (n = 258) take a strong lead, followed by Switzerland (n = 69), The Netherlands (n = 37), and Germany (n = 19). The US and UK are most active in SCs publications related to AI/ML and AI/DL. The prominent use of SysBio in ESC research was recently overtaken by prominent use of AI in iPSC and MSC research. This study reveals the global evolution and growing intersection among AI, SysBio, and SC research over the past 2 decades, with substantial growth in all 3 fields and exponential increases in AI-related research in the past decade.

Acute respiratory distress syndrome (ARDS) is a critical, life-threatening condition marked by severe inflammation and impaired lung function. Mesenchymal stromal/stem cells (MSCs) present a promising therapeutic avenue due to their immunomodulatory, anti-inflammatory, and regenerative capabilities. This review comprehensively evaluates MSC-based strategies for ARDS treatment, including direct administration, tissue engineering, extracellular vesicles (EVs), nanoparticles, natural products, artificial intelligence (AI), gene modification, and MSC preconditioning. Direct MSC administration has demonstrated therapeutic potential but necessitates optimization to overcome challenges related to effective cell delivery, homing, and integration into damaged lung tissue. Tissue engineering methods, such as 3D-printed scaffolds and MSC sheets, enhance MSC survival and functionality within lung tissue. EVs and MSC-derived nanoparticles offer scalable and safer alternatives to cell-based therapies. Likewise, natural products and bioactive compounds derived from plants can augment MSC function and resilience, offering complementary strategies to enhance therapeutic outcomes. In addition, AI technologies could aid in optimizing MSC delivery and dosing, and gene editing tools like CRISPR/Cas9 allow precise modification of MSCs to enhance their therapeutic properties and target specific ARDS mechanisms. Preconditioning MSCs with hypoxia, growth factors, or pharmacological agents further enhances their therapeutic potential. While MSC therapies hold significant promise for ARDS, extensive research and clinical trials are essential to determine optimal protocols and ensure long-term safety and effectiveness.

Multipotent mesenchymal stromal/stem cell (MSC) spheroids generated in three-dimensional culture are of considerable interest as a novel therapeutic tool for regenerative medicine. However, the lack of reliable methods for storing MSC spheroids represents a significant roadblock to their successful use in the clinic. An ideal storage medium for MSC spheroids should function as both a vehicle for delivery and a cryoprotectant during storage of spheroids for use at a later time. In this study, we compared the outcomes after subjecting MSC spheroids to a freeze/thaw cycle in three Good Manufacturing Practices-grade cryopreservation media, CryoStor10 (CS10), Stem-Cellbanker (SCB), and Recovery Cell Culture Freezing Media (RFM) or conventional freezing medium (CM) (CM, Dulbecco's modified Eagle's medium containing 20% fetal bovine serum and 10% dimethyl sulfoxide) as a control for 2 months. The endpoints tested were viability, morphology, and expression of stem cell markers and other relevant genes. The results of LIVE/DEAD™ assays and annexin V/propidium iodide staining suggested that viability was relatively higher after one freeze/thaw cycle in CS10 or SCB than after freeze/thaw in CM or RFM. Furthermore, the relative "stemness" and expression of MSC markers were similar with or without freeze/thaw in CS10. Scanning electron microscopy also indicated that the surface morphology of MSC spheroids was well preserved after cryopreservation in CS10. Thus, even though it was tested for a short-term period, we suggest that CS10, which has been approved for clinical use by the U.S. Food and Drug Association, is a promising cryopreservation medium that would facilitate the development of MSC spheroids for future clinical use.

Emerged health-related problems especially with increasing population and with the wider occurrence of these issues have always put the utmost concern and led medicine to outgrow its usual mode of treatment, to achieve better outcomes. Orthopedic interventions are one of the most concerning hitches, requiring advancement in several issues, that show complications with conventional approaches. Advanced studies have been undertaken to address the issue, among which stem cell therapy emerged as a better area of growth. The capacity of the stem cells to renovate themselves and adapt into different cell types made it possible to implement its use as a regenerative slant. Harvesting the stem cells, particularly mesenchymal stem cells (MSCs) is easier and can be further grown in vitro . In this review, we have discussed orthopedic-related issues including bone defects and fractures, nonunions, ligament and tendon injuries, degenerative changes, and associated conditions, which require further approaches to execute better outcomes, and the advanced strategies that can be tagged along with various ways of application of MSCs. It aims to objectify the idea of stem cells, with a major focus on the application of MSCs from different sources in various orthopedic interventions. It also discusses the limitations, and future scopes for further approaches in the field of regenerative medicine. The involvement of MSCs may transition the procedures in orthopedic interventions from predominantly surgical substitution and reconstruction to bio-regeneration and prevention. Nevertheless, additional improvements and evaluations are required to explore the effectiveness and safety of mesenchymal stem cell treatment in orthopedic regenerative medicine.

In biomedical research, biorepositories are pivotal resources that safeguard and supply clinical samples for scientific investigators. Proper long-term cryopreservation conditions are essential to maintain biospecimen quality. In this study, we analyzed the efficacy of sample cryopreservation at the Texas Heart Institute Biorepository and Biospecimen Profiling Core (THI-BRC). Our assessments included a thorough review of internal processes, quality reports, and both internal and external audit outcomes. We examined the integrity of human bone marrow-derived multipotent mesenchymal stromal cells (BM-MSCs) that were cryopreserved for over 5 years. These samples originated from randomly selected clinical trial participants or commercially sourced cell lines. Parameters such as cell viability, DNA and RNA integrity, population doubling time, sterility, and BM-MSC-specific attributes such as surface antigen expression and differentiation potential were studied. BM-MSC samples cryopreserved for ∼6 months served as our control. Our results demonstrated that the 5-year cryopreserved samples maintained their integrity compared with the shorter-term stored control samples. Moreover, THI-BRC has met accreditation agency standards and has not received any repeated deficiencies over 7 years. Collectively, our findings affirm that THI-BRC's biospecimen storage protocols align with accepted standards as confirmed by the quality assessment of long-term stored clinical samples.

Pain is an essential aspect of the body's physiological response to unpleasant noxious stimuli from either external sustained injuries or an internal disease condition that occurs within the body. Generally, pain is temporary. However, in patients with neuropathic pain, the experienced pain is persistent and uncontrollable, with an unsatisfactory treatment effectiveness. The activation of the immune system is a crucial factor in both central and peripheral neuropathic pain. The immune response plays an important role in the progression of the stages of neuropathic pain, and acts not only as pain mediators, but also produce analgesic molecules. Neuropathic pain has long been described as a result of dysfunctional nerve activities. However, there is substantial evidence indicating that the regulation of hyperalgesia is mediated by astrocytes and microglia activation. Mesenchymal stem cells currently hold an optimal potential in managing pain, as they can migrate to damaged tissues and have a robust immunosuppressive role for autologous or heterologous transplantation. Moreover, mesenchymal stem cells revealed their immunomodulatory capabilities by secreting growth factors and cytokines through direct cell interactions. The main idea underlying the use of mesenchymal stem cells in pain management is that these cells can replace damaged nerve cells by releasing neurotrophic factors. This property makes them the perfect option to modulate and treat neuropathic pain, which is notoriously difficult to treat.

An overly exuberant immune response, characterized by a cytokine storm and uncontrolled inflammation, has been identified as a significant driver of severe coronavirus disease 2019 (COVID-19) cases. Consequently, deciphering the intricacies of immune dysregulation in COVID-19 is imperative to identify specific targets for intervention and modulation. With these delicate dynamics in mind, immunomodulatory therapies have emerged as a promising avenue for mitigating the challenges posed by COVID-19. Precision in manipulating immune pathways presents an opportunity to alter the host response, optimizing antiviral defenses while curbing deleterious inflammation. This review article comprehensively analyzes immunomodulatory interventions in managing COVID-19. We explore diverse approaches to mitigating the hyperactive immune response and its impact, from corticosteroids and non-steroidal drugs to targeted biologics, including anti-viral drugs, cytokine inhibitors, JAK inhibitors, convalescent plasma, monoclonal antibodies (mAbs) to severe acute respiratory syndrome coronavirus 2, cell-based therapies (i.e., CAR T, etc.). By summarizing the current evidence, we aim to provide a clear roadmap for clinicians and researchers navigating the complex landscape of immunomodulation in COVID-19 treatment.

Mesenchymal stromal cells (MSCs) have become one of the most investigated and applied cells for cellular therapy and regenerative medicine. In this update of our review published in 2015, we show that studies continue to abound regarding the characterization of MSCs to distinguish them from other similar cell types, the discovery of new tissue sources of MSCs, and the confirmation of their properties and functions that render them suitable as a therapeutic. Because cryopreservation is widely recognized as the only technology that would enable the on-demand availability of MSCs, here we show that although the traditional method of cryopreserving cells by slow cooling in the presence of 10% dimethyl sulfoxide (Me2SO) continues to be used by many, several novel MSC cryopreservation approaches have emerged. As in our previous review, we conclude from these recent reports that viable and functional MSCs from diverse tissues can be recovered after cryopreservation using a variety of cryoprotectants, freezing protocols, storage temperatures, and periods of storage. We also show that for logistical reasons there are now more studies devoted to the cryopreservation of tissues from which MSCs are derived. A new topic included in this review covers the application in COVID-19 of MSCs arising from their immunomodulatory and antiviral properties. Due to the inherent heterogeneity in MSC populations from different sources there is still no standardized procedure for their isolation, identification, functional characterization, cryopreservation, and route of administration, and not likely to be a "one-size-fits-all" approach in their applications in cell-based therapy and regenerative medicine.

Diabetes has evolved into a worldwide public health issue. One of the most serious complications of diabetes is diabetic foot ulcer (DFU), which frequently creates a significant financial strain on patients and lowers their quality of life. Up until now, there has been no curative therapy for DFU, only symptomatic relief or an interruption in the disease's progression. Recent studies have focused attention on mesenchymal stem cells (MSCs), which provide innovative and potential treatment candidates for several illnesses as they can differentiate into various cell types. They are mostly extracted from the placenta, adipose tissue, umbilical cord (UC), and bone marrow (BM). Regardless of their origin, they show comparable features and small deviations. Our goal is to investigate MSCs' therapeutic effects, application obstacles, and patient benefit strategies for DFU therapy.

A comprehensive search was conducted using specific keywords relating to DFU, MSCs, and connected topics in the databases of Medline, Scopus, Web of Science, and PubMed. The main focus of the selection criteria was on English-language literature that explored the relationship between DFU, MSCs, and related factors.

Numerous studies are being conducted and have demonstrated that MSCs can induce re-epithelialization and angiogenesis, decrease inflammation, contribute to immunological modulation, and subsequently promote DFU healing, making them a promising approach to treating DFU. This review article provides a general snapshot of DFU (including clinical presentation, risk factors and etiopathogenesis, and conventional treatment) and discusses the clinical progress of MSCs in the management of DFU, taking into consideration the side effects and challenges during the application of MSCs and how to overcome these challenges to achieve maximum benefits.

The incorporation of MSCs in the management of DFU highlights their potential as a feasible therapeutic strategy. Establishing a comprehensive understanding of the complex relationship between DFU pathophysiology, MSC therapies, and related obstacles is essential for optimizing therapy outcomes and maximizing patient benefits.

Mesenchymal Stem Cells (MSCs) are being investigated as a treatment for a novel viral disease owing to their immunomodulatory, anti-inflammatory, tissue repair and regeneration characteristics, however, the exact processes are unknown. MSC therapy was found to be effective in lowering immune system overactivation and increasing endogenous healing after SARS-CoV-2 infection by improving the pulmonary microenvironment. Many studies on mesenchymal stem cells have been undertaken concurrently, and we may help speed up the effectiveness of these studies by collecting and statistically analyzing data from them. Based on clinical trial information found on clinicaltrials. gov and on 16 November 2020, which includes 63 clinical trials in the field of patient treatment with COVID-19 using MSCs, according to the trend of increasing studies in this field, and with the help of meta-analysis studies, it is possible to hope that the promise of MSCs will one day be realized. The potential therapeutic applications of MSCs for COVID-19 are investigated in this study.

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.

Rationale: Early post injury mitigation strategies in ARDS are in short supply. Treatments with allogeneic stromal cells are administered after ARDS develops, require specialized expertise and equipment, and to date have shown limited benefit. Objectives: Assess the efficacy of immediate post injury intravenous administration of autologous or allogeneic bone marrow-derived mesenchymal stromal cells (MSCs) for the treatment of acute respiratory distress syndrome (ARDS) due to smoke inhalation and burns. Methods: Yorkshire swine (n = 32, 44.3 ± 0.5 kg) underwent intravenous anesthesia, placement of lines, severe smoke inhalation, and 40% total body surface area flame burns, followed by 72 hours of around-the-clock ICU care. Mechanical ventilation, fluids, pressors, bronchoscopic cast removal, daily lung computed tomography scans, and arterial blood assays were performed. After injury and 24 and 48 hours later, animals were randomized to receive autologous concentrated bone marrow aspirate (n = 10; 3 × 106 white blood cells and a mean of 56.6 × 106 platelets per dose), allogeneic MSCs (n = 10; 6.1 × 106 MSCs per dose) harvested from healthy donor swine, or no treatment in injured control animals (n = 12). Measurements and Main Results: The intravenous administration of MSCs after injury and at 24 and 48 hours delayed the onset of ARDS in swine treated with autologous MSCs (48 ± 10 h) versus control animals (14 ± 2 h) (P = 0.004), reduced ARDS severity at 24 (P < 0.001) and 48 (P = 0.003) hours, and demonstrated visibly diminished consolidation on computed tomography (not significant). Mortality at 72 hours was 1 in 10 (10%) in the autologous group, 5 in 10 (50%) in the allogeneic group, and 6 in 12 (50%) in injured control animals (not significant). Both autologous and allogeneic MSCs suppressed systemic concentrations of TNF-α (tumor necrosis factor-α). Conclusions: The intravenous administration of three doses of freshly processed autologous bone marrow-derived MSCs delays ARDS development and reduces its severity in swine. Bedside retrieval and administration of autologous MSCs in swine is feasible and may be a viable injury mitigation strategy for ARDS.

This review explores the intricate relationship between acute respiratory distress syndrome (ARDS) and Type II diabetes mellitus (T2DM). It covers ARDS epidemiology, etiology and pathophysiology, along with current treatment trends and challenges. The lipopolysaccharides (LPS) role in ARDS and its association between non-communicable diseases and COVID-19 are discussed. The review highlights the therapeutic potential of human umbilical cord-derived mesenchymal stem cells (hUC-MSCs) for ARDS and T2DM, emphasizing their immunomodulatory effects. This review also underlines how T2DM exacerbates ARDS pathophysiology and discusses the potential of hUC-MSCs in modulating immune responses. In conclusion, the review highlights the multidisciplinary approach to managing ARDS and T2DM, focusing on inflammation, oxidative stress and potential therapy of hUC-MSCs in the future.

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.

Rheumatoid arthritis (RA) is considered to be a degenerative and progressive autoimmune disorder. Although several medicinal regimens are used to treat RA, potential adverse events such as metabolic disorders and increased risk of infection, as well as drug resistance in some patients, make it essential to find an effective and safe therapeutic approach. Mesenchymal stromal/stem cells (MSCs) are a group of non-hematopoietic stromal cells with immunomodulatory and inhibitory potential. These cells exert their regulatory properties through direct cell-to-cell interactions and paracrine effects on various immune and non-immune cells. As conventional therapeutic approaches for RA are limited due to their side effects, and some patients became refractory to the treatment, MSCs are considered as a promising alternative treatment for RA. In this review, we introduced various experimental and clinical studies conducted to evaluate the therapeutic effects of MSCs on animal models of arthritis and RA patients. Then, possible modulatory and suppressive effects of MSCs on different innate and adaptive immune cells, including dendritic cells, neutrophils, macrophages, natural killer cells, B lymphocytes, and various subtypes of T cells, were categorized and summarized. Finally, limitations and future considerations for the efficient application of MSCs as a therapeutic approach in RA patients were presented.

Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has become a global pandemic. The interplay between innate and adaptive immune responses plays a crucial role in managing COVID-19. Cell therapy has recently emerged as a promising strategy to modulate the immune system, offering immense potential for the treatment of COVID-19 due to its customizability and regenerative capabilities. This review provides an overview of the various subsets of immune cell subsets implicated in the pathogenesis of COVID-19 and a comprehensive summary of the current status of immune cell therapy in COVID-19 treatment.

Induced pluripotent stem cell-derived mesenchymal stem cells (iMSCs) hold great promise as a cell source for transplantation into injured tissues to alleviate inflammation. However, the therapeutic efficacy of iMSC transplantation for ischemic stroke remains unknown. In this study, we evaluated the therapeutic effects of iMSC transplantation on brain injury after ischemia-reperfusion using a rat transient middle cerebral artery occlusion model and compared its therapeutic efficacy with that of bone marrow mesenchymal stem cells (BMMSCs). We showed that iMSCs and BMMSCs reduced infarct volumes after reperfusion and significantly improved motor function on days 3, 7, 14, 28, and 56 and cognitive function on days 28 and 56 after reperfusion compared with the vehicle group. Furthermore, immunological analyses revealed that transplantation of iMSCs and BMMSCs inhibited microglial activation and expression of proinflammatory cytokines and suppressed oxidative stress and neuronal cell death in the cerebral cortex at the ischemic border zone. No difference in therapeutic effect was observed between the iMSC and BMMSC groups. Taken together, our results demonstrate that iMSC therapy can be a practical alternative as a cell source for attenuation of brain injury and improvement of neurological function because of the unlimited supply of uniform therapeutic cells.

Age is a significant risk factor for the coronavirus disease 2019 (COVID-19) severity due to immunosenescence and certain age-dependent medical conditions (e.g., obesity, cardiovascular disorder, and chronic respiratory disease). However, despite the well-known influence of age on autoantibody biology in health and disease, its impact on the risk of developing severe COVID-19 remains poorly explored. Here, we performed a cross-sectional study of autoantibodies directed against 58 targets associated with autoimmune diseases in 159 individuals with different COVID-19 severity (71 mild, 61 moderate, and 27 with severe symptoms) and 73 healthy controls. We found that the natural production of autoantibodies increases with age and is exacerbated by SARS-CoV-2 infection, mostly in severe COVID-19 patients. Multiple linear regression analysis showed that severe COVID-19 patients have a significant age-associated increase of autoantibody levels against 16 targets (e.g., amyloid β peptide, β catenin, cardiolipin, claudin, enteric nerve, fibulin, insulin receptor a, and platelet glycoprotein). Principal component analysis with spectrum decomposition and hierarchical clustering analysis based on these autoantibodies indicated an age-dependent stratification of severe COVID-19 patients. Random forest analysis ranked autoantibodies targeting cardiolipin, claudin, and platelet glycoprotein as the three most crucial autoantibodies for the stratification of severe COVID-19 patients ≥50 years of age. Follow-up analysis using binomial logistic regression found that anti-cardiolipin and anti-platelet glycoprotein autoantibodies significantly increased the likelihood of developing a severe COVID-19 phenotype with aging. These findings provide key insights to explain why aging increases the chance of developing more severe COVID-19 phenotypes.

Inflammatory response in COVID-19 contributes greatly to disease severity. Mesenchymal Stem Cells (MSCs) have the potential to alleviate inflammation and reduce mortality and length of stay in COVID-19 patients. We investigated the safety and effectiveness of normoxic-allogenic umbilical cord (NA-UC)-MSCs as an adjunctive treatment in severe COVID-19 patients. A double-blind, multicentric, randomized, placebo-controlled trial involving severe COVID-19 patients was performed from January to June 2021 in three major hospitals across Java, Indonesia. Eligible participants (n = 42) were randomly assigned to two groups (1:1), namely the intervention (n = 21) and control (n = 21) groups. UC-MSCs dose was 1 × 106 /kg body weight on day D0, D3, and D6. The primary outcome was the duration of hospitalization. Meanwhile, the secondary outcomes were radiographical progression (Brixia score), respiratory and oxygenation parameters, and inflammatory markers, in addition to the safety profile of NA-UC-MSCs. NA-UC-MSCs administration did not affect the length of hospital stay of severe COVID-19 patients, nor did it improve the Brixia score or mMRC dyspnoea scale better than placebo. Nevertheless, NA-UC-MSCs led to a better recuperation in oxygenation index (120.80 ± 72.70 baseline vs. 309.63 ± 319.30 D + 22, p = 0.038) and oxygen saturation (97.24 ± 4.10% vs. 96.19 ± 3.75% in placebo, p = 0.028). Additionally, compared to the placebo group, the treatment group had a significantly smaller increase in PCT level at D + 22 (1.43 vs. 12.76, p = 0.011). No adverse effects, including serious ones, were recorded until D + 91. NA-UC-MSCs therapy is a very safe adjunct for COVID-19 patients. It improves the oxygenation profile and carries potential to suppress inflammation.

Mesenchymal Stromal/Stem cells (MSCs) are an essential component of the regenerative and immunoregulatory stem cell compartment of the human body and thus of major importance in human physiology. The MSCs elicit their beneficial properties through a multitude of complementary mechanisms, which makes it challenging to assess their phenotype and function in environmental toxicity screening. We here employed the novel combinatorial assays matrix approach/technology to profile the MSC response to the herbicide Atrazine, which is a common environmental xenobiotic, that is in widespread agricultural use in the US and other countries, but banned in the EU. Our here presented approach is representative for screening the impact of environmental xenobiotics and toxins on MSCs as an essential representative component of human physiology and well-being.

We here employed the combinatorial assay matrix approach, including a panel of well standardized assays, such as flow cytometry, multiplex secretome analysis, and metabolic assays, to define the phenotype and functionality of human-donor-derived primary MSCs exposed to the representative xenobiotic Atrazine. This assay matrix approach is now also endorsed for characterization of cell therapies by leading regulatory agencies, such as FDA and EMA.

Our results show that the exposure to Atrazine modulates the metabolic activity, size, and granularity of MSCs in a dose and time dependent manner. Intriguingly, Atrazine exposure leads to a broad modulation of the MSCs secretome (both upregulation and downmodulation of certain factors) with the identification of Interleukin-8 as the topmost upregulated representative secretory molecule. Interestingly, Atrazine attenuates IFNγ-induced upregulation of MHC-class-II, but not MHC-class-I, and early phosphorylation signals on MSCs. Furthermore, Atrazine exposure attenuates IFNγ responsive secretome of MSCs. Mechanistic knockdown analysis identified that the Atrazine-induced effector molecule Interleukin-8 affects only certain but not all the related angiogenic secretome of MSCs.

The here described Combinatorial Assay Matrix Technology identified that Atrazine affects both the innate/resting and cytokine-induced/stimulated assay matrix functionality of human MSCs, as identified through the modulation of selective, but not all effector molecules, thus vouching for the great usefulness of this approach to study the impact of xenobiotics on this important human cellular subset involved in the regenerative healing responses in humans.

During the pandemic of severe respiratory distress syndrome coronavirus 2 (SARS-CoV2), many novel therapeutic modalities to treat Coronavirus 2019 induced disease (COVID-19) were explored. This study summarizes 195 clinical trials of advanced cell therapies targeting COVID-19 that were registered over the two years between January 2020 to December 2021. In addition, this work also analyzed the cell manufacturing and clinical delivery experience of 26 trials that published their outcomes by July 2022. Our demographic analysis found the highest number of cell therapy trials for COVID-19 was in United States, China, and Iran (N=53, 43, and 19, respectively), with the highest number per capita in Israel, Spain, Iran, Australia, and Sweden (N=0.641, 0.232, 0,223, 0.194, and 0.192 trials per million inhabitants). The leading cell types were multipotent mesenchymal stromal/stem cells (MSCs), natural killer (NK) cells, and mononuclear cells (MNCs), accounting for 72%, 9%, and 6% of the studies, respectively. There were 24 published clinical trials that reported on infusions of MSCs. A pooled analysis of these MSC studies found that MSCs provide a relative risk reduction for all-cause COVID-19 mortality of RR=0.63 (95% CI 0.46 to 0.85). This result corroborates previously published smaller meta-analyses, which suggested that MSC therapy demonstrated a clinical benefit for COVID-19 patients. The sources of the MSCs used in these studies and their manufacturing and clinical delivery methods were remarkably heterogeneous, with some predominance of perinatal tissue-derived products. Our results highlight the important role that cell therapy products may play as an adjunct therapy in the management of COVID-19 and its related complications, as well as the importance of controlling key manufacturing parameters to ensure comparability between studies. Thus, we support ongoing calls for a global registry of clinical studies with MSC products that could better link cell product manufacturing and delivery methods to clinical outcomes. Although advanced cell therapies may provide an important adjunct treatment for patients affected by COVID-19 in the near future, preventing pathology through vaccination still remains the best protection to date. We conducted a systematic review and meta-analysis of advanced cell therapy clinical trials as potential novel treatment for COVID-19 (resulting from SARS-CoV-2 coronavirus infection), including analysis of the global clinical trial landscape, published safety/efficacy outcomes (RR/OR), and details on cell product manufacturing and clinical delivery. This study had a 2-year observation interval from start of January 2020 to end of December 2021, including a follow-up period until end of July to identify published outcomes, which covers the most vivid period of clinical trial activity, and is also the longest observation period studied until today. In total, we identified 195 registered advanced cell therapy studies for COVID-19, employing 204 individual cell products. Leading registered trial activity was attributed to the USA, China, and Iran. Through the end of July 2022, 26 clinical trials were published, with 24 out of 26 articles employing intravenous infusions (IV) of mesenchymal stromal/stem cell (MSC) products. Most of the published trials were attributed to China and Iran. The cumulative results from the 24 published studies employing infusions of MSCs indicated an improved survival (RR=0.63 with 95% Confidence Interval 0.46 to 0.85). Our study is the most comprehensive systematic review and meta-analysis on cell therapy trials for COVID-19 conducted to date, clearly identifying the USA, China, and Iran as leading advanced cell therapy trial countries for COVID-19, with further strong contributions from Israel, Spain, Australia and Sweden. Although advanced cell therapies may provide an important adjunct treatment for patients affected by COVID-19 in the future, preventing pathology through vaccination remains the best protection.

Mesenchymal stromal/stem cells (MSCs) possess the ability to self-renew and differentiate into other cell types. Because of their anti-inflammatory and immunomodulatory abilities, as well as their more ready availability compared to other stem cell sources, MSCs hold great promise for the treatment of many diseases, such as haematological defects, acute respiratory distress syndrome, autoimmunity, cardiovascular diseases, etc. However, immune rejection remains an important problem. MSCs are considered to have low immunogenicity, but they do not have full immunological privilege. This review analyzes and discusses the safety of MSCs from the perspective of their immunogenicity, with the aim of providing a reference for future research and clinical application.

Many cell types, including cancer cells, release tissue factor (TF)-exposing extracellular vesicles (EVs). It is unknown whether MSC-EVs pose a thromboembolism risk due to TF expression. Knowing that MSCs express TF and are procoagulant, we hypothesize that MSC-EVs also might. Here, we examined the expression of TF and the procoagulant activity of MSC-EVs and the impact of EV isolation methods and cell culture expansion on EV yield, characterization, and potential risk using a design of experiments methodology. MSC-EVs were found to express TF and have procoagulant activity. Thus, when MSC-derived EVs are employed as a therapeutic agent, one might consider TF, procoagulant activity, and thromboembolism risk and take steps to prevent them.

Global pandemic identified as coronavirus disease 2019 (COVID-19) has resulted in a variety of clinical symptoms, from asymptomatic carriers to those with severe acute respiratory distress syndrome (SARS) and moderate upper respiratory tract symptoms (URTS). This systematic review aimed to determine effectiveness of stem cell (SC) applications among COVID-19 patients.

Multiple databases of PubMed, EMBASE, Science Direct, Google Scholar, Scopus, Web of Science, and Cochrane Library were used. Studies were screened, chosen, and included in this systematic review using Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020 flowchart diagram and PRISMA checklist. Included studies' quality was assessed employing Critical Appraisal Skills Programme (CASP) quality evaluation criteria for 14 randomized controlled trials (RCTs).

Fourteen RCTs were performed between the years of 2020 to 2022, respectively, with a sample size n = 574 (treatment group (n = 318); control group (n = 256)) in multiple countries of Indonesia, Iran, Brazil, Turkey, China, Florida, UK, and France. The greatest sample size reported from China among 100 COVID-19 patients, while the lowest sample of 9 COVID-19 patients from Jakarta, Indonesia, and the patient's age ranges from 18 to 69 years. Studies applied to the type of SC were "Umbilical cord MSCs, MSCs secretome, MSCs, Placenta-derived MSCs, Human immature dental pulp SC, DW-MSC infusion, Wharton Jelly-derived MSCs". The injected therapeutic dose was 1 × 10⁶ cells/kg, 1 × 10⁷ cells/kg, 1 × 10⁵ cells/kg, and 1 million cells/kg as per the evidence from the different studies. Studies focused on demographic variables, clinical symptoms, laboratory tests, Comorbidities, respiratory measures, concomitant therapies, Sequential Organ Failure Assessment score, mechanical ventilation, body mass index, adverse events, inflammatory markers, and PaO₂/FiO₂ ratio were all recorded as study characteristics.

Clinical evidence on MSC's therapeutic applications during COVID-19 pandemic has proven to be a promising therapy for COVID-19 patient recovery with no consequences and applied as a routine treatment for challenging ailments.

A novel coronavirus strain (COVID-19) caused severe illness and mortality worldwide from 31 December 2019 to 21 March 2023. As of this writing, 761,071,826 million cases have been diagnosed worldwide, with 6,879,677 million deaths accorded by WHO organization and has spread to 228 countries. The number of deaths is closely connected to the growth of innate immune cells in the lungs, mainly macrophages, which generate inflammatory cytokines (especially IL-6 and IL-1β) that induce "cytokine storm syndrome" (CSS), multi-organ failure, and death. We focus on promising natural products and their biologically active chemical constituents as potential phytopharmaceuticals that target virus-induced pro-inflammatory cytokines. Successful therapy for this condition is currently rare, and the introduction of an effective vaccine might take months. Blocking viral entrance and replication and regulating humoral and cellular immunity in the uninfected population are the most often employed treatment approaches for viral infections. Unfortunately, no presently FDA-approved medicine can prevent or reduce SARS-CoV-2 access and reproduction. Until now, the most important element in disease severity has been the host's immune response activation or suppression. Several medicines have been adapted for COVID-19 patients, including arbidol, favipiravir, ribavirin, lopinavir, ritonavir, hydroxychloroquine, chloroquine, dexamethasone, and anti-inflammatory pharmaceutical drugs, such as tocilizumab, glucocorticoids, anakinra (IL-1β cytokine inhibition), and siltuximab (IL-6 cytokine inhibition). However, these synthetic medications and therapies have several side effects, including heart failure, permanent retinal damage in the case of hydroxyl-chloroquine, and liver destruction in the case of remdesivir. This review summarizes four strategies for fighting cytokine storms and immunomodulatory deficiency induced by COVID-19 using natural product therapy as a potential therapeutic measure to control cytokine storms.

The capacity of self-renewal and multipotent differentiation makes mesenchymal stem cells (MSC) one of the most widely investigated cell lines in preclinical studies as cell-based therapies. However, the low survival rate and poor homing efficiency of MSCs after transplantation hinder the therapeutic application. Exosomes derived from MSCs have shown promising therapeutic potential in many diseases. However, the heterogeneity of MSCs may lead to differences in the function of secreting exosomes. In this study, the therapeutic effects of hUC-Exos and hFP-Exos on the DSS-induced colitis mouse model were investigated.

The colitis mouse models were randomly divided into four groups: (1) DSS administered for 7 days and euthanasia (DSS7D), (2) DSS administered for 7 days and kept for another 7 days without any treatment (DSS14D), (3) DSS administered for 7 days and followed with hUC-EVs infusion for 7 days (hUC-EVs) and (4) DSS administered for 7 days and followed with hFP-EVs infusion for 7 days (hFP-EVs). We analyzed colon length, histopathology, Treg cells, cytokines and gut microbiota composition in each group.

A large amount of IL-6, IL-17 and IFN-γ were produced along with the decrease in the number of CD4 + Foxp3 + and CD8 + Foxp3 + cells in DSS7D group, which indicated that Th17 cells were activated and Treg cells were suppressed. We found that the number of CD4 + Foxp3 + and CD8 + Foxp3 + cells increased in order to suppress inflammation, but the length of colon did not recover and the symotoms were worsened of the colonic tissue in DSS14D group. The subsequent infusion of either hUC-Exos or hFP-Exos mediated the transformation of Treg and Th17 cells in colitis mice to maintain immune balance. The infusion of hUC-Exos and hFP-Exos also both reduced the abundance of pro-inflammatory intestinal bacterial such as Verrucomicrobia and Akkermansia muciniphila to improve colitis.

We found that Foxp3 + Treg cells can inhibit the inflammatory response, and the over-activated Treg cells can still further damage the intestinal mucosa. hUC-Exos and hFP-Exos can control inflammation by regulating the balance between Th17 cells and Treg cells. Decreased inflammatory response improved the structure of colon wall in mice and reduced the abundance of pro-inflammatory bacteria in the intestine. The improvement of intestinal wall structure provides conditions for the reproduction of beneficial bacteria, which further contributes to the reduction of colitis.

The incidence of stroke and neurodegenerative diseases is gradually increasing in modern society, but there is still no treatment that is effective enough. Stem cells are cells that can reproduce (self-renew) and differentiate into the body, which have shown significance in basic research, while doctors have also taken them into clinical trials to determine their efficacy and safety. Existing clinical trials mainly include middle-aged and elderly patients with stroke or Parkinson's disease (mostly 40-80 years old), mainly involving injection of mesenchymal stem cells and bone marrow mesenchymal stem cells through the veins and the putamen, with a dosage of mostly 106-108 cells. The neural and motor functions of the patients were restored after stem cell therapy, and the safety was found to be good during the follow-up period of 3 months to 5 years. Here, we review all clinical trials and the latest advances in stroke, Alzheimer's disease, and Parkinson's disease, with the hope that stem cell therapy will be used in the clinic in the future to achieve effective treatment rates and benefit patients.

Diabetes mellitus (DM) is an important cause of chronic wounds and non-traumatic amputation. The prevalence and number of cases of diabetic mellitus are increasing worldwide. Keratinocytes, the outermost layer of the epidermis, play an important role in wound healing. A high glucose environment may disrupt the physiologic functions of keratinocytes, resulting in prolonged inflammation, impaired proliferation, and the migration of keratinocytes and impaired angiogenesis. This review provides an overview of keratinocyte dysfunctions in a high glucose environment. Effective and safe therapeutic approaches for promoting diabetic wound healing can be developed if molecular mechanisms responsible for keratinocyte dysfunction in high glucose environments are elucidated.

Xeno-free three-dimensional cultures are gaining attention for mesenchymal stem cell (MSCs) expansion in clinical applications. We investigated the potential of xeno-free serum alternatives, human serum and human platelet lysate, to replace the current conventional use of foetal bovine serum for subsequent MSCs microcarrier cultures. In this study, Wharton's Jelly MSCs were cultured in nine different media combinations to identify the best xeno-free culture media for MSCs culture. Cell proliferation and viability were identified, and the cultured MSCs were characterised in accordance with the minimal criteria for defining multipotent mesenchymal stromal cells by the International Society for Cellular Therapy (ISCT). The selected culture media was then used in the microcarrier culture of MSCs to determine the potential of a three-dimensional culture system in the expansion of MSCs for future clinical applications, and to identify the immunomodulatory potential of cultured MSCs. Low Glucose DMEM (LG) + Human Platelet (HPL) lysate media appeared to be good candidates for replacing conventional MSCs culture media in our monolayer culture system. MSCs cultured in LG-HPL achieved high cell yield, with characteristics that remained as described by ISCT, although the overall mitochondrial activity of the cells was lower than the control and the subsequent effects remained unknown. MSC microcarrier culture, on the other hand, showed comparable cell characteristics with monolayer culture, yet had stagnated cell proliferation, which is potentially due to the inactivation of FAK. Nonetheless, both the MSCs monolayer culture and the microcarrier culture showed high suppressive activity on TNF-α, and only the MSC microcarrier culture has a better suppression of IL-1 secretion. In conclusion, LG-HPL was identified as a good xeno-free media for WJMSCs culture, and although further mechanistic research is needed, the results show that the xeno-free three-dimensional culture maintained MSC characteristics and improved immunomodulatory activities, suggesting the potential of translating the monolayer culture into this culture system in MSC expansion for future clinical application.

Several perturbations in the number of peripheral blood leukocytes, such as neutrophilia and lymphopenia associated with Coronavirus disease 2019 (COVID-19) severity, point to systemic molecular cell cycle alterations during severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection. However, the landscape of cell cycle alterations in COVID-19 remains primarily unexplored. Here, we performed an integrative systems immunology analysis of publicly available proteome and transcriptome data to characterize global changes in the cell cycle signature of COVID-19 patients. We found significantly enriched cell cycle-associated gene co-expression modules and an interconnected network of cell cycle-associated differentially expressed proteins (DEPs) and genes (DEGs) by integrating the molecular data of 1469 individuals (981 SARS-CoV-2 infected patients and 488 controls [either healthy controls or individuals with other respiratory illnesses]). Among these DEPs and DEGs are several cyclins, cell division cycles, cyclin-dependent kinases, and mini-chromosome maintenance proteins. COVID-19 patients partially shared the expression pattern of some cell cycle-associated genes with other respiratory illnesses but exhibited some specific differential features. Notably, the cell cycle signature predominated in the patients' blood leukocytes (B, T, and natural killer cells) and was associated with COVID-19 severity and disease trajectories. These results provide a unique global understanding of distinct alterations in cell cycle-associated molecules in COVID-19 patients, suggesting new putative pathways for therapeutic intervention.