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.

Fibrodysplasia ossificans progressiva (FOP) is a genetic disease characterized by extraskeletal heterotopic ossification (HO). The underlying mechanism is the aberrant activation of bone morphogenetic protein (BMP) signaling caused by a point mutation in the ACVR1 gene. Although FOP is an ultra-rare disease, its symptoms severely impair patients' daily activities and quality of life. Furthermore, the HO is also observed in broader clinical contexts, including major surgeries and trauma, highlighting the significance of its study. We have previously reported that rapamycin suppressed Activin-A-triggered progression of cartilage formation in FOP mice. We recently found that the ACVR2B-Fc fusion protein produced by mesenchymal stem/stromal cells derived from induced pluripotent stem cells (iMSCs) attenuates BMP signaling activated by Activin-A and BMP-9 in FOP patient-derived iMSCs. Transplantation of ACVR2B-Fc-producing iMSCs (iMSC2B-Fc/Luci) reduces primary HO in FOP mice. In this study, we found that intraperitoneal administration of rapamycin reduced primary HO in a dose-dependent manner in FOP-ACVR1R206H transgenic mice. A low concentration of rapamycin (0.3 mg/kg, 5 times/wk) efficiently suppressed chondrogenesis. The combination of iMSC2B-Fc/Luci transplantation with low concentration of rapamycin significantly reduced primary and recurrent HO. Rapamycin improved cell survival in transplanted iMSC2B-Fc/Luci cells by attenuating chemokine secretion, likely resulting in improved ACVR2B-Fc fusion protein production. Our results suggest that combining stem cell therapy and rapamycin can reduce primary HO and surgery-induced HO.

Chronic cerebral ischemia (CCI) results in a prolonged insufficient blood supply to the brain tissue, leading to impaired neuronal function and subsequent impairment of cognitive and motor abilities. Our previous research showed that in mice with bilateral carotid artery stenosis, the collateral neovascularization post Encephalo-myo-synangiosis (EMS) treatment could be facilitated by bone marrow mesenchymal stem cells (MSCs) transplantation. Considering the advantages of biomaterials, we synthesized and modified a gelatin hydrogel for MSCs encapsulation. We then applied this hydrogel on the brain surface during EMS operation in rats with CCI, and evaluated its impact on cognitive performance and collateral circulation. Consequently, MSCs encapsulated in hydrogel significantly augment the therapeutic effects of EMS, potentially by promoting neovascularization, facilitating neuronal differentiation, and suppressing neuroinflammation. Furthermore, taking advantage of multi-RNA-sequencing and in silico analysis, we revealed that MSCs loaded in hydrogel regulate PDCD4 and CASP2 through the overexpression of miR-183-5p and miR-96-5p, thereby downregulating the expression of apoptosis-related proteins and inhibiting early apoptosis. In conclusion, a gelatin hydrogel to enhance the functionality of MSCs has been developed, and its combination with EMS treatment can improve the therapeutic effect in rats with CCI, suggesting its potential clinical benefit.

Mesenchymal stem cells (MSCs) are frequently used for therapeutic applications in both pre-clinical and clinical settings owing to their capacity for immune modulation and neuroprotective effects. However, transient fever is commonly observed as an adverse event following MSC injection in patients with Alzheimer's disease (AD). In this study, we investigated the potential impact of immunosuppressants such as dexamethasone and tacrolimus on altering the characteristics of human mesenchymal stem cells (hMSCs). Additionally, we examined whether these immunosuppressants affect the persistence of hMSCs or the immune response upon their administration into the brain parenchyma of AD mice. The exposure of hMSCs to high concentrations of dexamethasone and tacrolimus in vitro did not significantly alter the characteristics of hMSCs. The expression of genes related to innate immune responses, such as Irak1, Irf3, Nod1, and Ifnar1, was significantly downregulated by the additional administration of dexamethasone and tacrolimus to the brain parenchyma of AD mice. However, hMSC persistence in the AD mouse brain was not affected. The results of this study support the use of immunosuppressants to mitigate fever during stem cell therapy in patients with AD.

Mesenchymal stem/stromal cells (MSCs) possess immunoregulatory capacity, which is enhanced in an inflammatory environment. Participation of extracellular vesicles (EVs) in this function is proposed, as they can transport various immunoregulatory molecules. However, the impact of the inflammatory microenvironment on the load of the different types of EVs released by these cells is not fully known. Therefore, this work analyzes in detail the temporal effect of IFN-γ, alone or in combination with TNF-α (TNF-α + IFN-γ), on the cargo of immunoregulatory molecules (programmed cell death ligand 1 [PD-L1], CD73, and intercellular adhesion molecule 1 [ICAM-1]) in large extracellular vesicles (L-EVs) released by human bone marrow mesenchymal stem cells (BM-MSCs). The presence of these molecules on the surface of L-EVs was determined by flow cytometry. Our results demonstrate that exposing BM-MSCs to TNF-α + IFN-γ for 24 h increases the percentage of PD-L1+ and CD73+ L-EVs. However, if this stimulus persists, the release of L-EVs with an immunoregulatory phenotype (PD-L1+, CD73+, and PD-L1+CD73+) decreases. The impact of pro-inflammatory cytokines on the transport of ICAM-1 by L-EVs is late, since up to 72 h of treatment with IFN-γ or TNF-α + IFN-γ, the percentage of ICAM-1+ L-EVs increases. In contrast, stimulation with IFN-γ for 72 h favors the release of CD73high and ICAM-1high L-EVs, but this effect also decreases in the presence of TNF-α. Our study generates novel knowledge about the impact of the inflammatory microenvironment on the cargo composition of L-EVs released by BM-MSCs and demonstrates, for the first time, that the prolonged presence of TNF-α reduces the cargo of immunoregulatory molecules in these structures.

Acute graft-versus-host disease (aGVHD) is a major complication of allogeneic hematopoietic cell transplantation (allo-HCT) that is caused by donor immune cells attacking and damaging host tissues. Immune suppressive small molecule and protein-based therapeutics targeting donor anti-host immune cells are currently used for GVHD prophylaxis and treatment. Even with these therapies, aGVHD progresses to life-threatening steroid-refractory aGVHD (SR-aGVHD) in up to 50% of cases and is a risk factor for the subsequent development of debilitating chronic GVHD. To improve aGVHD-related outcomes, donor graft engineering techniques and adoptive transfer of immune modulatory cells have been explored. Highly rigorous donor graft T-cell depletion approaches have revealed that mitigation of aGVHD can be accompanied by slow immune recovery post-allo-HCT and reduction in anti-microbial and anti-leukemia responses resulting in increased relapse and infection rates, respectively. Recent T-cell separation techniques allowing for precision graft engineering by selectively eliminating aGVHD-causing T-cells (eg, naïve T-cells) without loss of T-cells with beneficial functions and retaining and/or enriching immune regulatory populations (eg, regulatory T-cells (Tregs) or myeloid-derived suppressor cells) have been tested and will continue to improve. Clinical cell-based regulatory therapies have been employed for targeting SR-aGVHD, particularly mesenchymal stem cells (MSCs) and more recently, Tregs. In this review, we summarize aGVHD pathophysiology, highlight newly discovered aGVHD mechanisms, and discuss current and emerging cellular and graft manipulation approaches for aGVHD prevention and treatment.

Mesenchymal stem cells (MSCs) have emerged as a promising option for gene and cell therapy due to their unique biological properties. MSC-based cell therapies have garnered significant attention for various clinical applications; however, repeated administrations are often necessary to achieve sustained therapeutic effects. Genetic modification techniques have enhanced MSCs' intrinsic capabilities, improving their therapeutic efficacy in both experimental and clinical settings. Key functional properties anti-inflammatory, anti-fibrotic, survival, and migratory capacities have become central targets for genetic enhancement. Numerous studies have explored the genetic modification of MSCs to address overcoming the transient nature of their therapeutic effects. Notably, the safety of genetically engineered MSCs remains a critical concern in preclinical and clinical investigations.In this review, we summarize current strategies for the genetic modification of MSCs and discuss recent findings on their application in animal disease models.

Recently, cell therapies, including chimeric antigen receptor (CAR) modified T cell therapy and mesenchymal stem cell (MSC) therapy, have demonstrated considerable potential for systemic lupus erythematosus (SLE). In this study, a CAR-MSC model was constructed, combining two cell therapies. The structural domains of the CAR were designed by using the anti-CD19 scFv, targeting the CD19 antigen on the surface of B cells and the intracellular region of the interferon-gamma receptor, activating the JAK-STAT1 signaling pathway. Then we screened and identified the most effective structural domain of CAR as CAR1, as it facilitates MSCs to maintain significantly higher levels of JAK2 phosphorylation and IDO expression, as shown by western blot analysis. We also demonstrated CAR1 could be consistently and stably expressed at high levels in MSCs, and CAR1 transduction did not significantly affect the surface antigenic phenotypic criteria of MSCs via flow analysis. Furthermore, immunofluorescence results showed CAR1-MSCs could stably bind CD19 antigen, and they were activated by human CD19 antigen resulting in significantly high JAK2 phosphorylation and IDO expression via western blot analysis following co-culture. Besides, when activated peripheral blood mononuclear cells (PBMCs) were co-cultured with untransduced MSCs (UTD-MSCs) and CAR1-MSCs in vitro, respectively, the results showed that the percentage of activated CD3+ T cells and CD19+ B cells was both significantly lower after co-culturing. The percentage of activated CD19+ B cells was lower in the CAR1-MSCs co-culture group than in the UTD-MSCs co-culture group, whereas the percentage of activated CD3+ T cells was similar in the two co-culture groups. This suggests that CAR1 increased the inhibitory ability of MSCs on activated CD19+ B cells and had no significant effect on the ability of MSCs to inhibit activated CD3+ T cells. In conclusion, CAR1-MSCs were successfully constructed and demonstrated the ability to enhance the inhibitory effect of MSCs on activated human CD19+ B cells, facilitating SLE therapy.

Mesenchymal stem cells (MSCs) have demonstrated significant potential in heart failure (HF) treatment, but the exact mechanisms are still not fully understood. This research utilized single-cell RNA sequencing to examine alterations in peripheral blood mononuclear cells from heart failure patients pre- and post-MSC therapy. Moreover, we utilized Mendelian randomization (MR) analysis to identify causal genes linked to HF. Specifically, through scRNA-seq, we observed a progressive increase in Natural Killer (NK) cells within peripheral blood mononuclear cells (PBMCs) following MSC treatment. Furthermore, MR analysis identified the differentially expressed gene (DEG) BAX as a potential target gene for HF. Notably, the expression of BAX was significantly downregulated after MSC treatment, suggesting its potential as a therapeutic response biomarker. Cell-cell communication analysis revealed that BAXhigh NK cells displayed reduced cell-cell communication and increased apoptotic activity. Enrichment analysis indicated an association between BAXhigh NK cells and the "coagulant" pathway. Taken together, our findings suggest that BAX may contribute to the pathogenesis of HF by promoting coagulation and apoptotic pathways. In contrast, MSCs appear to suppress BAX expression, thereby inhibiting these pathways. MSC treatment increases the proportion of NK cells and reduces BAXhigh NK cells, ultimately improving NK cell function, and ameliorating HF.

Primary graft dysfunction (PGD) is common in lung transplantation affecting 15-30% of recipients. It represents a multifactorial injury to the transplanted lung within the first 72 hours after transplantation.We aimed to investigate clinical safety and efficacy of allogeneic adipose tissue-derived stromal cells (ASCs), as an add-on therapy in patients undergoing double lung transplantation.

Single center, double-blinded, investigator-initiated randomized phase I/II study with intravenous infusion of either ASCs or placebo within two hours after lung transplantation. A total of 31 patients were included and randomized 1:1:1 to either 200 million or 100 million ASCs, or placebo infusion.The primary endpoint was difference in PGD grade 72 hours after transplantation between groups.

No significant differences in PGD were seen between the 3 groups 72 hours after lung transplantation (P=0.426). Combined ASC groups compared to placebo group did not show any difference in PGD 72 hours after transplantation (P=0.252). A reduced progression in PGD from day 1 to day 3 and day 2 to day 3 was observed between the ASC treated patients and patients in the placebo group (P=0.034 and P=0.034, respectively). There were no significant differences in number of serious adverse events or in secondary endpoints such as kidney function, lung function, or quality-of-life between groups.

Intravenous infusion of allogeneic ASCs in patients immediately after double lung transplantation was safe. The therapy did not show statistic difference in PGD between groups 72 hours after lung transplantation.

EudraCT number 2019-004848-30 and NCT04714801.

Considering the different behaviour of cells in response to diseases in different conditions and sex hormone-dependent cancers, we addressed the possible effect of the sex of the source of these cells from adipose tissue on prostate cancer cells. In this in vitro study, we evaluated the effects of male and female MSC Conditioned Media (MCM, FCM) on prostate cancer cells. The assessment included Hoechst dye staining, a scratch-wound assay, a colony formation assay, and a flow cytometric analysis of apoptosis and the cell cycle. We also performed real-time PCR to examine various genes, including apoptosis-related genes, epithelial-mesenchymal transition (EMT) genes, angiogenesis-related genes, and cell growth and survival biomarkers. Our results indicated that the IC50 values were 50% and 75% media in MCM and FCM in each of the three prostate cancer cell lines, respectively. An evaluation of gene expression revealed that in all three prostate cancer cell lines, treatment with MCM was more effective than FCM in reducing the expression of N-Cadherin and Vimentin, EGFR and BCL2 genes (p < 0.001). Furthermore, the MCM significantly increased the expression of BAX and E-Cadherin genes (p < 0.001) in the PC3 cell line. MCM proved to be more effective than FCM in reducing the expression of the epithelial-mesenchymal transition pathway, EGFR gene, and Apoptosis Regulator (BCL2) in the PC3 cell line. Due to its potential in regenerative medicine and cell therapy, this approach may serve as an effective treatment option for advanced prostate cancer.

Radiation induced hematopoietic failure was the primary cause of death after exposure to a moderate or high dose of whole body irradiation, causing increased challenge for nuclear or radiological treatment, so it is an urgent need to develop radioprotectors for attenuating hematopoietic damage caused by acute radiation syndrome (ARS). Given the excellent therapeutic effects and special benefits of mesenchymal stem cells (MSCs) in radiation damaged hematopoietic stem/progenitor cells (HSPCs) recovery and hematopoietic niche reconstruction, enhancing the hematopoietic niche with the radiotolerance MSCs can be an alternative solution to prevent and attenuate hematopoietic radiation damage, which needs to be studied.

Here, we constructed MSCs modified with Damage Suppressor Protein (DSUP), a radiotolerance gene identified from tardigrade Ramazzotius varieornatus, and verify its radiation protection effect in HSPCs-MSCs co-culture model in vitro and radiation damaged mice model in vivo.

Our results showed that DSUP protein had no significant toxic side effects on the basic stemness properties and differentiation potential of MSCs, and significantly enhanced the radiation tolerance and DNA protection ability of MSCs. Compared with the control (CON) group MSCs, the DSUP modified MSCs after radiation damage suffered less DNA damage, preserved most of proliferation activity and migration ability. In the HSPCs-MSCs co-culture model, DSUP modified MSCs have significant protective effect on HSPCs by providing a functional hematopoietic niche after radiation damage. The DSUP group irradiated HSPCs exhibited more rapid recovery, the higher HSPCs ratio and better hematopoietic differentiation potential. In animal studies, pre infusion of DSUP modified MSCs reduce irradiated mice mortality rate, reduce hematopoietic failure incidence, and provide a protective effect against radiation injury by protecting hematopoietic microenvironment and promoting HSCs recovery. DSUP modified MSCs can be used as a radioprotector and existed significant radiation protection effect for ARS at doses below 7 Gy total-body irradiation (TBI) of X-ray in both immunodeficient and immunocompetent mice models.

DSUP modified MSCs may serve as a new radioprotector for ARS. DSUP modified MSCs could attenuate radiation damage of HSPCs and promote HSPCs rapid recovery as well as hematopoietic reconstruction by providing a more functional niche after radiation, thereby reducing the occurrence of hematopoietic failure and improving survival rate.

Mesenchymal stem cells (MSCs) are currently being used in clinical trials for the treatment of a wide range of diseases and have a wide range of applications in the fields of tissue engineering and regeneration. Exosomes are extracellular vesicles containing a variety of components such as proteins, nucleic acids and lipids, which are widely present in biological fluids and have the functions of participating in intercellular information transfer, immune response and tissue repair, and can also be used as carriers to target and deliver tumors to improve therapeutic effects. Mesenchymal stem cell-derived Exosomes (MSC-Exos), which have the advantages of low immunogenicity and high tumor homing ability, have attracted much attention in targeted drug delivery. Here, we review the current knowledge on the involvement of MSC-Exos in tumor progression and their potential as drug delivery systems in targeted therapies. It also discusses the advantages and prospects of MSC-Exos as a drug carrier and the challenges that still need to be overcome.

Chemotherapy-related cardiotoxicity (CTRTOX) is a profound and common side effect of cancer-based therapy in a subset of patients. The underlying factors and the associated mechanisms contributing to severe toxicity of the heart among these patients remain unknown. While challenges remain in accessing human subjects and their ventricular cardiomyocytes (CMs), advancements in human induced pluripotent stem cell (hiPSC)-technology-based CM differentiation protocols over the past few decades have paved the path for iPSC-based models of human cardiac diseases. Here, we offer a detailed analysis of the underlying mechanisms of CTRTOX. We also discuss the recent advances in therapeutic strategies in different animal models and clinical trials. Furthermore, we explore the prospects of iPSC-based models for identifying novel functional targets and developing safer chemotherapy regimens for cancer patients that may be beneficial for developing personalized cardioprotectants and their application in clinical practice.

Mesenchymal stem cell derived extracellular vesicles (MSC-EVs) are key paracrine mediators involved in various autoimmune diseases. While current research on EVs predominantly focuses on their protein and nucleic acid components, small peptides received less attention. In this study, we found IFN-γ-treated MSC-EVs, as engineered EVs, exhibit better anti-inflammatory effects both in vitro and in vivo. Through LC-MS/MS and bioinformatics analysis, we identified four peptides-C3-1, C3-2, B2M-1, and IFIT3-1-that are highly expressed in IFN-γ-treated MSCs-EVs. These peptides significantly mitigate the proliferation inhibition of HUVEC cells induced by H₂O₂ and enhance their migratory capacity. Furthermore, they downregulate the expression of inflammatory cytokines TNF-α and IL-6 in H₂O₂-induced oxidative stress models of HUVEC and LPS-induced inflammatory models of RAW264.7 macrophages. The peptides also upregulate p-AKT and HIF-1α, with C3-1 demonstrating superior anti-inflammatory efficacy in both cell models. Consistent with the in vitro findings, in vivo experiments revealed that C3-1 reduces LPS-induced inflammatory cell infiltration in liver tissue and restores hepatocyte structural integrity, as evidenced by HE-stained liver sections. Western blot analysis further confirmed that C3-1 upregulates p-AKT expression and suppresses inflammatory cytokines. Collectively, these findings suggest that C3-1 exerts its anti-inflammatory effects via activation of the AKT signaling pathway and regulation of TNF-α and IL-6. This study not only highlights the anti-inflammatory potential of IFN-γ-treated MSC-derived EVs but also identifies C3-1 as a promising candidate for anti-inflammatory drug development. Notably, this is the first study to identify degraded peptides within EVs, providing a foundation for future research in this area.

Recent randomized controlled trials have consistently demonstrated the safety and potential efficacy of MSC therapy for heart failure patients. This study delves into mesenchymal stem cells' promising potential, offering a beacon of hope for the future of heart failure treatment with reduced ejection fraction (HFrEF).

We followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines for this systematic review and meta-analysis. We searched four databases and registers for RCTs, including PubMed, EBSCO, clinicaltrials.gov, ICTRP, and other relevant websites. We then selected thirteen RCTs with 1184 participants based on our pre-defined inclusion/exclusion criteria. Two independent assessors extracted the data and performed a quality assessment. The data were then plotted for various outcomes, including death, hospitalization, major adverse cardiac events, pump function parameters, and 6-min walk distance.

The safety of MSC-based treatment has been consistently demonstrated with MSCs from autologous (AutoMSCs) and allogeneic (AlloMSCs) sources. This reassuring finding underscores the reliability of MSC-based therapy irrespective of their source. However, AutoMSCs showed a trend toward greater protective benefits. Subgroup analysis revealed no significant differences between AutoMSCs and AlloMSCs in improving LVEF; 0.86% (95% CI - 1.21-2.94%) for AlloMSCs versus 2.17% (- 0.48%; 95% CI - 1.33-5.67%) for AutoMSCs. AlloMSCs significantly reduced end-diastolic volume (LVEDV) by - 2.08 mL (95% CI - 3.52-0.64 mL). Only AlloMSCs significantly improved 6-min walking distance (6-MWD); 31.88 m (95% CI 5.03-58.74 m) for AlloMSCs versus 31.71 m (95% CI - 8.91-71.25 m) for AutoMSCs. The exclusion of studies using adipose-derived cells resulted in even better safety and a significant improvement in LVEF for AlloMSCs treatment.

Our findings suggest that AlloMSCs are at par with AutoMSCs in improving functional outcomes in heart failure patients. This underscores the need for future investigations in a larger patient cohort, emphasizing the urgency and importance of further research to fully understand the potential of MSCs in treating heart failure.

Orthopedic diseases pose significant challenges to public health due to their high prevalence, debilitating effects, and limited treatment options. Additionally, orthopedic tumors, such as osteosarcoma, chondrosarcoma, and Ewing sarcoma, further complicate the treatment landscape. Current therapies, including pharmacological treatments and joint replacement, address symptoms but fail to promote true tissue regeneration. Cell-based therapies, which have shown successful clinical results in cancers and other diseases, have emerged as a promising solution to repair damaged tissues and restore function in orthopedic diseases and tumors. This review discusses the advances and potential application of cell therapy for orthopedic diseases, with a particular focus on osteoarthritis, bone fractures, cartilage degeneration, and the treatment of orthopedic tumors. We explore the potential of mesenchymal stromal cells (MSCs), chondrocyte transplantation, engineered immune cells and induced pluripotent stem cells to enhance tissue regeneration by modulating the immune response and addressing inflammation. Ultimately, the integration of cutting-edge cell therapy, immune modulation, and molecular targeting strategies could revolutionize the treatment of orthopedic diseases and tumors, providing hope for patients seeking long-term solutions to debilitating conditions.

Stem cells are specialised precursor cells that can replace aged or damaged cells and thereby maintain healthy tissue function. Stem cell therapy is increasingly used as a treatment for knee osteoarthritis, despite the lack of clarity around the mechanism by which stem cell therapy may slow down disease progression in osteoarthritis, and uncertainty regarding its benefits and harms.

To assess the benefits and harms of stem cell injections for people with osteoarthritis of the knee. A secondary objective is to maintain the currency of the evidence, using a living systematic review approach.

We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE and Embase on 15 September 2023, unrestricted by date or language of publication. We also searched ClinicalTrials.gov and the WHO International Clinical Trials Registry Platform (ICTRP) for relevant trial protocols and ongoing trials.

We included randomised controlled trials (RCTs), or trials using quasi-randomised methods of participant allocation, comparing stem cell injection with placebo injection, no treatment or usual care, glucocorticoid injection, other injections, exercise, drug therapy, surgical interventions, and supplements and complementary therapies in people with knee osteoarthritis.

Two review authors selected studies for inclusion, extracted trial characteristics and outcome data, assessed risk of bias and assessed the certainty of evidence using the GRADE approach. The primary comparison was stem cell injection compared with placebo injection. The primary time point for pain, function and quality of life was three to six months, and the end of the trial period for participant-reported success, joint structure changes and adverse event outcomes. Major outcomes were pain, function, quality of life, global assessment of success, radiographic joint progression, withdrawals due to adverse events and serious adverse events.

We found 25 randomised trials (1341 participants) comparing stem cell injections with placebo injection (eight trials), no treatment or usual care (analgesia, weight loss and exercise) (two trials), glucocorticoid injection (one trial), hyaluronic acid injection (seven trials), platelet-rich plasma injections (two trials), oral acetaminophen (paracetamol) (one trial), non-steroidal anti-inflammatory drugs plus physical therapy plus hyaluronic acid injection (one trial) and stem cell injection plus intra-articular co-intervention versus co-intervention alone (three trials) in people with osteoarthritis of the knee. Trials were predominantly small, with sample sizes ranging from 6 to 252 participants, with only two trials having more than 100 participants. The average age of participants across trials ranged from 51 to 66 years, and symptom duration varied from one to 10 years. Placebo-controlled trials were largely free from bias, while most trials without a placebo control were susceptible to performance and detection biases. Here, we limit reporting to the main comparison, stem cell injection versus placebo injection. Compared with placebo injection, stem cell injection may slightly improve pain and function up to six months after treatment. Mean pain (0 to 10 scale, 0 no pain) was 4.5 out of 10 points with placebo injection and 1.2 points better (2.5 points better to 0 points better) with stem cell injection (I2 = 80%; 7 studies, 445 participants). Mean function (0 to 100 scale, 0 best function) was 46.3 points with placebo injection and 14.2 points better (25.3 points better to 3.1 points better) with stem cell injection (I2 = 82%; 7 studies, 432 participants). We are uncertain whether stem cell injections improve quality of life or increase the number of people who report treatment success compared to placebo injection, because the certainty of the evidence was very low. Mean quality of life was 45.3 points with placebo injection and 22.8 points better (18.0 points worse to 63.7 points better) with stem cell injection (I2 = 96%; 2 studies, 288 participants) at up to six months follow-up. At the end of follow-up, 89/168 participants (530 per 1000) in the placebo injection group reported treatment success compared with 126/180 participants (683 per 1000) in the stem cell injection group (risk ratio (RR) 1.29, 95% CI 1.10 to 1.53; I2 = 0%; 4 trials, 348 participants). We downgraded the evidence to low certainty for pain and function due to indirectness (as the source, method of preparation and dose of stem cells varied across studies), and suspected publication bias (up to three larger RCTs have been conducted but withdrawn prior to reporting of results). For quality of life and treatment success, we further downgraded the evidence to very low certainty due to imprecision in addition to indirectness and suspected publication bias. We are uncertain of the potential harms associated with stem cell injection, as there were very low event rates for serious adverse events. At the end of follow-up, 5/219 participants (23 per 1000) in the placebo injection group experienced serious adverse events compared with 4/242 participants (16 per 1000) in the stem cell injection group (RR 0.72, 95% CI 0.20 to 2.64; I2 = 0%; 7 trials, 461 participants) and there were no reported withdrawals due to adverse events. We downgraded the evidence to very low certainty due to indirectness, suspected publication bias and imprecision. Radiographic progression was not assessed in any of the included studies.

Compared with placebo injections and based upon low-certainty evidence, stem cell injections for people with knee osteoarthritis may slightly improve pain and function. We are uncertain of the effects of stem cell injections on quality of life or the number who report treatment success. Although the putative benefits of stem cell therapies for osteoarthritis include potential regenerative effects on damaged tissues, particularly articular cartilage, we remain uncertain of the effect of stem cell injections on structural progression in the knee (measured by radiographic appearance). There is also uncertainty regarding the safety of stem cell injections. Serious adverse events were infrequently reported, although all invasive joint procedures (including injections) carry a small risk of septic arthritis. The risk of other important harms, including potential concerns related to the use of a therapy with the theoretical capacity to promote cell growth, or to the use of allogeneic cells, remains unknown.

Cell membrane-derived nanovesicles (NVs) have emerged as promising alternatives to extracellular vesicles (EVs) for wound healing applications, addressing the limitations of traditional EVs, which include insufficient targeting capability, low production yield, and limited drug-loading capacity. Through mechanical cell extrusion methods, NVs exhibit superior characteristics, demonstrating enhanced yield, stability, and purity compared to natural EVs. These NVs can be derived from various membrane sources, including single cell types (stem cells, blood cells, immune cells, and bacterial membranes), hybrid cell membranes and cell membranes mixed with liposomes, with each offering unique therapeutic properties. The integration of genetic engineering and surface modifications has further enhanced NV functionality, enabling precise targeting and improved drug delivery capabilities. Recent advances in NV-based therapies have demonstrated their potential across multiple biomedical applications. Although challenges persist in terms of standardization, storage stability, and clinical translation, the combination of natural cell-derived functions with artificial modification potential positions NVs as a promising platform for next-generation therapeutic delivery systems, thereby offering new possibilities in wound healing applications. Finally, we explore the challenges and future prospects of translating NV-based therapeutics into clinical practice, providing insights into the future development of this innovative approach in wound healing and tissue repair.

Patients with systemic lupus erythematosus (SLE) with inadequate responses to standard therapies have unmet therapeutic needs. The immunomodulatory, proangiogenic, and antifibrotic properties of mesenchymal stromal cells support their use in treating patients with SLE. We aimed to assess the safety of a single intravenous infusion of allogeneic umbilical cord-derived mesenchymal stromal cells in patients with severe SLE.

This prospective, single-centre, open-label, dose-escalation, Bayesian phase 1 study was done at the Saint-Louis University Hospital (Paris, France). Eligible patients were aged 18-70 years, were diagnosed with SLE according to American College of Rheumatology criteria with positive antinuclear antibodies, had a baseline Safety of Estrogens in Lupus Erythematosus National Assessment-SLE Disease Activity Index (SELENA-SLEDAI) score of 6 or more, and had disease that was refractory to first and second line SLE therapies. Patients were to receive a single intravenous infusion of 1 × 106, 2 × 106, or 4 × 106 umbilical cord-derived mesenchymal stromal cells per kg (manufactured from a single umbilical cord) in cohorts of five patients per dose, starting at 2 × 106 cells per kg. The primary endpoint was the rate of treatment-related severe adverse events (grade ≥3) in the first 10 days after infusion of umbilical cord-derived mesenchymal stromal cells. People with lived experience were involved in study design, patient enrolment, and dissemination of the study findings. This study is registered with ClinicalTrials.gov, NCT03562065, and the EU Clinical Trials Register, EudraCT2017-001400-29.

From May 14, 2019, to March 6, 2023, 29 patients were screened for eligibility, eight of whom were enrolled in the study. Enrolment was terminated early after inclusion of eight patients and no patients received the 1 × 106 dose of umbilical cord-derived mesenchymal stromal cells. Seven (88%) of eight participants were cisgender women and one (13%) was a cisgender man. The median age was 35 years (range 26-57) and the median SLE disease duration was 12 years (5-19). All patients received at least 2 × 106 cells per kg (range 2 × 106 to 4 × 106). No severe adverse events and three infusion-related adverse events (two grade 1 and one grade 2) occurred in two patients in the first 10 days after infusion. After 12·4 months (range 12-13) of follow-up, no treatment-related severe adverse events and three non-treatment-related severe adverse events occurred in one patient after relapse.

Our results suggest that a single infusion of 2 × 106 cells per kg or 4 × 106 cells per kg of allogeneic umbilical cord-derived mesenchymal stromal cells was safe in patients with severe SLE. Placebo-controlled trials are needed to confirm clinical efficacy and the role of B-cell modifications in clinical benefit.

Fondation du Rein, Alliance Maladies Rares AFM-Téléthon, Direction de la Recherche Clinique et de l'Innovation AP-HP, and ANR eCellFrance.

Stem cells are crucial for maintaining bodily stability, but their regenerative abilities decline with age. This decline is marked by reduced proliferation and differentiation capacities of stem cells, as well as exhaustion of the stem cell pool. The accumulation of aged mesenchymal stem cells (MSCs) can reduce the tissue regeneration, but the molecular mechanisms influencing MSCs aging remain unclear. Moreover, collecting MSCs from elderly individuals is not suitable for observing the early response of MSCs to senescence stress, and the factors involved in early senescence remain unclear. In our previous study, we established a fast MSC aging model using D-galactose. We discovered that, while not affecting the "stemness" markers of mesenchymal stem cells, the expression of LncRNA NEAT1-206 was notably increased during the early stages of aging induction (within 4 days). And LncRNA NEAT1-206 was observed to be localized in the cytoplasmic matrix due to enhanced nuclear export. We found that the LncRNA NEAT1-206 could trigger autophagy through the WNT5A/Ca2+ signaling pathway, thereby decreasing senescence markers and enhancing the osteogenic differentiation of MSCs. This study elucidated the role that LncRNA NEAT1-206 as a potential key factor in conferring resistance to D-galactose-induced cell senescence at the early stage and promoting the osteogenic differentiation of MSCs. This study may provide a foundational understanding for delaying the MSCs aging process.

Osteoarthritis (OA) is a chronic joint disease that has long been considered a simple wear-and-tear condition. Over the past decade, research has revealed that various inflammatory features of OA, such as low-grade peripheral inflammation and synovitis, contribute substantially to the pathophysiology of the disease. Technological advances in the past 5 years have revealed a large diversity of innate and adaptive immune cells in the joints, particularly in the synovium and infrapatellar fat pad. Notably, the presence of synovial lymphoid structures, circulating autoantibodies and alterations in memory T cell and B cell populations have been documented in OA. These data indicate a potential contribution of self-reactivity to the disease pathogenesis, blurring the often narrow and inaccurate line between chronic inflammatory and autoimmune diseases. The diverse immune changes associated with OA pathogenesis can vary across disease phenotypes, and a better characterization of their underlying molecular endotypes will be key to stratifying patients, designing novel therapeutic approaches and ultimately ameliorating treatment allocation. Furthermore, examining both articular and systemic alterations, including changes in the gut-joint axis and microbial dysbiosis, could open up novel avenues for OA management.

Periodontitis, the main cause of tooth loss in adults, is a public health concern; its incidence increases with age, and its prevalence increases with increasing life expectancy of the population. Innovative therapies such as cell therapy represent promising future solutions for guided tissue regeneration. However, these therapies may be associated with fears and mistrust from the general public. The aim of this study was to estimate the acceptability of an advanced therapy medicinal product combining allogeneic mesenchymal stromal cells from adipose tissue with a natural fibrin hydrogel in the treatment of periodontitis.

The methodology was based on a qualitative study conducted through semi-structured interviews with patients followed for periodontitis in the Oral Medicine Department of the Toulouse University Hospital, Toulouse, France. Qualitative studies are essential methodologies to understand the patterns of health behaviours, describe illness experiences, and design health interventions in a humanistic and person-centred way of discovering.

Eleven interviews (with 4 men and 7 women) were required to reach thematic saturation. Analysis allowed 4 main themes to emerge: (1) perception of new treatments, science, and caregivers; (2) conditions that the treatment must meet; (3) patient perception of the disease; and (4) factors related to the content of the treatment.

Patients find cell therapy for periodontitis to be acceptable. If they express a need to be informed about the benefit/risk ratio, they are not particularly worried about side effects of the treatment, for either allogeneic or blood-derived products. Periodontitis is a prototypical model of chronic inflammatory pathology and is multitissular, with hard- and soft-tissue lesions. In a patient-centred approach, the success of cell therapy will require a bilateral, informed decision, taking into account potential therapeutic effectiveness and patient expectations for regeneration.

Exosomes (Exos) are extracellular vesicles secreted by cells and serve as crucial mediators of intercellular communication. They play a pivotal role in the pathogenesis and progression of various diseases and offer promising avenues for therapeutic interventions. Exos derived from mesenchymal stem cells (MSCs) have significant immunomodulatory properties. They effectively regulate immune responses by modulating both innate and adaptive immunity. These Exos can inhibit excessive inflammatory responses and promote tissue repair. Moreover, they participate in antigen presentation, which is essential for activating immune responses. The cargo of these Exos, including ligands, proteins, and microRNAs, can suppress T cell activity or enhance the population of immunosuppressive cells to dampen the immune response. By inhibiting lymphocyte proliferation, acting on macrophages, and increasing the population of regulatory T cells, these Exos contribute to maintaining immune and metabolic homeostasis. Furthermore, they can activate immune-related signaling pathways or serve as vehicles to deliver microRNAs and other bioactive substances to target tumor cells, which holds potential for immunotherapy applications. Given the immense therapeutic potential of MSC-derived Exos, this review comprehensively explores their mechanisms of immune regulation and therapeutic applications in areas such as infection control, tumor suppression, and autoimmune disease management. This article aims to provide valuable insights into the mechanisms behind the actions of MSC-derived Exos, offering theoretical references for their future clinical utilization as cell-free drug preparations.

Stem cell-derived extracellular vesicles (EVs) have emerged as a safe and potent alternative to regenerative medicine in recent decades. Furthermore, the adjustment of EV functions has been recently enabled by certain stem cell preconditioning methods, providing an exceptional opportunity to enhance the therapeutic potential or confer additional functions of stem cell-derived EVs. In this review, we discuss the recent progress of functionalized EVs, based on stem cell preconditioning, for treating various organ systems, such as the musculoskeletal system, nervous system, integumentary system, cardiovascular system, renal system, and respiratory system. Additionally, we summarize the expected outcomes of preconditioning methods for stem cells and their EVs. With recent progress, we suggest considerations and future directions for developing personalized medicine based on preconditioned stem cell-derived EVs.

As one of the major human oncogenic viruses, Kaposi's Sarcoma-associated Herpesvirus (KSHV) is closely related to several cancers such as Kaposi's sarcoma (KS) and primary effusion lymphoma (PEL). KSHV can infect a broad tropism of human primary cells in vitro and in vivo. Embryonic stem cell-like pluripotent stem cells can be generated by the simultaneous introduction of several factors, into somatic cells, yielding induced pluripotent stem (iPS) cells. However, it remains unclear whether human induced pluripotent stem cells (hiPSCs) are permissive to KSHV and how this oncogenic virus infection may affect cellular gene profile.

In the current study, we examined whether hiPSCs were permissive to KSHV infection. The flow cytometry was used to assess the impacts of KSHV infection on hiPSCs viability and apoptosis. The Illumina RNA-Sequencing was used to determine cellular gene profile changed in KSHV-infected hiPSCs and lytically induced cells.

We report that KSHV successfully establishes latent infection in hiPSCs, which can be completely induced to lytic reactivation and release infectious virions. KSHV de novo infection arrests the growth of hiPSCs through inducing cell apoptosis. Transcriptomic analysis revealed significant changes in global cellular gene expression in KSHV-infected hiPSCs as well as lytically induced cells.

Our findings demonstrate hiPSCs as a powerful tool to explore the potential impacts of KSHV infection on stem cell functions and virus pathogenesis in stem cell differentiated cells.

Adipose-derived stem cells (ADSCs) have been shown to accelerate diabetic wound healing by promoting neovascularization, though the underlying mechanisms are not fully understood. This study aims to explore whether ADSCs influence endothelial progenitor cells (EPCs) function to enhance diabetic wound healing.

Human adipose-derived stem cells (hADSCs) were isolated from patient adipose tissue and cultured under normal and high glucose (HG) conditions. RNA sequencing analyzed gene expression, while immunofluorescence validated findings in patient wound tissues. Mouse adipose-derived stem cells (ADSCs) from C57BL/6 mice were evaluated in vitro for their effects on EPCs under HG using EdU, Transwell, and tube formation assays. A diabetic mouse wound model was used to assess ADSCs therapeutic effects via digital imaging, histology, and immunofluorescence. Kruppel-like factor 5 (KLF5), identified via the JASPAR database, was confirmed by immunohistochemistry and immunofluorescence. KLF5 and C-X-C motif chemokine 12 (CXCL12) expression levels were measured by enzyme-linked immunosorbent assay (ELISA), western blot, and quantitative reverse transcription polymerase chain reaction (RT-qPCR), and their relationship was validated through dual-luciferase assays.

We constructed a neovascularization-related signature (NRS) comprising 75 genes on the basis of differentially expressed genes (DEGs) linked to neovascularization. GO and KEGG analyses revealed that the NRS is primarily involved in vasculature development and receptor-ligand activity. Seven hub genes (CD34, CXCL12, FGF7, FGF18, FGF1, TEK, KIT) were identified and validated. In a diabetic mouse model, CXCL12 knockdown in ADSCs reduced their ability of promoting wound healing and neovascularization. KLF5 expression was lower in patients with diabetic ulcers and diabetic mice wound tissues compared with normal tissues, while ADSCs treatment significantly increased KLF5 expression in diabetic mice wounds. Dual-luciferase reporter assays confirmed KLF5 as an upstream transcription factor of CXCL12. Additionally, knocking down KLF5 in ADSCs impaired their therapeutic effects on diabetic wound healing. In vitro, the addition of exogenous CXCL12 recombinant protein restored EPCs proliferation, migration, and vasculogenic capacity in a high glucose environment after KLF5 silencing in ADSCs.

Our findings underscore the pivotal role of KLF5 in enhancing CXCL12 transcription within ADSCs, thereby facilitating EPC-mediated neovascularization and improving diabetic wound healing. Additionally, KLF5 emerges as a promising therapeutic target for accelerating tissue repair in diabetic wounds.

The long-term effect of adipose-derived mesenchymal stromal cells (ASC) on restoring radiation-induced salivary gland hypofunction in patients with previous head and neck cancer has not been validated in larger settings.

The study was a 12-month follow-up of a randomized trial, including patients with hyposalivation. Patients were randomized to receive allogeneic ASC or placebo in the submandibular glands. The primary endpoint was unstimulated whole saliva (UWS) followed by stimulated whole saliva, patient-reported outcomes (European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire, Head and Neck Module, and the xerostomia questionnaire), and safety.

Of the 120 enrolled patients, 117 (97.5%) were assessed at 12 months. Treatment with ASC did not increase UWS compared with placebo: Increase in UWS was 0.02 mL/minute [95% confidence interval (CI), 0.01-0.04] in the ASC group and 0.02 mL/minute (95% CI, 0-0.03) in the placebo group (P = 0.56). ASC reduced the symptom burden for dry mouth with -10.07 units (95% CI, -13.39 to -6.75) compared with -4.15 units (95% CI, -7.46 to -0.84) in the placebo group (P = 0.01). Compared with placebo, ASC did not improve sticky saliva (-9.27 vs. -4.55 units; P = 0.13), swallowing (-4.50 vs. 3.49 units; P = 0.5), or xerostomia (-3.12 vs. -2.74 units; P = 0.82). Treatment was safe and associated with a transient immune response.

Intraglandular ACS therapy in the submandibular glands significantly relieved subjective dry mouth symptoms. Both ASC and placebo increased UWS, but ASC did not prove superior to placebo in restoring salivary gland function, based on the salivary flow rate.

Rationale: The chronic lung disease bronchopulmonary dysplasia (BPD) remains the most common complication of extreme prematurity (<28 wk of gestation). Umbilical cord-derived mesenchymal stromal cells (UC-MSCs) represent an opportunity for autologous cell therapy, as UC-MSCs have been shown to improve lung function and structure in experimental BPD. However, characterization and repair capacity of UC-MSCs derived from donors with pregnancy-related complications associated with prematurity remain unexplored. Objectives: To characterize UC-MSCs' transcriptome and determine if pregnancy-related complications (preeclampsia and chorioamnionitis) alter their therapeutic potential. Methods: Single-cell RNA sequencing was used to compare the transcriptome of UC-MSCs derived from 5 term donors, 16 preterm donors, and human neonatal dermal fibroblasts (control cells of mesenchymal origin) and correlated with their therapeutic potential in experimental BPD. Using publicly available neonatal lung single-nucleus RNA sequencing data, we also determined putative communication networks between UC-MSCs and resident lung cell populations. Measurements and Main Results: Most UC-MSCs displayed a similar transcriptome despite their pregnancy-related conditions and mitigated hyperoxia-induced lung injury in newborn rats. Conversely, human neonatal dermal fibroblasts and one term and two preterm with preeclampsia UC-MSC donors exhibited a distinct transcriptome enriched in genes related to fibroblast function and senescence and were devoid of therapeutic benefit in hyperoxia-induced BPD. Conversely, therapeutic UC-MSCs displayed a unique transcriptome active in cell proliferation and distinct cell-cell interactions with neonatal lung cell populations, including NEGR (neuronal growth regulator 1) and NRNX (neurexin) pathways. Conclusions: Term and preterm UC-MSCs are lung protective in experimental BPD. Single-cell RNA sequencing allows us to identify donors with a distinct UC-MSC transcriptome characteristic of reduced therapeutic potential.

Mesenchymal stromal cell-derived extracellular vesicles (MSC-EVs) have shown significant therapeutic potential across a wide range of clinical conditions, complementing the progress of MSC-based therapies, some of which have already received regulatory approval. However, the high cost of these therapies has limited their accessibility, creating an urgent need to explore manufacturing strategies that reduce the cost of goods and selling prices. This study presents the design and simulation of a scalable manufacturing platform for the co-production of clinical-grade MSC and MSC-EVs using SuperPro Designer. Various production scenarios were evaluated to maximise manufacturing capacity while analysing their impact on economic performance. Our findings demonstrate that for MSC-EVs doses containing 1010 and 1011 particles, selling prices range from 166 to 309€ and from 1659 to 3082€, respectively. For clinical doses of MSC, selling prices vary between 965 and 42,673€ depending on dose size and production scale. Importantly, the co-production approach enables cost-sharing between products, contributing to significantly lower prices compared to individual production. Overall, the proposed platform achieved an attractive payback time of 3 years and a return on investment of 36%. By increasing the number of staggered production units, further price reductions and improved economic metrics could be attained. In conclusion, this study highlights the potential of the proposed manufacturing platform to deliver cost-effective, clinical-grade MSC and MSC-EVs products, advancing the field of regenerative medicine and enhancing the accessibility of these innovative treatments.

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by the accumulation of amyloid-β plaques, neurofibrillary tangles, and chronic neuroinflammation. Microglial cells, the resident immune cells in the central nervous system, play a crucial role in the pathogenesis of AD. Microglia can undergo polarization, shifting between pro-inflammatory (M1) and anti-inflammatory (M2) phenotypes in response to different stimuli. Dysregulation of microglial polarization towards the pro-inflammatory phenotype leads to the release of inflammatory cytokines, oxidative stress, and synaptic dysfunction. These processes contribute to neuronal damage and cognitive decline in AD. However, several challenges remain in this field. The complex molecular mechanisms governing microglial polarization in AD need to be further elucidated. In this review, we discuss the mechanisms underlying microglial polarization in AD and its implications in disease progression.

Pressure ulcers are a common issue in elderly and medically compromised individuals, posing significant challenges in healthcare. Human umbilical cord mesenchymal stem cells (HUMSCs) offer therapeutic benefits like inflammation modulation and tissue regeneration, yet challenges in cell survival, retention, and implantation rates limit their clinical application. Hydrogels in three-dimensional (3D) stem cell culture mimic the microenvironment, improving cell survival and therapeutic efficacy. A thermosensitive injectable hydrogel (adEHG) combining gallic acid-modified hydroxybutyl chitosan (HBC-GA) with soluble extracellular matrix (adECM) has been developed to address these challenges. The hybrid hydrogel, with favorable physical and chemical properties, shields stem cells from oxidative stress and boosts their therapeutic potential by clearing ROS. The adEHG hydrogel promotes angiogenesis, cell proliferation, and collagen deposition, further enhancing inflammation modulation and wound healing through the sustained release of therapeutic factors and cells. Additionally, the adEHG@HUMSC composite induces macrophage polarization towards an M2 phenotype, which is crucial for wound inflammation inhibition and successful healing. Our research significantly propels the field of stem cell-based therapies for pressure ulcer treatment and underscores the potential of the adEHG hydrogel as a valuable tool in advancing regenerative medicine.

Microneedle systems (MNs) loading living cells are a powerful platform to treat various previously incurable diseases in the era of precision medicine. Herein, an overview of recent advances in MN-based strategies for cell delivery is summarized, including material selection, design of morphological structures, and processing methods. We also systematically outlined the law of microstructural design relative to the structure-effective/function relationship in transdermal delivery or precision medicine and the design principles of cell microneedle (CMN). Furthermore, the representative works of precision treatments focusing on inflammatory skin diseases were tracked and discussed using CMN. Indeed, it highlights a practical path to solving the dilemma of cell therapy and raising the hope of precision medicine. However, there are still some challenges in developing CMN since they need multi-dimensional comprehensive properties, including mechanical properties, cell viability preservation, release, therapeutic effect, etc. The manuscript could provide insights into developing an innovative fit-to-purpose vehicle in cell therapy for interested researchers.

Peripheral nerve injuries are clinical conditions that often result in functional deficits, compromising patient quality of life. Given the relevance of these injuries, new treatment strategies are constantly being investigated. Although mesenchymal stem cells already demonstrate therapeutic potential due to their paracrine action, the transdifferentiation of these cells into Schwann-like cells (SLCs) represents a significant advancement in nerve injury therapy. Recent studies indicate that SLCs can mimic the functions of Schwann cells, with promising results in animal models. However, challenges remain, such as the diversity of transdifferentiation protocols and the scalability of these therapies for clinical applications. A recent study by Zou et al provided a comprehensive overview of the role of bone marrow-derived mesenchymal stem cells in the treatment of peripheral nerve injuries. Therefore, we would like to discuss and explore the use of SLCs derived from bone marrow-derived mesenchymal stem cells in more detail as a promising alternative in the field of nerve regeneration.

Heart failure is known as the leading cause of mortality and morbidity in adults, not only in USA but worldwide. Since the world's population is aging, the burden of cardiovascular disorders is increasing. Mesenchymal stem/stromal cells (MSCs) from a patient's bone marrow or other tissues have been widely used as the primary source of stem cells for cellular cardiomyoplasty. The incongruencies that exist between various cell-therapy approaches for cardiac diseases could be attributed to variations in cell processing methods, quality of the process, and cell donors. Off-the-shelf preparations of MSCs, enabled by batch processing of the cells and controlled cell processing factories in regulated facilities, may offer opportunities to overcome these problems. In this study, for the first time, we focused on the fetal membranes and childbirth byproducts as a promising source of cells for regenerative medicine. While many studies have described the advantages of cells derived from these organs, their advantage as a source of younger cells has not been sufficiently covered by the literature. Thus, herein, we highlight challenges that may arise from the impairment of the regenerative capacity of MSCs due to donor age and how allograft cells from fetal adnexa can be a promising substitute for the aged patients' stem cells for myocardial regeneration. Moreover, obstacles to the use of off-the-shelf cell-therapy preparations in regenerative medicine are briefly summarized here.

Asthma, a prevalent allergic disease affecting approximately 300 million individuals globally, remains a significant public health challenge. Mesenchymal stromal cells (MSCs) and hepatocyte growth factor (HGF), both recognized for their immunomodulatory properties, hold therapeutic potential for asthma. However, their precise mechanisms remain underexplored. The current study aimed to engineer human HGF overexpressing human dental pulp stromal cells (HGF-DPSCs) and evaluate their efficacy in asthma management while elucidating underlying mechanisms. The results showed that the constructed HGF-DPSCs overexpressed HGF both in vitro and in vivo. Also, compared with DPSCs, they demonstrated a more pronounced distribution within lung tissue. In house dust mite (HDM)-induced asthma, HGF-DPSCs showed a more significant inhibitory effect on airway hyperresponsiveness (AHR), inflammatory infiltration, and CD4+ T-cell recruitment compared with DPSCs. Immunofluorescence analysis revealed a spatial overlap between HGF-DPSCs and pulmonary epithelial cells. Protein array analysis identified the chemokine Ckβ8-1 as a pivotal factor in the interaction between HGF-DPSCs and bronchial epithelial Beas-2B cells. Subsequent mechanistic investigations demonstrated that administration of HGF-DPSCs markedly reduced both the expression of Ckβ8-1 protein and the proportion of CD4+CCR1+ T lymphocytes in the lungs of asthmatic mice. Furthermore, transwell migration assays incorporating a CKβ8-1 antagonist revealed a significant inhibition of CD4+ T-cell migration. Flow cytometry analysis indicated that CD4+CCR1+ T cells from the lungs of asthmatic mice exhibit a pronounced Th2 phenotype, characterized by high expression levels of IL-4, IL-5, and IL-13 cytokines. In conclusion, HGF-DPSCs ameliorate HDM-induced asthma by suppressing CCR1+ Th2 cell responses via modulation of the Ckβ8-1/CCR1 axis, highlighting their potential as a novel therapeutic strategy.