Stem Cell Research & Therapy最新文献

Background: Our previous study revealed that intravenous administration of mesenchymal stromal cells (MSCs) increases local cell engraftment and improves heart function. This study aims to investigate whether MSCs overexpressing HLA-G1 have further increased local transplanted cells engraftment and improved heart function.

Methods: The mice were intravenously administered saline or human umbilical cord blood-derived MSCs (hUCB-MSCs) 7 days before myocardial infarction (MI) induction. Then, the MI mouse model was established by ligating the left anterior descending coronary artery. The mice were then subjected to intramyocardial transplantation of human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) 30 min after MI induction. Echocardiographic analysis was carried out to assess heart function. Furthermore, in vivo fluorescent imaging analysis was performed to analyze cell engraftment. Moreover, flow cytometry of splenic regulatory T cells (Tregs) and natural killer (NK) cells was conducted to evaluate the immunomodulatory effect of hUCB-MSCs.

Results: The results showed that systemic intravenous administration of hUCB-MSCs substantially enhanced Tregs, decreased NK cells, and increased intramyocardially transplanted hiPSC-CMs' engraftment, thus improving heart function. Compared with hUCB-MSCs, HLA-G1 overexpressing hUCB-MSCs reduced systemic NK cells (7.13 ± 0.19% vs. 9.12 ± 0.06%, p < 0.05), increased Tregs (5.03 ± 0.17% vs. 3.36 ± 0.05%, p < 0.05), improved cell engraftment (Radiant efficiency: 3.01 ± 0.36 × 10⁹ vs. 2.19 ± 0.27 × 10⁹, p < 0.05) and heart function (LVEF: 73.00 ± 0.44 vs. 62.36 ± 1.01, p < 0.05). The in vitro assays revealed that HLA-G1 overexpressing hUCB-MSCs modulated the immune response by decreasing pro-inflammatory cytokines.

Conclusions: This study showed that systemic intravenous administration of HLA-G1 overexpressing hUCB-MSCs modulated immune response and increased transplanted hiPSC-CMs' engraftment to improve heart function following AMI.

To elucidate spatiotemporal dynamics of tissue renewal, we developed evProTracer, an enhanced dual-recombinase lineage tracing system for cumulative in vivo labeling of proliferating cells. Robust longitudinal tracing using evProTracer in murine tracheal epithelium revealed near-complete homeostatic turnover (91.6 ± 1.29% epithelial replacement over 25 weeks), while basal cell-specific ​Trp63-evProTracer​ uncovered a dorsally biased proliferation pattern​, contributing 33.88 ± 1.44% of total epithelial renewal over 6 months, with early differentiation bias toward club cells. These data demonstrate that ventral epithelial renewal is primarily mediated by non-basal facultative progenitors, revealing their constitutive activation during homeostasis. This study uncovers spatially stratified renewal hierarchies: dorsal basal stem cell reservoirs versus ventral facultative non-basal progenitors. evProTracer provides a versatile platform for investigating tissue plasticity hierarchies in regenerative organs.

Background: Pulmonary arterial hypertension (PAH) is a fatal condition characterized by progressive vascular remodeling in the pulmonary arteries, eventually leading to right heart failure and death. Dysregulated extracellular matrix (ECM) remodeling is central to PAH pathogenesis and represents a potential therapeutic target. Mesenchymal stromal cells (MSCs) have shown promise in preclinical studies; however, the optimal therapeutic window, dosing frequency, and mechanistic basis for their regulation of vascular ECM remain unclear.

Methods: We employed a monocrotaline (MCT)-induced rat model of PAH to evaluate different MSC treatment regimens, including early administration (day 1 post-MCT), delayed administration (days 7 and 14), and repeated dosing (days 1 and 11). Additionally, we combined in vivo and in vitro approaches to investigate how MSCs modulate the activation of pulmonary arterial adventitial fibroblasts (PAAFs) and influence ECM remodeling.

Results: Biodistribution studies indicated that MSC retention in lung tissue peaked within 24 h and gradually declined by day 21. A single early dose of MSCs (on day 1) significantly ameliorated PAH progression, increasing the 28-day survival rate, reducing right ventricular systolic pressure (RVSP), improving right ventricular function, and attenuating small pulmonary vascular remodeling, including reductions in medial thickening, excessive muscularization, and collagen deposition. Repeated MSC administration did not provide additive therapeutic benefit. Both in animal models and cell cultures, MSCs effectively suppressed PAAF activation and reduced ECM protein production. This anti-fibrotic effect was mediated, at least in part, via the pathway involving the upregulation of SOCS3 and consequent inhibition of STAT3 phosphorylation.

Conclusion: Our findings underscore the importance of early intervention in the PAH disease course for MSC-based therapy. MSCs attenuate vascular remodeling and disease progression, possibly through the SOCS3/STAT3 signaling pathway, by targeting PAAF activation and ECM dysregulation. These results offer a novel mechanistic foundation for MSC treatment in PAH.

Two international stem cell consortia, the International Stem Cell Initiative (ISCI) and the International Stem Cell Biobanking Initiative (ISCBI, www.iscbi.org ) held a workshop on June 15th 2025 in Hong Kong on genetic variants in human pluripotent stem cell (hPSC) lines and accurate and standardized documentation of donor/hPSC genetic information including ethnicity. The occurrence and detection of genetic variants is a key issue for assuring reproducible stem cell research data and the safety of stem cell derived medicinal products. Presentations by leading experts addressed the nature of hPSC genetic variants, their detection and accurate recording of genetic data and ethnicity. The audience of stem cell researchers, cell banking directors and experts in ethic, policy and stem cell databases, from 13 countries across the globe, discussed progression of the ISCI consortium's efforts in providing further data and thought leadership on the management of genetic variants, and the challenges for standardizing biobanking approaches for hPSC genetic data including ethnicity. This paper records the key elements of this discussion and the conclusions and consensus reached and ongoing work to provide guidance for hPSC biobanks.

Mesenchymal stem cell-derived extracellular vesicles (MSC-EVs) have emerged as promising cell-free therapeutic strategies for musculoskeletal regeneration. MSC-EVs, which are enriched with diverse cargos, exert multifaceted biological effects, including the modulation of inflammation, the promotion of angiogenesis, and the regulation of immune responses. They also activate key regenerative signaling pathways, such as the PI3K/Akt, Wnt/β-catenin, TGF-β/Smad, and NF-κB pathways, thereby promoting osteogenesis, chondrogenesis, tenogenesis, and muscle repair to support the repair of bone, cartilage, tendon, and muscle tissues. In addition to their intrinsic activity, advances in bioengineering, including surface modification, cargo engineering, and integration with biomaterial scaffolds, have further increased their therapeutic potential and delivery. Preclinical studies consistently demonstrate efficacy across diverse musculoskeletal tissues, and early clinical trials highlight their translational promise. Nevertheless, clinical application remains constrained by challenges in large-scale production, standardization, and long-term safety evaluation. This review summarizes current knowledge on the mechanisms, therapeutic applications, engineering strategies, delivery systems, and clinical progress of the use of MSC-EVs in musculoskeletal regeneration while highlighting critical obstacles and future directions for their clinical implementation.

Previous studies have confirmed that scald injuries can lead to disturbances in hepatic lipid metabolism, and bone marrow-derived mesenchymal stem cells (BMSCs) have emerged as a promising therapeutic strategy for alleviating such disorders. However, research focusing on the regulation and restoration of liver lipid metabolic processes remains limited. In this study, we investigated the effects of BMSCs on hepatic lipid metabolism disorders induced by scald injury in rats through integrated transcriptomic and metabolomic analyses. The results demonstrated that portal vein infusion of BMSCs markedly improved body weight recovery, reduced hepatic lipid accumulation, normalized serum lipid profiles, and attenuated liver injury following scalding. Combined transcriptomic and metabolomic data further suggested that the therapeutic mechanism may involve inhibition of NF-κB/Gadd45a signaling in hepatocytes, restoration of sphingolipid metabolism, enhancement of hepatic lipid conversion, and suppression of adipocyte lipolysis. Overall, this study provides a theoretical basis for the potential clinical application of BMSCs in treating hepatic lipid metabolism disorders secondary to severe burn injury.

Background: Spinal cord injury (SCI) leads to persistent neurological deficits partly by disruption of the blood-spinal cord barrier (BSCB). Small extracellular vesicles (sEVs) from human umbilical cord mesenchymal stem cells (hUC-MSCs) can promote BSCB repair, but their active components remain unclear. This study examined whether miR-149 carried by hUC-MSC-derived sEVs (hUC-MSCs-sEVs) protects the BSCB after SCI by targeting endothelin-1 (ET-1).

Methods: Human brain microvascular endothelial cells (HBMECs) were subjected to oxygen-glucose deprivation/reoxygenation (OGD/R) to model barrier injury, and rats underwent a thoracic SCI. hUC-MSCs-sEVs were isolated and loaded with miR-149 mimics or inhibitors. Endothelial cell viability, paracellular permeability (FITC-dextran assay), and junction protein levels (ZO-1, Claudin-5, β-Catenin, Occludin) were measured by viability assays, Western blot, and immunofluorescence. ET-1 levels and PI3K/Akt pathway activation were measured by ELISA and Western blot. In SCI rats, sEVs (with or without the miR-149 inhibitor) were injected; motor function (BBB locomotor score), BSCB permeability (Evans blue/FITC-dextran leakage) and spinal cord histology were evaluated.

Results: hUC-MSCs-sEVs were internalized by HBMECs and significantly improved cell survival and barrier function after OGD/R. sEVs treatment restored tight and adherens junction proteins and suppressed OGD/R-induced ET-1 upregulation and PI3K/Akt activation. OGD/R reduced miR-149 expression, which was rescued by sEVs. sEVs loaded with miR-149 mimic further enhanced these protective effects, whereas a miR-149 inhibitor abolished them. Notably, co-administration of an ET-1 receptor antagonist reversed the barrier disruption caused by miR-149 inhibition. In vivo, hUC-MSCs-sEVs treatment improved locomotor recovery and reduced BSCB leakage and tissue damage, whereas miR-149 inhibition abolished these benefits.

Conclusions: hUC-MSC-derived exosomal miR-149 preserves BSCB integrity and promotes functional recovery after SCI by targeting ET-1 and inhibiting the PI3K/Akt pathway, thereby enhancing junctional protein expression. The miR-149/ET-1 axis may represent a promising therapeutic target for SCI.

Background: Research indicates that the occurrence of periodontitis is related to oxidative stress and mitochondrial dysfunction. Alleviating oxidative stress and mitochondrial dysfunction may be a promising treatment strategy for periodontitis. In this study, bone marrow mesenchymal stem cells (BMSCs) were pretreated with lipopolysaccharide (LPS), and their derived exosomes (LPS-BMSCs-Exo) were extracted. In vitro and in vivo experiments were conducted to study the therapeutic effects of alleviating oxidative stress, mitochondrial disorders, and periodontitis.

Methods: BMSCs were pretreated with LPS, and LPS-BMSCs-Exo were extracted and identified via transmission electron microscopy (TEM), nanoparticle tracking analysis (NTA), and Western blotting. The biosafety of the exosomes was assessed through CCK-8, migration, and uptake assays. A cell oxidative stress model was established and treated with BMSCs-Exo or LPS-BMSCs-Exo, the following tests were performed: the effects of the two types of exosomes on the oxidative stress of periodontal ligament stem cells (PDLSCs) were determined, the mitochondrial state and the membrane potential were detected, the content of adenosine triphosphate (ATP) was determined, apoptosis was detected, and the effect of the exosomes on the osteogenic ability of the PDLSCs was detected. A periodontitis rat model was established, and PBS, BMSCs-Exo, and LPS-BMSCs-Exo were administered separately. Micro-CT, HE staining, Masson staining, immunohistochemistry, and ROS fluorescence staining were used to evaluate the therapeutic effect of each group on periodontitis in rats.

Results: The proposed LPS-BMSCs-Exo exhibits characteristics similar to those of exosomes, can be successfully taken up and internalized by PDLSCs, and promotes the proliferation and migration of these cells. LPS-BMSCs-Exo can effectively improve the oxidative stress state, alleviate mitochondrial dysfunction in cells, increase membrane potential, enhance ATP content, reduce apoptosis, and improve the osteogenic ability of PDLSCs. Micro-CT data revealed that alveolar bone-related indicators were significantly increased after LPS-BMSCs-Exo treatment, which could reduce the degradation and inflammation of periodontal tissue in rats and alleviate their oxidative stress.

Conclusion: LPS-BMSCs-Exo can significantly alleviate the oxidative stress and mitochondrial dysfunction caused by periodontitis in periodontal tissue, thereby reducing inflammation in periodontal tissue and alveolar bone resorption.

Background: Premature ovarian insufficiency (POI) is a clinically challenging condition characterized by amenorrhea and infertility in women less than 40 years of age. Although both human amniotic epithelial cells (hAECs) and human umbilical cord mesenchymal stem cells (hUC-MSCs) have shown promise in treating POI, their comparative therapeutic efficacy and mechanisms remain poorly understood.

Methods: hAECs and hUC-MSCs were isolated from human amniotic membrane and umbilical cords, respectively, and characterized using standard protocols. A chemotherapy-induced POI mouse model was established to evaluate follicular development, ovarian fibrosis, and fertility recovery after hAEC and hUC-MSC transplantation. Longitudinal in vivo bioluminescence imaging was used to track and compare the biodistribution and retention rates of the transplanted cells. RNA sequencing and in vitro functional assays under oxidative stress and apoptosis-induced conditions were employed to analyze the differential stress responses of hAECs and hUC-MSCs. Furthermore, cytokine arrays were utilized to profile their secretomes.

Results: In the chemotherapy-induced POI mouse model, both hAECs and hUC-MSCs transplantation improved ovarian function, as evidenced by increased ovarian weight, restored estrous cycle, elevated follicle counts, reduced fibrosis, and enhanced fertility. In vivo imaging revealed that both cell types primarily homed to the lungs, liver, and spleen post-transplantation, with signal intensity declining over time. Quantitative analysis revealed significantly longer in vivo retention of hAECs compare to hUC-MSCs. RNA sequencing and in vitro assays confirmed the superior antioxidant capacity of hAECs under stress conditions. Cytokine profiling showed that hAEC-CM was enriched in pro-angiogenic factors, while hUC-MSC-CM contained higher levels of immunoregulatory cytokines, a functional difference further validated by in vitro experiments.

Conclusion: Our findings demonstrate that both hAECs and hUC-MSCs are effective in restoring ovarian function and fertility in a chemotherapy-induced POI mouse model. However, these two cell types exhibit distinct therapeutic advantages attributable to their differential metabolic kinetics and paracrine profiles. Specifically, hAECs displayed prolonged in vivo retention rates compared to hUC-MSCs, consistent with their enhanced antioxidant capabilities. In terms of secretory function, hAECs demonstrated superior pro-angiogenic activity, while hUC-MSCs exhibited stronger immunomodulatory effects. These distinct properties provide critical insights for cell-type-specific selection in developing targeted therapies for ovarian dysfunction.

Introduction: Stem cell therapy has emerged as a potential regenerative approach for Acute myocardial infarction (AMI). Despite decades of research and advancement in acute myocardial infarction (AMI) management, translating innovative therapies from bench to bedside remains a central challenge. Nonetheless, clinical outcomes exhibit considerable variability. This review provides a comprehensive overview of the clinical landscape of stem cell therapy for AMI, specifically focusing on how variations in cell type, delivery timing, routes, and dosages can affect cell therapy efficacy.

Methods: This study is a systematic review of randomized clinical trials. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines were followed, and the study was conducted in accordance with the Cochrane Handbook for Systematic Reviews of Interventions.

Results: After searching the relevant databases, a total of 5276 studies were assessed, and 43 trials were considered eligible for inclusion in the present systematic review. The safety and efficacy of various types of stem cells, including bone marrow-derived mononuclear cells (BM-MNCs), mesenchymal stem cells (MSCs), cardiac progenitor cells, and, more recently, induced pluripotent stem cells, have been evaluated in numerous clinical trials and meta-analyses. Among these, BM-MNCs and MSCs have been the most extensively studied. Although results vary from trial to trial and can even be contradictory, from frank failures to monumental achievements, overall, the evidence supports modest but statistically significant improvements in surrogate endpoints, such as left ventricular ejection fraction (LVEF), ventricular remodeling, and reduced infarct size.

Conclusion: We have critically reviewed how methodological approaches-especially the definitions of endpoints and clinical outcome measures-have significantly influenced the reported efficacy and direction of the field. The interpretation of clinical trial results in cell therapy for AMI is heavily impacted by the specific metrics used to define success. A key focus is distinguishing between clinical trials on patients with acute and recent myocardial infarction (which is the main focus of this review) and those with chronic ischemic or non-ischemic cardiomyopathies, as they involve different treatment strategies. Patient selection is essential for improving responses in patients with AMI. Those with a severely reduced LVEF (LVEF < 40%) and younger age tend to benefit more. Limiting the transplantation window to the first 3-7 days after AMI may improve the intervention's effectiveness.