Stem Cell Research & Therapy最新文献

Using adipose-derived stem cells (ADSCs) has recently become a crucial approach for treating bone defects owing to their ease of accessibility and substantial differentiation potential. N6-methyladenosine (m6A) modification greatly influences biological processes and determines the differentiation fate of stem cells. However, the specific mechanisms by which m6A modification influences the osteogenic differentiation of ADSCs remain unclear. We identified FOXO1 as the key m6A-modified gene during the osteogenesis of ADSCs. Furthermore, demethylase FTO enhanced RUNX2 expression while inhibiting PPARG expression by modifying FOXO1, thereby facilitating ADSC osteogenesis. FTO knockdown inhibited ADSC migration and proliferation and impaired osteogenesis by suppressing FOXO1. At the mechanistic level, we first revealed that FTO was exported to the cytoplasm and then directly bound with FOXO1 mRNA at its 1760th bp site. Consistent use of non-steroidal anti-inflammatory drugs (NSAIDs) containing FTO inhibitors impeded ADSC-mediated bone formation both in vivo and in vitro. In summary, our study reveals the role of m6A modification based on the FTO-FOXO1-RUNX2/PPARG axis in regulating the osteogenic differentiation of ADSCs, thereby improving the clinical use of ADSCs and providing strategies for related drug applications in bone regeneration.

Background: Psoriasis is a chronic skin disease featured with aberrant keratinocyte proliferation, inflammatory cell infiltration, and immune dysregulated. Although the imbalance of M1/M2 macrophage polarization is implicated in its pathogenesis, the underlying mechanisms remain unclear. Mesenchymal stem cells exhibited potent immunomodulatory properties, representing a promising therapeutic approach for psoriasis. This study aimed to explore the role and the underlying mechanism of human urine-derived stem cells (hUSCs) in mouse psoriatic models.

Methods: hUSCs were isolated from urine of heath volunteer and cultured in serum-free medium, and characterized by multiple approaches such as morphological analysis, biological markers examination, differentiation potentials and tumorigenicity assay. Histological analysis, immunofluorescence staining, ELISA, flow cytometry, antibody array, western blot and qRT-PCR analysis were used to assess the therapeutic effects and the underlying mechanism of hUSCs in imiquimod (IMQ)-induced mouse psoriasis models and multiple cell models.

Results: hUSCs had the potential for self-renewal and multipotent differentiation with low immunogenicity and lacking tumorigenicity both in vitro and in vivo. Our results showed that hUSCs significantly alleviated IMQ-induced psoriasis via their paracrine, evidenced by improving morphologies, inhibiting the infiltration of macrophages, reducing the releases of the pro-inflammatory cytokines. Mechanistically, we revealed that the protective effects of hUSCs on psoriasis were involved in suppressing M1 and promoting M2 macrophage polarization, and inhibiting NETs formation through inhibiting JAK2/STAT3 pathway. Finally, we further demonstrated that hUSCs-derived TGF-β1 selectively inhibited the JAK2/STAT3 pathway-mediated the polarization of M1 and M2 macrophages to alleviate psoriasis in mouse and cellular models.

Conclusions: Our data demonstrated that hUSCs remarkably ameliorated psoriasis by suppressing M1 and promoting M2 macrophage polarization through they-derived TGF-β1 inhibiting the JAK2/STAT3 pathway. Our results have revealed the molecular mechanism of hUSCs in treating psoriasis, highlighting a safe and effective cellular treatment method for psoriasis.

Background: COL4A1 defects are known to cause a variety of multisystem disorders with significant vascular dysfunction leading to neuronal damage. Case reports suggest that patients with COL4A1 mutations or extracellular COL4A1 deficiency in the basement membrane may put individuals at increased risk for developing visual deficits with neurotrauma. However, no experimental evidence is available. This study investigated the impact of Col4a1 deficiency on visual dysfunction following mild traumatic brain injury (mTBI) and evaluated the therapeutic efficacy of COL4A1-enriched adipose-derived stem cell-conditioned medium (ASC-CCM) in mitigating associated neurovascular deficits.

Methods: Using a retina-targeted knockdown approach in C57Bl/6 mice via intravitreal delivery of AAV2-Col4a1 shRNA, followed by a controlled 50-psi air-blast to induce mTBI, we assessed visual performance, retinal histopathology, and gene expression profiles for 4 weeks post-injury. Treatment with ASC-CCM was administered intravitreally post-blast. In-vitro, Col4a1 knockdown in human retinal endothelial cells (HRECs) assessed the therapeutic benefit of COL4A1-enriched ASC-CCM.

Results: After blast injury, Col4a1-deficient mice displayed significantly greater reductions in visual acuity and contrast sensitivity thresholds compared to control mice, which were substantially restored following ASC-CCM treatment. Histological and molecular analyses revealed marked glial activation, vascular instability, and synaptic disorganization in Col4a1-deficient retinas post-injury, which were attenuated upon ASC-CCM administration. In-vitro assays further confirmed that COL4A1 plays a crucial role in endothelial integrity. After Col4a1 knockdown, HRECs showed impaired cell migration and increased leukocyte transmigration, effects that were reversed by treatment with COL4A1-enriched, but not COL4A1-depleted, ASC-CCM. Moreover, COL4A1-enriched ASC-CCM suppressed inflammatory responses in cytokine-stimulated microglia and stabilized TNF-α-induced endothelial permeability.

Conclusions: These findings collectively identify COL4A1 deficiency as a sensitizing factor for post-traumatic visual dysfunction and demonstrate that ASC-CCM exerts therapeutic effects by preserving retinal vascular structure and modulating inflammatory responses, positioning it as a promising candidate for treating TBI-related ocular neurovascular injury.

Background: The Monopterus albus serves as a unique model for studying sex reversal, transitioning naturally from female to male. However, the origins of male germline stem cells (GSCs) and the roles of somatic cells during sex reversal remain poorly understood.

Methods: We performed single-cell RNA sequencing (scRNA-seq) on ovarian, ovotestis, and testicular tissues to construct a gonadal cell atlas. RNA fluorescence in situ hybridization (RNA-FISH) validated cell subpopulations.

Results: Cell types of germ cells and somatic cells in gonads were identified, and their differentiation trajectories during sex reversal were depicted. Our results show that GSCs^wdr17+tep1- in the ovaries possess bipotential differentiation capacity and can transform into GSCs^{wdr17+ tep1+} with the capability to differentiating into sperm during sex reversal. Two theca cell subpopulations cooperate to synthesize steroid precursors in ovaries, with Leydig cells in testes likely originating from theca cell transitions. Proliferative gdf9⁺ follicle cells promoted folliculogenesis and persisted in male gonads with reduced hsd17b1 expression. Stromal heterogen-eity analysis revealed bmp4⁺ mesenchymal stem cells (MSCs^bmp4+) as potential precursors for Sertoli cells in testes.

Conclusions: This study provides a comprehensive cellular roadmap of gonadal cell dynamics during sex reversal in Monopterus albus. Our findings unveil the molecular mechanisms underlying germline and somatic cell fate determination, offering novel insights into vertebrate sex reversal and potential therapeutic strategies for disorders of sex development (DSD).

Background: Non-alcoholic fatty liver disease (NAFLD) is characterized by abnormal lipid accumulation in hepatocytes and defective autophagy has been implicated in its pathogenesis. Human umbilical cord-derived MSCs (hUC-MSCs) have shown therapeutic potential in treating NAFLD, while underlying molecular mechanisms remained largely unknown.

Methods: Male C57BL/6J mice fed a choline-deficient high fat diet (CD-HFD) and HepG2 cells exposed to palmitic acid/oleic acid were established as in vivo and in vitro models of NAFLD, respectively. Both models were subjected to treatment with human umbilical cord-derived MSCs (hUC-MSCs). Lipid content, proinflammatory cytokines, fibrosis markers and the hepatic transcriptome were assessed to determine the effect of hUC-MSCs.

Results: Here, hUC-MSCs decreased hepatic lipid content and alanine aminotransferase/aspartate aminotransferase levels, as well as attenuated inflammation and fibrosis in choline-deficient high-fat diet (CD-HFD)-induced NAFLD mice. Mechanistically, hUC-MSCs restored impaired autophagic flux and mitigated liver steatosis through the AMPK-mTOR-TFEB pathway in both NAFLD mice and oleic acid/palmitic acid-induced "fatty" HepG2 cells. Of note, hUC-MSCs have been found to promote nuclear translocation of TFEB in PA/OA-induced HepG2 cells. Additionally, TFEB knockdown partially attenuated the effect of hUC-MSCs on enhancing autophagy and lipid metabolism in vitro.

Conclusions: This study suggests that hUC-MSCs represent a potential therapeutic approach to treating NAFLD through activating TFEB-mediated autophagy.

Background: Radiation-induced xerostomia (RIX) is a frequent, debilitating complication of head and neck radiotherapy for cancer. Preclinical studies suggest that mesenchymal stem cells (MSCs) may protect and regenerate salivary glands, but clinical evidence remains fragmented. This study evaluates the safety and efficacy of MSC therapy for RIX patients.

Methods: Comprehensive searches of PubMed, Wiley Online Library, Cochrane, and CNKI were conducted up to July 2025 to identify relevant clinical studies. Two investigators independently screened records. A total of seven trials (n = 360 participants) were included. Meta-analyses were conducted using RevMan 5.4 and R Studio, with unstimulated whole salivary flow rate (UWS) as the primary endpoint. Secondary endpoints included stimulated whole salivary flow rate (SWS), Xerostomia Questionnaire (XQ) scores, and serious adverse events (SAE). Meta-analyses were conducted using RevMan 5.4 and R 4.5.1, with UWS as the primary endpoint. Heterogeneity was assessed by I² and large-study effects by Egger's test. The protocol was registered on PROSPERO (CRD420250521958).

Results: Pooled analysis of the seven trials showed a statistically significant but clinically negligible increase in UWS with MSCs compared to controls (WMD = 0.02 mL/min, 95% CI: 0.00 to 0.03, p = 0.04). No significant differences were found for SWS (WMD = - 0.12 mL/min, 95% CI - 0.28 to 0.04) or XQ scores (WMD = - 0.54, 95% CI - 1.96 to 0.88; p = 0.46). The risk of SAE was not significantly different between groups (OR = 1.96, 95% CI 1.00-3.84, p = 0.05). Substantial heterogeneity was observed (I² >90%). Exploratory network meta-analysis suggested that bone marrow-derived MSCs (BMMSC) might outperform adipose-derived MSCs (ADMSC), but this finding is hypothesis-generating due to being based on a single BMMSC study.

Conclusions: MSC transplantationresults in a statistically significant but clinically marginal improvement in UWS for RIX, with no significant increase in SAE. The current evidence does not support the superiority of MSC therapy over conventional management. Future large-scale trials are required to determine if optimized MSC strategies can achieve clinically meaningful benefits.

Background: Interferon gamma (IFNγ) priming is a prominent approach to enhance the immune-regulatory capacity of mesenchymal stromal cells (MSCs). Despite its potential, the concentration of IFNγ vary between studies, and how MSCs response to different concentrations of IFNγ is unclear.

Methods: MSCs were treated with various concentrations of IFNγ (0, 1, 5, 10, 50, and 100 ng/mL) for 48 h. Followed by RNA sequencing (RNA-seq) and Assay for Transposase-Accessible Chromatin using sequencing (ATAC-seq) to profile gene expression and chromatin accessibility, respectively. Integrative analysis was conducted to elucidate the epigenetic regulation of MSCs response to different doses of IFNγ.

Results: We found that low dose IFNγ (1 ng/mL) treatment was sufficient to induced significant changes in gene expression and chromatin accessibility. RNA-seq revealed that IFNγ activated genes involved in immune response and inactivated genes related to cell-cycle regulation. ATAC-seq showed that IFNγ reduced global enhancer accessibility of MSCs, possibly by downregulation of the SWI/SNF complex. Moreover, IFNγ selectively opened enhancer regions associated with immune response genes while closing regions linked to proliferation-related genes. Motif enrichment analysis identified binding sites for transcription factors such as IRF and AP-1 family members in open and closed regions, respectively, highlighting selective regulatory mechanisms.

Conclusions: This study demonstrates that low dose IFNγ is sufficient to modulate the transcriptional and epigenetic landscape of MSCs by selectively altering enhancer landscape. Our results provide insights into the regulatory mechanisms underlying IFNγ priming and offer a resource for the rational design of strategies to optimize MSC licensing for therapeutic applications.

Introduction: Autism Spectrum Disorder (ASD) is a complex neurodevelopmental condition characterized by deficits in social communication and repetitive behaviors. Accumulating evidence implicates neuroimmune dysregulation and gut microbiota dysbiosis in its pathogenesis, yet effective therapies targeting these mechanisms are lacking. This study investigated the therapeutic efficacy of human umbilical cord-derived mesenchymal stem cells (hUCMSCs) and their extracellular vesicles (EVs), both alone and in combination, in a valproic acid (VPA)-induced ASD mouse model.

Methods: VPA-exposed C57BL/6 mice were randomized into five groups: control, VPA, hUCMSCs alone, EVs alone, and hUCMSCs + EVs combination. Behavioral tests, biochemical analyses, 16 S rRNA sequencing, immunofluorescence, and transmission electron microscopy (TEM) were performed RESULTS: While both hUCMSCs and EVs alone showed some beneficial effects on certain ASD-like symptoms, each exhibited limited efficacy in achieving comprehensive remediation. In contrast, the combined hUCMSCs + EVs therapy yielded the most robust improvements across multiple domains, including social interaction and repetitive behaviors. Furthermore, the combination therapy synergistically normalized neuroinflammatory cytokine levels and oxidative stress, restored synaptic and mitochondrial ultrastructure in key brain regions, and promoted gut microbiota homeostasis by enriching beneficial bacteria such as Lactobacillus and reducing pathogens.

Discussion: These results highlight that although individual treatments offer partial relief, only the combined strategy fully restores neuroimmune-microbiota homeostasis, demonstrating a complementary and synergistic therapeutic effect. This study establishes a novel dual-target approach leveraging systemic hUCMSCs and CNS-targeted EVs, providing a promising translational strategy for ASD through orchestrated regulation of the neuro-immune-microbiota axis.

Rheumatoid arthritis (RA) is a chronic systemic autoimmune disease, and it cannot be cured currently. Mesenchymal stem cells (MSCs), an emerging therapeutic method, have been applied to treat RA. It is essential to learn more about RA and MSCs. A total of 1,296 records were retrieved from the Web of Science. Then, Citespace and VOSviewer were used for the scientometric analysis of the data, including national distribution, institutional distribution, author distribution, journals, funding, and keywords. Our analysis presents basic information on the research into treating RA with MSCs, identifies research hotspots, and outlines clear research directions for interested researchers. At present, research on MSCs and RA focuses on the diversity of therapeutic effects, inflammatory mechanisms, molecular mechanisms of MSCs from different sources, and extracellular vesicles of MSCs on RA. Cutting-edge research in this field is booming, and this study will promote the development of the scientific research and clinical applications of MSCs in treating RA.