Stem Cell Research & Therapy最新文献

Background: The imbalance between osteogenic and adipogenic differentiation of bone marrow mesenchymal stem cells (BMSCs) is a central pathological feature of osteoporosis (OP). The translocator protein (TSPO) is a multifunctional protein, yet its precise role in bone metabolism remains elusive. This study aimed to investigate the role and mechanism of TSPO in OP pathogenesis.

Methods: We integrated bioinformatic analyses of human and mouse OP-related datasets and validated TSPO expression in BMSCs from osteoporotic patients and mouse models. Gain- and loss-of-function experiments in human BMSCs (h-BMSCs) assessed the impact of TSPO on proliferation, senescence, migration, and lineage differentiation. RNA sequencing and mechanistic rescue experiments were employed to identify the involved signaling pathway. The therapeutic effect of Adeno-associated virus 9 (AAV-9)-mediated TSPO silencing was evaluated in ovariectomized (OVX) mice.

Results: TSPO was significantly upregulated in BMSCs from both OP patients and preclinical models. Functionally, TSPO overexpression suppressed h-BMSC proliferation, migration, and osteogenesis while promoting senescence and adipogenesis. Conversely, TSPO knockdown enhanced cellular fitness and osteogenic capacity. Mechanistically, TSPO functioned as a critical upstream regulator of the PI3K/AKT/GSK-3β signaling axis, suppressing the downstream phosphorylation cascade and ultimately inhibiting β-catenin-mediated osteogenic transcription. Crucially, local TSPO silencing in OVX mice effectively improved bone microarchitecture, enhanced bone formation, and reduced marrow adiposity, concomitant with the reactivation of the PI3K/AKT/GSK-3β/β-catenin pathway.

Conclusion: Our study identifies TSPO as a key pathogenic regulator that impairs osteogenesis by disrupting the PI3K/AKT/β-catenin pathway. Targeting TSPO presents a novel anabolic strategy for osteoporosis, potentially addressing the unmet clinical need for therapies that restore bone formation.

The rapidly growing diabetic population is at high risk of dental implant failure due to a disrupted peri-implant immune microenvironment. Mesenchymal stem cells-derived exosomes (MSC-Exos) have emerged as a potent nanotherapeutic platform to remodel this hostile niche. Their mechanisms involve reprogramming macrophage polarization to alleviate inflammation, delivering pro-angiogenic miRNAs to restore vascular-osteogenic coupling, and modulating neuro-immune crosstalk to reestablish homeostasis. Collectively, these actions break the vicious cycle of impaired healing. Furthermore, engineering strategies such as membrane modification, integration with biomaterials, and preconditioning of parent cells can enhance the targeting, stability, and controlled release of MSC-Exos, thereby improving osseointegration outcomes in diabetic models. These engineering innovations, which focus on precise delivery and controlled release, are as critical to therapeutic development as elucidating the underlying biological mechanisms. This review systematically delineates the mechanisms by which MSC-Exos recalibrate the diabetic bone immune niche to foster osseointegration and critically discusses the clinical translation prospects of engineered exosome-based therapies.

The issue of kidney disease represents a significant global health challenge. While current treatment options may provide symptomatic relief, they are limited by several factors. Consequently, there is a pressing need to create more effective therapeutic strategies. Mesenchymal stromal cell (MSCs) and their secretome have attracted considerable attention in the field of regenerative medicine owing to their multidirectional differentiation potential, immunomodulatory properties, and paracrine effects, which offer a promising solution to this challenge. However, direct transplantation of MSCs and their secretome faces problems such as low survival rate and unstable therapeutic effect in practical applications. These challenges have prompted researchers to explore strategies to enhance the therapeutic potential of MSCs and their secretory factors through pretreatment. This review summarizes the current research progress on pretreated MSCs and their secretome in the treatment of kidney diseases and discusses how various pretreatment approaches can enhance their therapeutic efficacy and clinical application in renal disorders, thereby providing insights for the future optimization and therapeutic use of MSCs.

Background: Early vascularization is one of the limitations of periodontal tissue engineering (PTE) based on mesenchymal stem cells (MSCs). Directed differentiation of endothelial progenitor cells (EPCs) into endothelial cells facilitates the osteogenic effect of MSCs. Therefore, this study constructed EPCs/peripheral blood derived-MSCs (EPCs/PBMSCs) sheets and evaluated their repair value and potential molecular mechanisms in bone regeneration.

Methods: Different ratios of EPCs and PBMSCs were co-cultured to prepare EPCs/PBMSCs sheets and the osteogenic differentiation was assessed. Exploring the bone regeneration properties of EPCs/PBMSC sheets in an animal model of alveolar bone defects. The effect of the SLIT3/ROBO1 axis on angiogenic-osteogenic coupling of EPCs/PBMSCs sheets was explored using exogenous modulation by shRNA lentivirus and neutralizing antibody.

Results: EPCs/PBMSCs sheets could form angiogenic-osteogenic coupling, and different ratios of EPCs/PBMSCs sheets had higher angiogenic and osteogenic differentiation properties than EPCs or PBMSCs alone, especially the ratio 4:6. Moreover, EPCs/PBMSCs sheets accelerated bone regeneration in the alveolar bone defect model and the treatment was superior to PBMSCs alone. The expression patterns of SLIT3 and ROBO1 were consistent with the angiogenic-osteogenic coupling of EPCs/PBMSCs sheets. Knockdown of SLIT3 in PBMSCs and/or neutralization of ROBO1 protein in EPCs effectively suppressed calcified nodule formation and markers expression of osteogenic differentiation and angiogenesis (ALP, RUNX2, OCN, Osx, EMCN, and CD31) in EPCs/PBMSCs sheets, and hindered its therapeutic effect in the alveolar bone defect model.

Conclusion: EPCs/PBMSCs sheets ameliorate the limitations of early vascularization in PTE and the SLIT3/ROBO1 axis mediates the angiogenic-osteogenic coupling of EPCs/PBMSCs sheets, thereby augmenting their osteogenic effects.

Background: Research on cartilage repair in the knee joint is crucial for treating knee arthritis or injuries. The application of mesenchymal stem cells (MSCs) for cartilage tissue regeneration represents a promising therapeutic approach. Among the critical aspects in cartilage formation, the enhancement of MSC chondrogenic differentiation stands as a pivotal challenge. WDR63 is a cytoplasmic dynein that plays a significant role in promoting stem cell differentiation and is closely associated with the cytoskeleton and energy metabolism processes. In the current study, our objective is to elucidate the phenotypic manifestations and mechanisms of WDR63 in relation to its chondrogenic differentiation function in MSCs.

Methods: Stem cells from apical papilla (SCAP) were used. The Alcian Blue staining technique, pellet culture system, and cell transplantation in rabbit knee cartilage defects were employed to assess the chondrogenic differentiation capabilities of MSCs. Western blot and real-time RT-PCR were utilized to investigate the molecular mechanisms involved.

Results: In vitro, WDR63 overexpression in SCAPs enhanced chondrogenic differentiation, as evidenced by upregulating collagen type II (COL2), collagen type V (COL5), and sex-determining region Y box protein 9 (SOX9), and robust pellet formation, whereas WDR63 knockdown produced opposite effects. In vivo, implantation of WDR63-overexpressing SCAP promoted cartilage repair in a rabbit osteochondral defect model, showing improved hyaline cartilage matrix deposition, higher COL2 expression, reduced collagen type X(COLX) expression, and increased collagen type Ι (COL1) expression in the subchondral bone. Mechanistically, WDR63 interacted and co-localized with vimentin (VIM), and its overexpression enhanced VIM expression and WDR63-VIM binding. WDR63 upregulates DRP1 expression, and rescues the Mdi-suppressed mitochondrial fission.

Conclusions: WDR63 may promote chondrogenic differentiation of SCAPs by interacting with VIM and enhancing its expression, potentially through facilitating mitochondrial fission.

Background: Biliary atresia (BA) is a nongenetic cholangiopathy characterized by biliary obliteration. However, the underlying pathological mechanism remains unclear. We aimed to explore the epigenetic BA pathology by using BA-specific deciduous dental pulp stem cells (BA-SHED), which develop in parallel with cholangiocyte progenitor cells in human embryos.

Methods: BA-SHED were isolated from human exfoliated deciduous teeth of patients with BA using the colony-forming unit fibroblast method. After sequential stimulation with cytokines and chemicals in cultured BA-SHED, the in vitro bile duct-forming capacity was analyzed using quantitative reverse transcription polymerase chain reaction (RT-qPCR) and immunofluorescence. Expression of hepatocyte nuclear factor 6 (HNF6) and transforming growth factor beta receptor 2 (TGFBR2) was analyzed using immunoblotting and RT-qPCR. The regulation of chromatin architecture at the HNF6 promoter was analyzed using nuclease-accessible chromatin-qPCR and chromatin immunoprecipitation-qPCR.

Results: BA-SHED showed an inheritable increase in HNF6 levels, resulting in TGFBR2 suppression and deficiency in bile duct formation. BA-SHED also accumulated Brahma and P65 complexes around the HNF6 promoter with chromatin architecture remodeling. Tumor necrosis factor-alpha and interferon-gamma co-stimulation mimicked the epigenetic signatures of BA-SHED.

Conclusion: The present epigenetic memory in BA-SHED implies that BA-SHED imprint bile duct deficiency through TGFBR2 dysregulated by the HNF6 promoter activation epigenetically. Thus, BA-SHED are a potential model for expanding our knowledge in BA research.

Background: Evidence shows neural involvement in bone remodeling; regulating maxillofacial nerve repair modulates jawbone. Neural stem cell (NSC) therapy is limited by sources/ethics, but neural crest-derived dental mesenchymal stem cells (MSCs) like stem cells from the apical papilla (SCAPs) have strong neuroregenerative potential for NSC transdifferentiation. Schisantherin A (Sch-A), neuroprotective, enhances NSC proliferation/differentiation. This study explores optimal Sch-A concentration/duration for SCAP neural differentiation and effects on rat mental nerve repair/mandibular development.

Methods: SCAPs' mesenchymal stem cell properties were verified via flow cytometry and trilineage differentiation. Effects of different Sch-A concentrations were evaluated using CCK-8, colony formation, scratch assay, qRT-PCR, immunofluorescence, and Western blot. Transcriptome sequencing identified underlying mechanisms and determined optimal. A mental nerve injury model was established in 4-week-old SD rats (five groups; n = 4 per group) to assess neurorepair, functional recovery, and mandibular development following transplantation of Sch-A-induced SCAPs.

Results: Treatment with 10^- 9 mol/L Sch-A for 1 week induced robust neural differentiation in SCAPs, with high expression of nestin and NSE. Mental nerve-injured SD rats exhibited reduced lip sensation, abnormal nerve morphology, and inhibited transverse development of the anterior mandibular. Transcriptome analysis revealed Sch-A primarily acts via neuroactive ligand-receptor interaction pathway. Transplantation of induced SCAPs promoted nerve repair and restored mandibular development.

Conclusion: Sch-A at 10^- 9 mol/L concentration promotes the transdifferentiation of SCAPs into neural stem cell-like cells primarily through the neuroactive ligand-receptor interaction pathway. These Sch-A induced SCAPs effectively repair mental nerve injury and facilitate normal mandibular development.

Background: Hematopoietic stem cell transplantation (HSCT) is a cornerstone in the treatment of hematological disorders. However, its application is frequently complicated by acute and chronic graft-versus-host disease (aGVHD/cGVHD), pathological conditions in which donor-derived immune cells attack host tissues. With suboptimal survival rates and limited therapeutic options, GVHD remains a major clinical challenge. Mesenchymal stem cells (MSCs) have emerged as a promising therapeutic modality due to their immunomodulatory capabilities, yet standardized protocols for their use in preventing or treating GVHD have not been established.

Methods: We performed a comprehensive literature search of PubMed, Web of Science, EMBASE, and the Cochrane Library up to 10 February 2025 to identify eligible randomized controlled trials (RCTs). Study selection was based on the PICOS framework, and the risk of bias was assessed using appropriate quality appraisal tools. Outcome data were systematically extracted and synthesized via meta-analysis.

Results: A total of 15 RCTs were included. The meta-analysis revealed that MSC administration significantly reduced the incidence of aGVHD (OR: 0.47; 95% CI 0.32-0.71; p = 0.00003) and cGVHD (OR: 0.50; 95% CI 0.34-0.74; p = 0.0005) compared with controls. MSC therapy was also associated with improved response rates in steroid-refractory aGVHD (SR-aGVHD) (OR: 1.50; 95% CI 1.04-2.17; p = 0.03).

Conclusion: MSCs demonstrate efficacy in preventing both aGVHD and cGVHD following HSCT, particularly in moderate to severe forms. A dose range of 1 × 10⁶ to < 4 × 10⁶ cells/kg was associated with optimal prophylactic outcomes. For SR-aGVHD, MSC infusion resulted in significantly higher remission rates compared to conventional treatments, especially in severe cases.

Chronic traumatic encephalopathy (CTE), a progressive neurodegenerative disorder, poses a significant threat to human health. The lack of validated animal models has impeded mechanistic studies and the development of treatments for CTE. Recent evidence suggests that bone marrow mesenchymal stem cell-derived exosomes (BMSC-exos) represent a promising strategy for treating central nervous system injuries; however, their efficacy and mechanisms of action in CTE remain unexplored. In this study, we developed and optimized a CTE mouse model that recapitulates the core clinical features observed in CTE patients, including the delayed symptom onset. Using this model, we investigated the therapeutic effects of BMSC-exos. Our results indicate that BMSC-exos ameliorated anxiety-like behaviors and cognitive deficits in CTE mice, restoring them to levels comparable to those in noninjured control mice. Mechanistically, analysis of the hippocampal subgranular zone (SGZ) revealed that BMSC-exos restored the chronic CTE-induced reduction in the number of doublecortin (DCX)-positive immature neurons without altering the population of Sox2-Nestin-double-positive neural stem cells, indicating a primary effect on promoting neuronal differentiation efficiency or immature neuron survival rather than stem cell proliferation. Furthermore, BMSC-exos preserved neuronal structural integrity during late-stage CTE, indicating a critical role in maintaining synaptic plasticity and dendritic complexity. Collectively, our study provides promising evidence for the therapeutic potential of BMSC-exos in CTE, offering new insights for future CTE therapeutics.

Retinoblastoma (RB), which is the most common pediatric intraocular malignancy driven by RB1 inactivation, presents with clinical challenges, such as treatment toxicity, relapse, and resistance. Traditional models inadequately replicate human RB genetics or tumor heterogeneity, warranting the development of advanced in vitro platforms. Retinal organoids generated from human pluripotent or patient-specific stem cells enable three-dimensional(3D) modeling of the tumor microenvironment, drug screening, and mechanistic studies. This review summarizes RB pathogenesis, including RB1 loss, MYCN amplification, epigenetic dysregulation (e.g., METTL3-mediated m6A), and dysregulated pathways (PI3K/AKT/mTOR, Hedgehog), and highlights CRISPR-engineered organoids for identifying cone precursors as tumor origins and validating therapies (CDK4/6 inhibitors and sunitinib). Despite these advances, organoid applications are limited by high costs, variable success rates, incomplete immune/vascular mimicry, and limited scalability. Current microfluidic systems partially address vascularization but lack functional perfusion. Future efforts should integrate multiomics, refine vascularization via 3D bioprinting, and develop immunocompetent models to address the disparity between preclinical research and clinical application. Organoid technology has the potential to advance personalized therapies and ultimately enhance the survival and quality of life of patients with RB worldwide.