Stem Cell Research & Therapy最新文献

{"title":"PTGIS inhibited osteogenic and promoted angiogenic differentiation of bone marrow mesenchymal stem cells via endoplasmic reticulum stress mediated PI3K/AKT signaling.","authors":"Han Bao, Jiaohong Wang, Haoqing Yang, Huina Liu, Xiao Han, Zhipeng Fan","doi":"10.1186/s13287-026-05144-9","DOIUrl":"10.1186/s13287-026-05144-9","url":null,"abstract":"<p><strong>Background: </strong>Mesenchymal stem cells (MSCs) play a key role in ectopic mineralization. Effective treatment requires both inhibiting pathological calcification and promoting vessel growth. While prostacyclin synthase (PTGIS) is critical for vascular health, its role in regulating osteogenic and angiogenic differentiation in MSCs remains unclear.</p><p><strong>Methods: </strong>Following PTGIS modulation in bone marrow mesenchymal stem cells (BMSCs), osteogenesis was assessed by alkaline phosphatase (ALP) activity, Alizarin Red staining (ARS), and hydroxyapatite/tricalcium phosphate (HA/TCP) particles implantation. Angiogenesis was evaluated via a co-culture system of BMSCs and human umbilical vein endothelial cells (HUVECs). Mechanistic studies involved Ca²⁺ dynamics, western blotting, and pharmacological inhibition.</p><p><strong>Results: </strong>Knockdown of PTGIS enhanced ALP activity, mineralization, the expression of the osteogenic marker DMP1/BSP, and bone-like tissue formation both in vitro and in vivo. Conversely, PTGIS knockdown reduced tubule formation in vitro and impaired blood vessel formation, and the expression of the angiogenic marker CD31 in vivo. Mechanistically, the overexpression of PTGIS promoted Ca²⁺ efflux, endoplasmic reticulum (ER) dilation and vacuolization, increased the levels of the ER stress markers BIP/GRP75, and elevated PI3K/AKT phosphorylation. The inhibition of either ER stress or AKT activity restored osteogenic capacity by enhancing ALP activity and mineralization, and suppressed angiogenic capacity by inhibiting tubule formation in BMSCs.</p><p><strong>Conclusion: </strong>PTGIS inhibited osteogenic and promoted angiogenic differentiation of BMSCs through ER stress mediated PI3K/AKT signaling pathway. This PTGIS-dependent regulatory pathway offers new insight into MSC fate determination and represents a potential therapeutic strategy for treating ectopic mineralization disorders.</p>","PeriodicalId":21876,"journal":{"name":"Stem Cell Research & Therapy","volume":" ","pages":""},"PeriodicalIF":7.8,"publicationDate":"2026-07-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13613854/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148388057","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Identification and enrichment of human retinal organoid-derived red/green cone-competent precursors with enhanced axon dynamics.","authors":"Praveen J Susaimanickam, Elizabeth Capowski, Mai N Xiong, Kimberly L Edwards, Yashdeep Phanse, Madalynn J Welch, Austin Pier, Steven J Mayerl, Maria A Fernandez Zepeda, Kyle D Peterson, M Joseph Phillips, Divya Sinha, Timothy M Gomez, David M Gamm","doi":"10.1186/s13287-026-05128-9","DOIUrl":"10.1186/s13287-026-05128-9","url":null,"abstract":"<p><strong>Background: </strong>Cell replacement therapies aimed at restoring foveal vision require a robust source of red/green (long/medium wavelength, or L/M) cone photoreceptors with intrinsic properties conducive to functional integration into host retina. Recent evidence has shown that cones present within mature human retinal organoids (ROs) can generate light responses comparable to macaque foveal cones. However, only cone precursors from early developing ROs possess a capacity for cell-autonomous axonogenesis. Therefore, we sought to identify and enrich for a population of early L/M cone-competent precursors with intrinsically superior axon dynamics that would provide an ideal donor cell source for future foveal reconstruction efforts.</p><p><strong>Methods: </strong>We developed a dual L/M cone/rod reporter (L/M-CRR) line to unequivocally identify early L/M cone-competent precursors from human ROs. To do so, we used CRISPR/Cas9 to link a tdTomato transgene to the endogenous THRB2 promoter in the WA09 NRL^+/eGFP rod reporter line. Differentiated ROs were characterized at early (day 50) and intermediate (day 100) developmental stages using a combination of live fluorescence imaging, immunocytochemistry, and flow cytometry, followed by fluorescence-activated cell sorting and bulk RNAseq analysis to delineate the unique molecular signature of early L/M cone-competent precursors.</p><p><strong>Results: </strong>THRB2-driven tdTomato fluorescence faithfully demarcated L/M cone-competent precursors throughout RO development, although fluorescence declined in later ROs as L/M cones matured. Transcriptomic profiling revealed that day 50 sorted tdTomato⁺ cells were specifically enriched for genes associated with neural development, axon extension and guidance, and cell migration, which included a gene encoding the cell surface protein CD166/ALCAM. Magnetic-activated cell sorting using an anti-CD166 antibody resulted in specific enrichment of early, highly axonogenic L/M cone-competent precursors assessed by time-lapse imaging.</p><p><strong>Conclusions: </strong>The L/M-CRR line enables definitive identification and transcriptomic characterization of L/M cone-competent precursors throughout early to mid-stage RO development. Our investigation also revealed that CD166/ALCAM can be used to independently identify and enrich for a subset of early L/M cone-competent precursors that selectively display axon dynamicity conducive for retinal circuit integration. Our studies provide the first insights into early human L/M cone development and establish a method to isolate L/M cone-competent precursors with enhanced axon dynamics, which constitutes a compelling cell population for treating central vision loss caused by photoreceptor degeneration.</p>","PeriodicalId":21876,"journal":{"name":"Stem Cell Research & Therapy","volume":" ","pages":""},"PeriodicalIF":7.8,"publicationDate":"2026-07-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13613627/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148388022","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"PBAE nanoparticle-mediated delivery of ASCL1 and NGN2 genes for astroglia-to-neuron reprogramming to remodel glial scar for spinal cord injury repair.","authors":"Jianbin Guo, Lin Li, Zijian Liu, Shihao Yuan, Xiaoyu Ma, Dandan Zhang, Peng Deng, Jinchao Wang, Bo Chen, Jing An, Junping Li, Quanrui Ma, Hao Yang","doi":"10.1186/s13287-026-05159-2","DOIUrl":"10.1186/s13287-026-05159-2","url":null,"abstract":"<p><strong>Background: </strong>Irreversible loss of neuronal cells elicited by neurotraumatic injuries or neurodegenerative disorders is particularly devastating due to the limited regenerative capacity of the central nervous system (CNS). Cell reprogramming-based therapies have emerged as promising therapeutic avenues for neuronal replenishment. However, their therapeutic potential in neural regeneration still faces formidable challenges, including risks of viral vector gene delivery, potential damage from cell transplantation, and significant glial scar (GS) formation following CNS injury. Therefore, developing an optimal approach that simultaneously replaces lost neurons and overcomes these persistent obstacles is crucial for neural regeneration and functional recovery.</p><p><strong>Methods: </strong>We engineered a non-viral gene delivery platform using biodegradable poly(β-amino ester) (PBAE) nanoparticles (NPs) to effectively co-deliver plasmids encoding proneural transcription factors ASCL1 and NGN2 directly to astroglia (ATG) within GS region, in combination with neural induction. The biochemical and physiological properties of reprogrammed ATGs were characterized both in vivo and in vitro. The therapeutic potential of PBAE-A/N delivery was assessed in spinal cord injury (SCI) animal models through behavioral evaluations. Finally, the molecular mechanisms underlying ASCL1/NGN2-mediated ATG-to-neuron reprogramming were investigated.</p><p><strong>Results: </strong>PBAE-mediated delivery of ASCL1/NGN2 plasmids effectively reprogrammed resident ATGs within GSs into functional neurons, as evidenced by the acquisition of neuronal morphology and biochemical phenotype (neuronal marker expression), loss of ATG characteristics, scar remodeling, and functionality indistinguishable from those of genuine neurons, including specialized calcium signaling, synaptic activity, and action potential firing. Critically, local administration of PBAE-ASCL1/NGN2 NPs into the GS region of the injured spinal cord significantly ameliorated neurological deficits. Mechanistically, this reprogramming event likely involved the modulation of downstream targeting signaling mediated by Cend1, RanBPM, and Dyrk1, along with crosstalk with the Notch1/Cyclin D1 axis.</p><p><strong>Conclusions: </strong>This study demonstrates that PBAE-mediated ASCL1/NGN2 delivery enables in situ reprogramming of ATG into functional neurons while actively dissolving GSs, thereby addressing both neuronal loss and GS barriers in CNS repair. The identified Cend1/RanBPM/Dyrk1 signaling and its crosstalk with Notch1/Cyclin D1 axis provide mechanistic insights into the events. Collectively, this work presents a novel therapeutic alternative for CNS repair and neurodegeneration by simultaneously replacing lost neurons and eliminating endogenous GSs through in situ cell reprogramming.</p>","PeriodicalId":21876,"journal":{"name":"Stem Cell Research & Therapy","volume":" ","pages":""},"PeriodicalIF":7.8,"publicationDate":"2026-07-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13613702/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148388013","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Lipoaspirate-derived secretome restores redox homeostasis to attenuate pathological scar formation.","authors":"Xin Huang, Pengbing Ding, Zhixuan Sun, Haibo Xiang, Muqian Wei, Hongsen Bi, Zhenmin Zhao","doi":"10.1186/s13287-026-05123-0","DOIUrl":"10.1186/s13287-026-05123-0","url":null,"abstract":"&lt;p&gt;&lt;strong&gt;Background: &lt;/strong&gt;Pathological scars are characterized by persistent fibroblast activation and excessive extracellular matrix (ECM) deposition. Although oxidative stress and dysregulated NRF2 signaling contribute to TGF-β1-mediated fibrosis in internal organs, their roles in cutaneous pathological scarring remain unclear. Secretome-based cell-free therapies have shown regenerative and antifibrotic potential, but whether lipoaspirate-derived secretome can restore fibroblast redox homeostasis and thereby attenuate pathological scarring is unknown.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Methods: &lt;/strong&gt;Lipoaspirate fluid obtained during standard tumescent liposuction was processed by 100-kDa ultrafiltration to generate lipoaspirate-derived secretome (LA), while secretome from adipose-derived stromal cell (ADSC) culture supernatant served as a comparator (CS). LA and CS were characterized by nanoparticle tracking analysis, transmission electron microscopy, and immunoblotting for EV markers. In vivo efficacy was evaluated in a rabbit ear scar model with weekly intradermal LA injection, followed by gross, histological, collagen, and qPCR assessments. Comparative proteomic profiling of LA and CS was performed using data-independent acquisition LC-MS/MS with enrichment analysis, and paired human scar and normal skin samples were analyzed by single-cell RNA sequencing. In vitro, TGF-β1-stimulated fibroblasts were treated with LA or CS, and NRF2 involvement was assessed using the inhibitor ML385 or Nrf2-targeting siRNA. Redox balance, NRF2 signaling, and profibrotic responses were assessed by fluorometric assays, qPCR, and immunoblotting.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Results: &lt;/strong&gt;LA showed a substantially higher particle yield than CS and contained abundant extracellular vesicles. Weekly intradermal LA injections reduced scar formation and improved collagen organization in the rabbit ear model. Comparative proteomics of LA versus CS highlighted cytoprotective pathways, including glutathione metabolism and NRF2-associated antioxidant signaling. Analyses of human scar tissues revealed elevated NOX4 expression, increased 4-HNE, and impaired NRF2-associated antioxidant signaling in scar fibroblasts. In vitro, both LA and CS attenuated TGF-β1-driven profibrotic fibroblast activation, whereas LA showed greater antioxidant activity, including stronger suppression of oxidative stress-related responses and improved GSH/GSSG balance. Pharmacological inhibition and genetic silencing of NRF2 partially reversed the antioxidant and antifibrotic effects of LA.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Conclusion: &lt;/strong&gt;Lipoaspirate-derived secretome (LA) is a clinically accessible cell-free therapeutic candidate for pathological scarring. LA restores redox homeostasis, in part through NRF2-associated antioxidant signaling, attenuates TGF-β1-driven profibrotic fibroblast activation, and improves scar remodeling in vivo. These findings support LA as a promising cell-free strategy for attenuating pathological scar fo","PeriodicalId":21876,"journal":{"name":"Stem Cell Research & Therapy","volume":" ","pages":""},"PeriodicalIF":7.8,"publicationDate":"2026-07-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13613836/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148388005","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"DLP bioprinting of cartilage organoid-laden bioinks yields high-fidelity auricular constructs with enhanced chondrogenesis.","authors":"Yuxuan Chen, Yifan Zhang, Pengxiang Luo, Shanshan Su, Wenbin Jiang, Chao Luo, Xia Cai, Jiaming Sun, Zhenxing Wang","doi":"10.1186/s13287-026-05156-5","DOIUrl":"10.1186/s13287-026-05156-5","url":null,"abstract":"<p><strong>Purpose: </strong>To develop and validate a cartilage organoid (CO)-laden digital light processing (DLP) bioprinting strategy for auricular reconstruction and to compare its performance with conventional chondrocyte-laden prints.</p><p><strong>Materials and methods: </strong>Rat bone-marrow stromal cells (BMSCs) were aggregated into spheroid and chondrogenically induced to form CO. Organoid construction and characterization included EdU proliferation assay, CD73/CD90 immunofluorescence (IF), and real-time quantitative polymerase chain reaction (qPCR) of chondrogenic genes. O-nitrobenzyl functionalized gelatin (GelNB)/ methacrylated hyaluronic acid (HAMA) bioinks were screened by gross morphology, tensile/ compressive mechanics, enzymatic degradability (0.1% collagenase II), and swelling, identifying 10% (w/v) GelNB + 1% (w/v) HAMA as the working bioink. Full-scale ears were DLP-printed from acellular, chondrocyte-laden, or CO-laden inks. In vitro, whole-mount Live/Dead imaging was performed at 7/14/21 days and qPCR quantified COL2A1, aggrecan (ACAN), COL10A1. In vivo, constructs were implanted subcutaneously in nude mice and analyzed at 4/8 weeks by Hematoxylin-eosin (H&E), Safranin O/Fast Green, ACAN and COL II IHC staining, and compressive Young's modulus measurement on implants.</p><p><strong>Results: </strong>The 10% GelNB + 1% HAMA ink balanced print fidelity, mechanical robustness, and controlled degradability. Loading CO did not impair printability. During 21-day culture, viability remained high; at day 21, CO-laden ears showed higher COL2A1/ACAN and lower COL10A1 than chondrocyte-laden controls. After implantation, CO-laden explants exhibited more abundant lacuna-like cartilage morphology, stronger ACAN and COL II staining, increased EVG-positive elastic fiber-associated matrix, and a higher compressive Young's modulus at 8 weeks.</p><p><strong>Conclusions: </strong>CO-laden DLP bioprinting enhances chondrogenesis and mitigates hypertrophy versus chondrocyte-laden printing, offering an exploratory high-fidelity strategy for auricular cartilage-like tissue engineering rather than definitive mature elastic cartilage regeneration.</p>","PeriodicalId":21876,"journal":{"name":"Stem Cell Research & Therapy","volume":" ","pages":""},"PeriodicalIF":7.8,"publicationDate":"2026-07-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13613730/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148382817","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Therapeutic potential of mesenchymal stem cell-derived apoptotic vesicles in liver fibrosis: targeting the IGFBP3/PI3K-AKT axis via miR-409-3p.","authors":"Bin Lu, Xingzhi Chen, Hui Wang, Mengyue Li, Yuhui Shi, Yongheng Huang, Jie Ding, Yi Wang, Ling Li, Jing Luo, Changchang Jia, Nan Lin, Yuan Feng","doi":"10.1186/s13287-026-05143-w","DOIUrl":"10.1186/s13287-026-05143-w","url":null,"abstract":"<p><strong>Background: </strong>Hepatic fibrosis is a progressive pathology driven by hepatic stellate cell (HSC) activation and excessive extracellular matrix deposition. While mesenchymal stem cell (MSC) therapies show promise, their clinical translation is hindered by the inherent safety constraints of live cell transplantation. MSC-derived apoptotic vesicles (MSC-ApoVs), a structurally distinct class of extracellular vesicles, emerge as a compelling cell-free alternative. However, their specific therapeutic efficacy and mechanistic targets in hepatic fibrosis remain elusive.</p><p><strong>Methods: </strong>MSC-ApoVs were isolated from human umbilical cord MSCs and stringently characterized to exclude non-vesicular contaminants. Their anti-fibrotic efficacy was evaluated in vitro using TGF-β1-activated LX-2 cells and in vivo within a CCl₄-induced murine fibrosis model. To elucidate and functionally validate the underlying mechanisms, we integrated transcriptomic profiling (RNA-seq), dual-luciferase reporter assays, and dual-directional pharmacological interventions. Furthermore, human clinical liver biopsies were analyzed to determine the clinico-pathological relevance of the identified targets.</p><p><strong>Results: </strong>We demonstrated that MSC-ApoVs were efficiently internalized by HSCs, significantly blunting TGF-β1-induced activation, proliferation, and migration, alongside a marked reduction in fibrotic markers (α-SMA, MMP2, and Collagen-I). Transcriptomic screening identified Insulin-like Growth Factor Binding Protein 3 (IGFBP3) as a crucial pro-fibrotic mediator. Mechanistically, MSC-ApoV-enriched miR-409-3p directly targeted and downregulated IGFBP3, thereby restricting the PI3K-AKT signaling cascade-a dependency unequivocally validated by targeted rescue and blockade assays. In vivo, systemic MSC-ApoV administration robustly ameliorated CCl₄-induced hepatic fibrosis and restored liver function. Crucially, clinical analyses revealed a strong positive correlation between elevated IGFBP3 expression and the severity of human fibrotic progression.</p><p><strong>Conclusions: </strong>This study delineates a novel cell-free therapeutic paradigm, demonstrating that MSC-ApoVs mitigate hepatic fibrosis largely through the miR-409-3p-mediated silencing of the IGFBP3/PI3K-AKT axis. By integrating robust in vitro, in vivo, and clinical evidence, these findings highlight MSC-ApoVs as a highly efficacious and translatable alternative to traditional live stem cell therapies for hepatic fibrosis.</p>","PeriodicalId":21876,"journal":{"name":"Stem Cell Research & Therapy","volume":" ","pages":""},"PeriodicalIF":7.8,"publicationDate":"2026-07-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13602725/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148382873","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"ITGA1 promotes osteogenic differentiation of human periodontal ligament stem cells via FAK-mediated PI3K-Akt activation.","authors":"Jie Tan, Haoli Tang, Shuangshuang Peng, Xin Li, Meng Dai, Maike Xu, Shijia Zhu, Rui Zhang, Chengcheng Pi, Fuheng Jiang, Kun Yang, Jun Li","doi":"10.1186/s13287-026-05139-6","DOIUrl":"10.1186/s13287-026-05139-6","url":null,"abstract":"<p><strong>Background: </strong>Human periodontal ligament stem cells (hPDLSCs) possess promising potential for bone regeneration; however, the regulation of their osteogenic differentiation remains incompletely understood. Integrin α1 (ITGA1) has been implicated in multiple cellular processes, but its role in hPDLSC osteogenesis requires further investigation.</p><p><strong>Methods: </strong>ITGA1 was overexpressed in hPDLSCs using an adenoviral vector, and osteogenic differentiation was evaluated by alkaline phosphatase (ALP) staining and gene expression analysis. Loss-of-function experiments were performed using ITGA1 knockdown. Data-independent acquisition (DIA) proteomics, protein-protein interaction (PPI) analysis, immunoprecipitation-mass spectrometry (IP-MS), and co-immunoprecipitation (Co-IP) were employed to explore the underlying mechanisms. Functional validation was performed using gene silencing and pharmacological inhibition, and in vivo efficacy was assessed in a rat mandibular bone defect model.</p><p><strong>Results: </strong>Overexpression of ITGA1 enhanced osteogenic differentiation, while its knockdown produced the opposite effect. Proteomic analysis identified multiple differentially expressed proteins, including integrin family members, suggesting potential functional specificity. ITGA5 knockdown did not impair ITGA1-mediated osteogenesis. PPI and Co-IP analyses supported an interaction between ITGA1 and focal adhesion kinase (FAK). Inhibition of FAK or PI3K-Akt signalling reduced the pro-osteogenic effects of ITGA1. In vivo, transplantation of ITGA1-overexpressing hPDLSCs promoted bone regeneration in rat mandibular defects.</p><p><strong>Conclusions: </strong>Activation of the FAK/PI3K-Akt signalling pathway contributes to the promoting effect of ITGA1 on osteogenic differentiation of hPDLSCs. These findings provide insight into integrin-mediated regulation of hPDLSC osteogenesis and may inform future strategies for bone regeneration.</p>","PeriodicalId":21876,"journal":{"name":"Stem Cell Research & Therapy","volume":" ","pages":""},"PeriodicalIF":7.8,"publicationDate":"2026-07-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13613795/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148382879","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"SERINC3 promotes osteogenic differentiation of BMSCs via IL-32/AMPK-mediated autophagy and mitochondrial energy metabolism.","authors":"Zhichao Zheng, Tianru Xu, Janak L Pathak, Shaofen Xu, Jiarui Lu, Shuiqing Yu, Zhihe Fu, Wei Xie, Haohui Zhu, Richard T Jaspers, Huade Zheng, Lihong Wu, Jiang Li","doi":"10.1186/s13287-026-05135-w","DOIUrl":"10.1186/s13287-026-05135-w","url":null,"abstract":"<p><strong>Background: </strong>SERINC3, a member of the serine incorporator protein family, is known for its roles in viral resistance and tumorigenesis, however, its function in osteogenesis remains unexplored.</p><p><strong>Methods: </strong>Lentivirus infection, alkaline Phosphatase/Alizarin Red S Staining, and RT-qPCR were used to evaluate the osteogenic differentiation of mesenchymal stem cells mediated by SERINC3. MicroCT, H&E, and Masson staining were performed to investigate the bone formation and bone defect repair via Serinc3 knockout (KO) mice and nude mice. RNA sequencing, Co-IP, Western blotting, and Seahorse energy metabolism analysis were performed to elucidate the regulatory mechanism of SERINC3.</p><p><strong>Results: </strong>Here, we identify SERINC3 as a critical regulator of osteogenic differentiation of bone marrow-derived stem cells (BMSCs) and bone regeneration. SERINC3 expression was significantly upregulated during osteogenic differentiation of BMSCs and stem cells from human exfoliated deciduous teeth (SHED). Functional assays revealed that SERINC3 overexpression enhanced osteogenic differentiation, proliferation, and migration of MSCs, while Serinc3-KO impaired these processes and led to osteopenia in mice. In a calvarial defect model, Serinc3-KO mice exhibited 42% less bone volume (BV/TV) and 35% lower bone mineral density (BMD), whereas SERINC3-overexpressing BMSCs significantly improved bone repair. Mechanistically, RNA sequencing and pathway analysis revealed that SERINC3 interacts with IL32 to activate the AMPK-ULK1-autophagy axis, thereby promoting osteogenesis. Additionally, SERINC3 enhanced mitochondrial energy metabolism by upregulating tricarboxylic acid cycle enzymes (ACO1, DLAT, SDHA) and increasing oxygen consumption rates. Rescue experiments confirmed that AMPK inhibition or autophagy blockade abolished SERINC3-mediated osteogenic effects, whereas mitochondrial electron transport chain activators restored osteogenesis in SERINC3-knockdown cells.</p><p><strong>Conclusions: </strong>In summary, this study identifies SERINC3 as a novel regulator of bone formation that orchestrates osteogenesis through IL32-AMPK-autophagy signaling axis and mitochondrial metabolism. These findings highlight SERINC3 as a potential therapeutic target for enhancing bone regeneration and treating skeletal defects.</p>","PeriodicalId":21876,"journal":{"name":"Stem Cell Research & Therapy","volume":" ","pages":""},"PeriodicalIF":7.8,"publicationDate":"2026-07-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13613861/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148382807","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Differentiation of human induced pluripotent stem cells into cardiac valve cells using 2D and 3D differentiation protocols.","authors":"Z Farzaneh, A Brückner, B K Fleischmann, S Rieck","doi":"10.1186/s13287-026-05132-z","DOIUrl":"10.1186/s13287-026-05132-z","url":null,"abstract":"<p><strong>Background: </strong>Given the high relevance of human cardiac valve disease, recent research aims to differentiate human induced pluripotent stem cells (hiPSCs) into valve endothelial-like cells (VELCs) and, through endothelial-to-mesenchymal transition (EndMT), into valve interstitial-like cells (VILCs).</p><p><strong>Methods: </strong>Here, we modified a 2D differentiation protocol demonstrating that VEGF can serve as the sole driver for differentiating cardiac progenitor cells (CPCs) into VELCs. Next, we utilized the so-called GiWi protocol (inhibition of glycogen synthase kinase, followed by inhibition of the Wnt pathway) to derive VELCs from 3D endocardial spheres. To this aim, hiPSCs were first differentiated into cardiac progenitor (CP) spheres using CHIR99021 (12 µM) and IWP2 (5 µM). Subsequent treatment with E8 medium containing high-dose FGF2 (100 ng/ml) resulted in endocardial spheres enriched for VELCs. For EndMT induction, endocardial spheres were MACS-sorted for PECAM1⁺ VELCs and transdifferentiated into ACTA2⁺/CDH5^- VILCs using TGFβ1 (200 ng/ml).</p><p><strong>Results: </strong>Using VEGF as main driver to differentiate CPCs into VELCs in 2D, the generated VELCs appeared stable over time, can be maintained in vitro and transdifferentiated into ACTA2⁺ VILCs using FGF2 (100 ng/ml) and TGFβ1 (50 ng/ml). Besides, our novel 3D differentiation protocol yielded endocardial spheres, which were highly enriched with VELCs, as shown by the expression of GATA4 (≈ 83%), PECAM1 (≈ 69%), and nuclear NFATC1 (≈ 76%), along with typical functional characteristics such as network formation, LDL uptake and the ability to undergo EndMT.</p><p><strong>Conclusions: </strong>Overall, we developed a 2D differentiation protocol that produces stable VELCs and a high percentage of VILCs upon EndMT induction. We also established a new, efficient, and cost-effective protocol for the 3D differentiation of endocardial spheres to better mimic a physiologically relevant environment, thereby enabling improved maturation.</p>","PeriodicalId":21876,"journal":{"name":"Stem Cell Research & Therapy","volume":"17 1","pages":""},"PeriodicalIF":7.8,"publicationDate":"2026-07-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13330356/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148376403","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Adcyap1r1-driven astrocyte reprogramming attenuates neuroinflammation and promotes dopaminergic neuroprotection in Parkinson's Disease.","authors":"Yang-Yang Zheng, Li-Rong Hu, Yu Gu, Mei-Yun Cai, Xiao-Wen Wang, Wen-Fang Chen","doi":"10.1186/s13287-026-05133-y","DOIUrl":"10.1186/s13287-026-05133-y","url":null,"abstract":"<p><strong>Background: </strong>Parkinson's disease (PD), the second most prevalent neurodegenerative disorder globally, is characterized by progressive degeneration of dopaminergic (DA) neurons and sustained neuroinflammatory cascades. Strategies that simultaneously suppress neuroinflammation and protect DA neurons are urgently needed, particularly through targeting astrocytes (As). Building on our previous discovery that combined miR-124 and small molecule interventions synergistically suppress As activation and induce their transdifferentiation into dopaminergic-like neurons, this study identified Adcyap1r1 as a pivotal regulator via RNA-seq analysis. Here, we systematically investigated its cAMP-mediated dual functional roles in neuroinflammatory modulation and DA neuron preservation.</p><p><strong>Methods: </strong>TGF-β1-activated neonatal SD rat cortical reactive astrocytes (RAs) were used for Adcyap1r1 overexpression. We assessed astrocyte reactivity, neuroinflammation, neuron-like transition, and cAMP pathway activity in vitro. In MPTP-induced PD mice, AAV-mediated Adcyap1r1 overexpression was targeted to striatal As. Motor function, astrocyte activation, neuroinflammation, and endogenous DA neuron survival in the nigrostriatal system were evaluated through behavioral, histopathological, and molecular analyses.</p><p><strong>Results: </strong>In activated RAs, Adcyap1r1 overexpression significantly attenuated reactivity, reduced pro-inflammatory mediator expression (e.g., COX-2, iNOS), activated cAMP signaling, and promoted the acquisition of a tyrosine hydroxylase-positive (TH⁺) neuron-like phenotype. In MPTP-induced PD mice, astrocyte-targeted Adcyap1r1 overexpression in the striatum effectively inhibited astrocytic activation and neuroinflammation, protected endogenous TH⁺ neurons in the nigrostriatal system, and alleviated motor deficits, thereby supporting its DA neuroprotective potential.</p><p><strong>Conclusions: </strong>Our study demonstrates that Adcyap1r1 functions through a cAMP-dependent dual mechanism to suppress astrocyte reactivity and neuroinflammatory cascades, and facilitate the transition of RAs into a DA neuron-like phenotype. This dual regulatory mechanism protects the nigrostriatal DA system and ameliorates motor dysfunction in PD mice, providing a theoretical foundation for developing innovative therapeutic strategies against PD.</p>","PeriodicalId":21876,"journal":{"name":"Stem Cell Research & Therapy","volume":" ","pages":""},"PeriodicalIF":7.8,"publicationDate":"2026-07-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13599220/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148376979","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}