Cells最新文献

{"title":"Fibrotic Remodeling in Retinal Vascular Diseases: Cellular Origins, Molecular Mechanisms, and Therapeutic Perspectives.","authors":"Jia Yu Ning, Brian Wang, Miyuki Ishida Yamamoto, Kaori H Yamada","doi":"10.3390/cells15191772","DOIUrl":"10.3390/cells15191772","url":null,"abstract":"<p><p>Fibrosis is a major vision-threatening complication of neovascular retinal diseases, including neovascular age-related macular degeneration (nAMD) and proliferative diabetic retinopathy (PDR). Although vascular endothelial growth factor (VEGF) inhibition effectively suppresses vascular leakage and neovascularization, some patients still develop fibrosis and experience irreversible vision loss. Recent studies have identified multiple interconnected signaling pathways that contribute to fibrotic progression, highlighting the potential need for combination or multitargeted therapeutic strategies. This review summarizes the cellular origins of myofibroblasts, the molecular mechanisms underlying fibrosis, and recent advances in antifibrotic therapies. We particularly highlight the angio-fibrotic switch, mesenchymal transition, cellular stress responses, extracellular matrix remodeling, mechanotransduction, and emerging therapeutic approaches for ocular fibrosis. Relevant preclinical and clinical studies were identified through searches of PubMed and clinical trial registries.</p>","PeriodicalId":9743,"journal":{"name":"Cells","volume":"15 19","pages":""},"PeriodicalIF":6.0,"publicationDate":"2026-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13664481/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149191675","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Protein Tyrosine Phosphatases in Cancer: From Oncogenic Drivers to Therapeutic Targets.","authors":"Sravan Perla, Jonathan Pascale, Matthew Liu, Ashish Kumar, Sivaraman Kuppuswamy, Charanraj Goud Alladi, Vishnu Amaram Samara","doi":"10.3390/cells15191767","DOIUrl":"10.3390/cells15191767","url":null,"abstract":"<p><p>Protein tyrosyl phosphorylation is a dynamic reversible regulatory process that is essential for virtually all aspects of cellular function. The dysregulation of protein tyrosyl phosphorylation is one of the main causes of human diseases such as cancer, diabetes, autoimmune disorders, and neurological diseases. Protein tyrosine kinases (PTKs) have paved the way towards defining the significance of protein tyrosyl phosphorylation in human health and disease. However, homeostatic control of protein tyrosyl phosphorylation is also regulated by protein tyrosine phosphatases (PTPs). The actions of PTPs are diverse functioning to both positively and negatively regulate signaling pathways through specific substrate dephosphorylation. PTKs are now matured targets with numerous drugs that have been developed for the treatment of human diseases such as cancer and immunological disorders. In contrast, PTPs are relatively in their infancy as compared with their PTK counterparts with regard to drug development for the treatment of human diseases. However, mounting evidence supports the view that PTPs are not only valid targets but are indeed targetable. This review focuses primarily on the roles of PTPs as oncogenic drivers and therapeutic targets in cancer, while briefly noting their broader relevance to other diseases in which tyrosyl phosphorylation is dysregulated. This review will highlight recent developments in the PTP field, with an emphasis on cancer, which provide support for the emergence of PTPs as therapeutic targets, and will also briefly touch upon their relevance to related conditions such as obesity, type II diabetes and rare diseases.</p>","PeriodicalId":9743,"journal":{"name":"Cells","volume":"15 19","pages":""},"PeriodicalIF":6.0,"publicationDate":"2026-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13664233/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149191149","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Neutrophil Extracellular Traps at the Asthma + COPD Interface: Mechanisms, Experimental Models, and Therapeutic Targeting.","authors":"Leandro do Nascimento Camargo, Renato Fraga Righetti, Iolanda de Fátima Lopes Calvo Tibério","doi":"10.3390/cells15191769","DOIUrl":"10.3390/cells15191769","url":null,"abstract":"<p><p>Asthma and chronic obstructive pulmonary disease (COPD) are distinct chronic airway diseases with different pathophysiological mechanisms, but they may coexist and share clinical, functional, inflammatory, and structural features. The historical terminology used to describe this coexistence has shifted away from the notion of a single overlap syndrome toward a traits-based framework, emphasizing coexisting clinical, functional, inflammatory, and structural features rather than a uniform disease entity. Within this context, neutrophil extracellular traps (NETs) are emerging as a potential mechanistic link between allergic airway inflammation, cigarette smoke injury, neutrophilic activation, mucus obstruction, and tissue remodeling. Animal models combining allergen exposure with cigarette smoke, lipopolysaccharide, infection, or elastase provide useful platforms to dissect specific components of the asthma-COPD interface. This review examines NET biology with a primary focus on animal models that reproduce overlapping asthma and COPD features, emphasizing how epithelial injury, oxidative stress, protease activity, neutrophilic inflammation, and inflammatory cytokine networks converge to promote NET formation. NETs, composed of extracellular deoxyribonucleic acid (DNA), citrullinated histone H3, myeloperoxidase, neutrophil elastase, and granular proteins, may amplify mucus viscosity, epithelial damage, innate immune activation, airway remodeling, emphysema-like injury, and persistent airflow limitation. Strategies to target this axis include deoxyribonuclease I (DNase I), peptidylarginine deiminase 4 (PAD4) inhibition, neutrophil elastase and myeloperoxidase blockade, antioxidant approaches, C-X-C motif chemokine receptor 2 (CXCR2) modulation, and interleukin-17 (IL-17) inhibition. These interventions act at distinct stages of neutrophil recruitment, NET formation, NET persistence, or NET-mediated tissue injury. A rigorous interpretation of these models requires precise terminology, multiparametric NET detection, and integration of lung mechanics, histology, inflammatory profiling, and structural outcomes. Targeting NETs may help shift preclinical research from broad overlap labels toward mechanism-driven therapeutic strategies for coexisting asthma and COPD features.</p>","PeriodicalId":9743,"journal":{"name":"Cells","volume":"15 19","pages":""},"PeriodicalIF":6.0,"publicationDate":"2026-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13664007/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149191543","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Melatonin Regulates Sheep Granulosa Cell Proliferation and Apoptosis Through a Novel Micropeptide, IGF1Raa.","authors":"Weiming Zhong, Jianyu Ma, Zhibo Wang, Hua Yang, Xiuyuan Wang, Yang Gao, Shang Gao, Peiyong Chen, Yongjie Wan, Yanli Zhang, Feng Wang","doi":"10.3390/cells15191771","DOIUrl":"10.3390/cells15191771","url":null,"abstract":"<p><p>Melatonin is a hormone primarily secreted by the pineal gland, best known for regulating circadian rhythms. It also plays a critical role in ovarian physiology by modulating granulosa cell (GC) function during follicular development, although the underlying molecular mechanisms remain incompletely understood. Recent advances in ribosome sequencing (Ribo-seq) have revealed that many small open reading frames (sORFs), previously overlooked in conventional annotations, actually encode functional micropeptides. However, whether melatonin exerts its ovarian effects through such micropeptides has remained unexplored. In the present study, we identified a previously unannotated sORF within the 5'untranslated region (UTR) of sheep IGF1R mRNA and demonstrated that this sORF encodes a 32-amino-acid micropeptide, which we named IGF1Raa. Knockdown and overexpression of IGF1Raa in sheep GCs, assessed by CCK-8, Edu, flow cytometry, and ELISA, revealed that IGF1Raa negatively regulates GC proliferation and E2 secretion and promotes apoptosis. Co-ip assays and RNA-seq show that IGF1Raa physically associates with PPP2R2B, a regulatory subunit of protein phosphatase 2A (PP2A), and modulates PP2A protein expression. Consequently, IGF1Raa regulates the phosphorylation of AMPK (Thr172) and its downstream effector Raptor (Ser792), thereby controlling the AMPK/mTOR signaling cascade. Importantly, melatonin suppresses IGF1Raa expression, and overexpression of IGF1Raa partially abrogates melatonin's stimulatory effects on GC proliferation and steroidogenesis. Collectively, our findings identify IGF1Raa as a melatonin-responsive micropeptide that governs GC function through the PP2A/AMPK/mTOR axis, providing new insights into the regulatory network of ovarian physiology and offering potential therapeutic targets for reproductive disorders.</p>","PeriodicalId":9743,"journal":{"name":"Cells","volume":"15 19","pages":""},"PeriodicalIF":6.0,"publicationDate":"2026-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13664153/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149191575","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"HLA-Engineered iPSC-Derived Mesenchymal Stromal Cells for the Treatment of Osteoarthritis in Mice.","authors":"Ze Wei, Tian Gan, Annan Liang, Su Liu, Jing Hao, Wei Zou, Lun Li, Xuemeng Mu, Huitian Han, Wenjing Ma, Jinyi Xing, Yifan Wei, Hao Fan, Lijin Liu, Fei Liu, Zhifa Zheng, Zhihong Wu, Lina Zhao","doi":"10.3390/cells15191777","DOIUrl":"10.3390/cells15191777","url":null,"abstract":"<p><p>Osteoarthritis (OA) is one of the most prevalent degenerative joint diseases, and there is no approved pharmacological therapy that can reliably reverse cartilage degeneration or restore cartilage structure. Allogeneic mesenchymal stromal cells (MSCs) have shown therapeutic potential for OA, but inflammatory conditions can enhance HLA expression and increase allogeneic immune recognition risk. Here, we generated B2M and CIITA double-knockout induced pluripotent stem cells (dKO-iPSCs) using CRISPR/Cas9 and subsequently differentiated them into dKO-iMSCs. B2M/CIITA double-knockout did not affect iPSC pluripotency, karyotype, or teratoma formation. dKO-iMSCs retained characteristic MSC phenotypes, exhibited greater proliferative capacity than tissue-derived MSCs, and could be expanded to passage 18. Notably, HLA-ABC and HLA-DR expression remained undetectable in dKO-iMSCs even after IFN-γ stimulation. In co-culture assays with PHA-L-stimulated allogeneic PBMCs, dKO-iMSCs suppressed PBMC and T-cell proliferation as effectively as wild-type iMSCs, indicating preservation of their immunomodulatory activity. Intra-articular administration of dKO-iMSCs significantly reduced cartilage degeneration in the destabilization of the medial meniscus (DMM) mouse model of OA. The treatment showed greater therapeutic efficacy than wild-type iMSCs and tissue-derived MSCs and did not cause evident systemic organ toxicity. Single-cell RNA sequencing of BM-MSCs and dKO-iMSCs after in vitro IFN-γ stimulation revealed enhanced extracellular matrix-associated cell-cell communication and markedly reduced IL1B expression in dKO-iMSCs, indicating a less pro-inflammatory and more matrix-supportive cellular state under inflammatory conditions. Collectively, B2M/CIITA double-knockout enables sustained reduction in HLA expression while preserving the MSC phenotype and immunomodulatory activity, and enhances the therapeutic efficacy of iMSCs in the mouse OA model, providing a potential strategy for developing iPSC-derived MSCs with reduced HLA expression for allogeneic cell therapy.</p>","PeriodicalId":9743,"journal":{"name":"Cells","volume":"15 19","pages":""},"PeriodicalIF":6.0,"publicationDate":"2026-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13664303/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149191379","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"TRPs-NCX2 Axis Jointly Preserves Pancreatic Beta Cell Susceptibility/Sensitivity to Elevated Glucose.","authors":"Adlet Sagintayev, Furkan E Oflaz, Andra Kanlinuro, Savina van Amsterdam, Benjamin Gottschalk, Rene Rost, Zhanat Koshenov, Roland Malli, Wolfgang F Graier","doi":"10.3390/cells15191766","DOIUrl":"10.3390/cells15191766","url":null,"abstract":"<p><p><i>Background:</i> For appropriate glucose sensing, pancreatic beta-cells essentially establish a constant mitochondria-directed endoplasmic reticulum (ER) Ca²⁺ leak via phosphorylated presenilin-1 (PS1). In the current work, we investigated how cells maintain the ER Ca²⁺ content during this continuous Ca²⁺ leak. <i>Methods:</i> Ca²⁺ imaging for ER, cytosolic and subplasmalemmal Ca²⁺, high resolution respirometry, and ELISA for insulin secretion were used. <i>Results:</i> A novel ER Ca²⁺ refilling mechanism driven by reverse-mode NCX2, which is fueled by local Na⁺ influxes through TRPC3 and TRPV4 channels that are independent of STIM-ORAI1 was found in pancreatic rodent and human beta cell lines. Disrupting this TRPs-NCX2 axis reduces subplasmalemmal Ca²⁺ levels, abolishes glucose-induced cytosolic Ca²⁺ oscillations, suppresses glucose-triggered elevation in mitochondrial energetics, and impairs first-phase insulin secretion. <i>Conclusions:</i> We identified a novel, ORAI1-independent \"TRPs-NCX2\" relay that couples Na⁺ influx via TRPC3 and TRPV4 to NCX2 reverse mode to maintain ER Ca²⁺ stores during physiological basal ER Ca²⁺ leakage, which is fundamental to beta-cell responsiveness to elevated glucose.</p>","PeriodicalId":9743,"journal":{"name":"Cells","volume":"15 19","pages":""},"PeriodicalIF":6.0,"publicationDate":"2026-09-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13663930/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149191678","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Meta-Analysis of Porcine Beige Adipogenesis with Cross-Species CD137-CD137L Molecular Docking: Potential Implications for Pig-to-Human Xenotransplantation.","authors":"Zhenhua Guo, Liang Wang, Xinmiao He, Shuo Yang, Hong Ma, Bo Fu, Fang Wang, Di Liu, Dongjie Zhang","doi":"10.3390/cells15191758","DOIUrl":"10.3390/cells15191758","url":null,"abstract":"<p><p>Breakthroughs in gene-editing technologies have brought pig-to-human xenotransplantation to the clinical forefront. Nevertheless, the micro-scale impacts of the complex pathophysiological milieu within recipients on grafts have long been overlooked by the academic community. Focusing on stromal vascular fraction (SVF) cells and preadipocytes widely present in donor organs, this study explores the potential mechanism underlying beige adipogenesis induced by post-operative anti-inflammatory drugs (e.g., dexamethasone) and surgical stress (norepinephrine), as well as its possible relationship with host immune system activation. The literature search and study-selection reporting were informed by PRISMA 2020. Five information sources were searched, and nine relevant studies on experimentally induced porcine adipose beiging, predominantly in vitro, were included in marker-specific meta-analyses. The meta-analysis showed a higher pooled expression of <i>CD137</i>, <i>CIDEA</i>, <i>UCP3</i>, <i>PGC1α</i> and <i>DIO2</i> during experimentally induced porcine beige adipogenesis. To explore the structural plausibility of cross-species interaction, molecular docking analysis of the candidate protein CD137 was performed using AlphaFold 3. The predicted binding energies were -9.4 kcal/mol for porcine CD137-human CD137L and -9.0 kcal/mol for the human homologous complex. These computational predictions suggest a structurally plausible interaction, but the results do not demonstrate stronger biological binding, macrophage activation, or immune rejection. Overall, the findings support a hypothesis that porcine adipocyte beiging and CD137-related cross-species interactions may be relevant to xenograft immunometabolism; direct experimental validation in xenotransplantation models is required.</p>","PeriodicalId":9743,"journal":{"name":"Cells","volume":"15 19","pages":""},"PeriodicalIF":6.0,"publicationDate":"2026-09-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13664533/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149191533","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"METTL14 Promotes Chicken Preadipocyte Differentiation by Modulating mRNA Stability via a Dual-Reader m⁶A Mechanism.","authors":"Saibo Zhang, Qi Zhang, Yawen Yang, Chang Liu, Fei Teng, Shouzhi Wang, Hui Li, Bohan Cheng","doi":"10.3390/cells15191761","DOIUrl":"10.3390/cells15191761","url":null,"abstract":"<p><p>Preadipocyte differentiation is an essential process in adipogenesis. METTL14, an essential constituent of the <i>N</i>⁶-methyladenosine (m⁶A) methyltransferase complex, plays an important role in mammalian preadipocyte differentiation. However, its role in avian adipogenesis remains unclear. More importantly, the m⁶A mechanism by which METTL14 regulates preadipocyte differentiation has not been elucidated. Here, we found that the level of METTL14 expression was substantially elevated within the adipose tissue of the abdominal region of fat chickens relative to lean chickens. Knockdown of METTL14 inhibited preadipocyte differentiation, whereas overexpression of METTL14 promoted this process. Through the integration of MeRIP-seq and RNA-seq, we confirmed that <i>chBMI1</i>, <i>chTMED3</i>, and <i>chMFAP2</i> were functionally essential targets of METTL14-dependent m⁶A modification in adipogenesis. METTL14-mediated <i>chBMI1</i> mRNA stabilization and the degradation of <i>chTMED3</i> and <i>chMFAP2</i> mRNAs depend on IGF2BP1/2 and YTHDF2, respectively. Overall, our findings establish that METTL14 promotes chicken preadipocyte differentiation by modulating the stability of target mRNAs through a dual-reader m⁶A mechanism.</p>","PeriodicalId":9743,"journal":{"name":"Cells","volume":"15 19","pages":""},"PeriodicalIF":6.0,"publicationDate":"2026-09-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13664386/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149191535","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"GSC State Plasticity Drives Therapeutic Resistance and Recurrence in Glioblastoma.","authors":"Jinxi Shuai, Cuicui Chang, Yanju Gong","doi":"10.3390/cells15191757","DOIUrl":"10.3390/cells15191757","url":null,"abstract":"<p><p>Glioblastoma (GBM) is the most aggressive primary brain tumor in adults, and treatment failure is closely linked to the presence of GBM stem cells (GSCs). Rather than representing a fixed marker-defined state, GSC identity is better understood as a dynamic and reversible stem-like state. GBM cells exhibit transcriptional plasticity, most clearly reflected by the proneural-to-mesenchymal transition, although direct interconversion among neural progenitor cell-like, oligodendrocyte precursor cell-like, astrocyte-like, and mesenchymal-like states remains unproven. GBM cells can also transition bidirectionally between stem-like and differentiated phenotypes, shift between quiescent and proliferative states, and reprogram metabolism in response to nutrient deprivation, hypoxia, and therapy. Perivascular, hypoxic, extracellular matrix, and immunosuppressive niches further regulate these transitions. This plasticity contributes to therapeutic resistance because radiotherapy, temozolomide, and targeted agents can both select preexisting tolerant populations and induce adaptive states. Therapy-persistent GSC-like cells may form residual reservoirs that undergo further remodeling and contribute to recurrence. Emerging strategies, most still preclinical, aim to destabilize stem-like states, broaden coverage across heterogeneous GSC populations and protective niches and block therapy-induced adaptive transitions. Thus, constraining GSC state plasticity may provide a framework for overcoming therapeutic resistance and recurrence in GBM.</p>","PeriodicalId":9743,"journal":{"name":"Cells","volume":"15 19","pages":""},"PeriodicalIF":6.0,"publicationDate":"2026-09-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13664183/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149191638","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"HOXA3 Knockdown Impairs hESC-Derived Thymic Epithelial-like Cell Differentiation and CXCL12-Associated Early T-Lineage Support.","authors":"Huanhuan Shan, Yingjie Fu, Xinyi Shi, Sen Chen, Yuyou Duan","doi":"10.3390/cells15191764","DOIUrl":"10.3390/cells15191764","url":null,"abstract":"<p><p>Thymic epithelial cells (TECs) provide essential signals for T-cell development, yet the mechanisms governing human TEC differentiation and the acquisition of T-cell-supporting function remain incompletely understood. Using a three-stage system that directs human embryonic stem cells (hESCs) through definitive endoderm and third pharyngeal pouch endoderm (3PPE) toward a thymic epithelial-like lineage, we investigated the role of HOXA3 during thymic epithelial-like cell (TEC-like cell) differentiation. HOXA3 knockdown during 3PPE-to-TEC-like cell transition impaired thymic epithelial differentiation, as indicated by reduced K8, AIRE, and CD205 expression and decreased FOXN1 protein. HOXA3-knockdown TEC-like cells also showed a markedly reduced capacity to support the generation of CD45⁺CD3⁺ cells from cord blood CD34⁺ progenitors. Bulk RNA sequencing identified 1040 upregulated and 774 downregulated genes, revealing broad remodeling of cell-cycle, motility, chemotaxis, angiogenesis, and tissue-remodeling programs. CXCL12 was among the downregulated genes, and its reduction was confirmed at both mRNA and protein levels. Motif analysis identified a putative HOXA3-binding site, and conventional ChIP-PCR showed enrichment of the predicted CXCL12 regulatory region in HOXA3 immunoprecipitates. Recombinant CXCL12 significantly increased CD45⁺CD3⁺ cell generation in HOXA3-knockdown co-cultures. Together, these data support an association between HOXA3 knockdown, reduced acquisition of a thymic epithelial-like phenotype, and diminished early T-lineage support, with CXCL12 partially accounting for the functional phenotype. This study provides a tractable hESC-based model for studying human thymic epithelial development and TEC-mediated early T-lineage differentiation.</p>","PeriodicalId":9743,"journal":{"name":"Cells","volume":"15 19","pages":""},"PeriodicalIF":6.0,"publicationDate":"2026-09-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13664202/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149191506","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}