Stem Cell Reviews and Reports最新文献

{"title":"Next-Generation Hepatocyte Expansion: Bridging Molecular Reprogramming with Multicellular Organoids for Clinical Translation.","authors":"Yiyang Zhou, Min Zeng, Gongbo Fu, Yi Gao","doi":"10.1007/s12015-026-11172-y","DOIUrl":"10.1007/s12015-026-11172-y","url":null,"abstract":"<p><p>Orthotopic liver transplantation (OLT) remains the gold standard treatment for end-stage liver disease but is severely limited by donor scarcity and immune rejection. Consequently, bioartificial liver (BAL) systems and hepatocyte transplantation have emerged as promising alternatives, yet their clinical efficacy hinges on the unresolved challenge of generating functional hepatocytes at scale. This review systematically examines the molecular landscape governing hepatocyte proliferation, dissecting the key regulatory roles of Wnt/β-catenin, Hippo-YAP, Notch, and TGF-β signaling pathways in balancing proliferation and differentiation. We critically evaluate current in vitro expansion strategies, contrasting viral-mediated genetic modification approaches with emerging non-genome-editing strategies. Particular emphasis is placed on \"next-generation\" methodologies, including chemically defined media, bioreactor-based dynamic cultures, and multicellular co-culture systems that recapitulate the native hepatic niche. Furthermore, we highlight recent breakthroughs in liver organoid technology-such as the construction of multi-zonal and vascularized architectures-that bridge the gap between in vitro expansion and in vivo physiological relevance. Finally, we summarize the translational progress of these expanded hepatocytes in BAL devices, cell transplantation trials, and high-fidelity pharmacotoxicological models. We further discuss how emerging technologies, including CRISPR-Cas9-mediated gene correction and bioengineering innovations, may help address current limitations, while acknowledging that substantial preclinical validation remains necessary.</p>","PeriodicalId":21955,"journal":{"name":"Stem Cell Reviews and Reports","volume":" ","pages":"2752-2767"},"PeriodicalIF":4.9,"publicationDate":"2026-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148259669","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Comment: Plasma as the Extracellular Matrix of Platelets-Rethinking the Mechanistic Basis of PRP Therapy.","authors":"Ju Tian, Jing Ding, Haixia Wang, Xiaoying He, Dandan Shi, Biao Cheng","doi":"10.1007/s12015-026-11167-9","DOIUrl":"10.1007/s12015-026-11167-9","url":null,"abstract":"","PeriodicalId":21955,"journal":{"name":"Stem Cell Reviews and Reports","volume":" ","pages":"2958-2960"},"PeriodicalIF":4.9,"publicationDate":"2026-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148138858","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Stem Cell and Stem Cell-Derived Extracellular Vesicles: Therapeutic Potential and Mechanistic Insights in Anti-Aging.","authors":"Jinfeng Liu, Dong Li, Shuxing Wu, Na Liu","doi":"10.1007/s12015-026-11157-x","DOIUrl":"10.1007/s12015-026-11157-x","url":null,"abstract":"<p><p>Aging is driven by interconnected molecular and cellular processes (senescence, inflammation, proteostasis decline, mitochondrial dysfunction) that reduce tissue repair and organismal resilience, resulting in an increased prevalence of chronic degenerative conditions. Accordingly, the development of strategies to prevent, delay, or mitigate multiple age-related diseases is imperative. Embryonic stem cells (ESCs) and other pluripotent stem cells (PSCs) offer substantial therapeutic potential owing to their self-renewal and cellular plasticity, but their direct clinical use is limited by concerns of immunogenicity, tumorigenicity, and ethical constraints. ESC- and PSC-derived extracellular vesicles (ESC-EVs/PSC-EVs) have emerged as promising alternatives that may capture many of the regenerative and modulatory benefits of their parent cells while reducing associated risks. Cumulative evidence shows that EVs from young or stem-like cells mainly produce rejuvenating effects across tissues and molecular pathways. Here we summarize key biological features of stem cells and their EVs, outline mechanisms by which EVs impact aging hallmarks, and assess preclinical and early clinical findings on stem cell and EVs interventions for aging and age-related diseases. Careful optimization of EVs production, standardized characterization, and thorough safety and efficacy testing in diverse disease models and clinical contexts are essential to translate PSC-EVs approaches into viable therapies.</p>","PeriodicalId":21955,"journal":{"name":"Stem Cell Reviews and Reports","volume":" ","pages":"2740-2751"},"PeriodicalIF":4.9,"publicationDate":"2026-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148228500","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"m¹A Modification: An Emerging Epitranscriptomic Regulator of Stem Cell Fate.","authors":"Ni Gan, Kang Yan, Jianbo Yang, Kangyuan Zou, Meilin Tan, Linru Zeng, Jun He, Xiangwen Peng, Sifeng Wang","doi":"10.1007/s12015-026-11177-7","DOIUrl":"10.1007/s12015-026-11177-7","url":null,"abstract":"","PeriodicalId":21955,"journal":{"name":"Stem Cell Reviews and Reports","volume":" ","pages":"2977-2978"},"PeriodicalIF":4.9,"publicationDate":"2026-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148266119","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"ANXA3 activates HIF-1α/VEGF Signaling Via the PI3K/AKT/mTOR Pathway to Promote Osteosarcoma Stem Cell-Like Phenotype.","authors":"Shengtao Wang, Yan Sun, Wei Peng, Yuhan Sui, Shujuan Xu, Yufan Bai, Zhaoxu Li, Wenzhi Zhao","doi":"10.1007/s12015-026-11158-w","DOIUrl":"10.1007/s12015-026-11158-w","url":null,"abstract":"<p><strong>Background: </strong>Aberrant activation of HIF‑1α contributes to the maintenance of CSC phenotypes in various malignancies. Our previous work revealed that ANXA3 is up‑regulated in OS cells. Here, we further investigated how ANXA3 regulates CSC‑like properties of OS cells through the HIF‑1α/VEGF signaling pathway.</p><p><strong>Methods: </strong>Lentiviral vectors were used to modulate ANXA3 expression in OS cell lines. The expression of stemness‑associated genes was examined by qPCR and Western blotting, and sphere‑formation assays were performed to evaluate CSC self‑renewal capacity. Migration, invasion, and clonogenic survival under cisplatin treatment were assessed using Transwell and colony‑formation assays. An orthotopic intratibial implantation model in NOD-SCID mice was established to evaluate the effects of ANXA3 on tumor growth, metastasis, and CSC‑related features. Potential signaling mechanisms were analyzed by Western blotting and ELISA, and pathway‑specific inhibitors were applied to dissect the PI3K/Akt/mTOR-HIF‑1α/VEGF cascade.</p><p><strong>Results: </strong>ANXA3 expression was markedly elevated in osteosarcoma spheres compared with parental cells. ANXA3 knockdown down‑regulated stemness‑related genes, impaired sphere formation, and increased cisplatin sensitivity, whereas ANXA3 overexpression produced opposite effects. In vivo, ANXA3 silencing significantly suppressed tumor growth and pulmonary metastasis. Mechanistically, ANXA3 activated the PI3K/Akt/mTOR pathway, thereby enhancing HIF‑1α/VEGF expression. Knockdown of PI3K or HIF‑1α abrogated ANXA3‑induced stemness and chemoresistance, confirming the signaling axis mediates ANXA3‑driven oncogenic effects.</p><p><strong>Conclusion: </strong>ANXA3 plays a critical role in maintaining CSC‑like traits in osteosarcoma by up‑regulating the HIF‑1α/VEGF pathway in a PI3K/Akt/mTOR‑dependent manner. Targeting ANXA3 or its downstream signaling components may represent a promising therapeutic strategy for reversing CSC phenotypes and overcoming chemoresistance in osteosarcoma.</p>","PeriodicalId":21955,"journal":{"name":"Stem Cell Reviews and Reports","volume":" ","pages":"2919-2937"},"PeriodicalIF":4.9,"publicationDate":"2026-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13354625/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148272391","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Stem Cell Therapy for Traumatic Brain Injury: Translational Mechanisms, Biomarkers, and Clinical Trials.","authors":"William T Creel, Sukhpreet Randhawa, Richard E Hartman","doi":"10.1007/s12015-026-11175-9","DOIUrl":"10.1007/s12015-026-11175-9","url":null,"abstract":"<p><p>Traumatic brain injury (TBI) is a leading cause of persistent cognitive, motor, and neuropsychiatric impairment, arising from both the initial mechanical insult and a prolonged cascade of secondary injury processes. While primary injury reflects structural damage, secondary mechanisms, including neuroinflammation, oxidative stress, apoptosis, and blood-brain barrier disruption, evolve over time and critically influence long-term outcomes. Despite extensive investigation, therapies targeting isolated components of secondary injury have demonstrated limited clinical success, highlighting the need for approaches that support coordinated neural repair. Stem cell-based therapies have emerged as a promising neurorestorative strategy. Rather than replacing lost neurons directly, transplanted cells primarily act through paracrine signaling, immunomodulation, neurotrophic support, and preservation of vulnerable neural networks. However, clinical translation has been constrained by heterogeneity in cell sources, delivery routes, treatment timing, and outcome measures, limiting mechanistic interpretability across trials. This review presents a mechanism-aligned translational framework linking injury stage, biological targets, route of administration, and clinically meaningful outcomes across stages of TBI. We integrate current knowledge of post-injury repair mechanisms with evidence from recent human clinical trials of stem cell therapies. Particular emphasis is placed on safety, feasibility, and emerging signals across structural and functional endpoints, as well as how injury stage, biological targets, delivery strategies, and meaningful endpoints interact to shape treatment responsiveness and inform biomarker-guided clinical trial design.</p>","PeriodicalId":21955,"journal":{"name":"Stem Cell Reviews and Reports","volume":" ","pages":"2808-2823"},"PeriodicalIF":4.9,"publicationDate":"2026-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13354699/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148272814","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Induced Pluripotent Stem Cells and the Future of Male Infertility: A Translational Perspective.","authors":"Asli Metin Mahmutoglu","doi":"10.1007/s12015-026-11173-x","DOIUrl":"10.1007/s12015-026-11173-x","url":null,"abstract":"","PeriodicalId":21955,"journal":{"name":"Stem Cell Reviews and Reports","volume":" ","pages":"2968-2971"},"PeriodicalIF":4.9,"publicationDate":"2026-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148219894","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Stem Cell-based Therapeutic and Endogenous Regeneration Approaches for Congenital Tooth Agenesis.","authors":"Pierre-Yves Collart-Dutilleul, Damien Veret, Richard Younes, Estelle Moulis, Frédéric Cuisinier, Clara Joseph, Azel Zine","doi":"10.1007/s12015-026-11153-1","DOIUrl":"10.1007/s12015-026-11153-1","url":null,"abstract":"<p><p>Congenital tooth agenesis, including hypodontia and oligodontia, represents one of the most common developmental anomalies of the craniofacial complex and reflects failure of odontogenesis rather than postnatal tissue degeneration. The absence of teeth during growth affects mastication, speech, facial development and psychosocial well-being, while current management remains limited to prolonged temporization during childhood followed by definitive prosthetic rehabilitation after craniofacial maturation. No curative therapy is presently available. Recent advances in cell biology and developmental genetics have renewed interest in regenerative strategies for congenital organ defects. In this context, tooth agenesis provides a stringent model to examine the feasibility of stem cell-based interventions in conditions governed by tightly regulated embryonic programs. Two principal paradigms have emerged: (1) whole-tooth replacement via bioengineering strategies that attempt to reconstruct odontogenic processes ex vivo, and (2) endogenous developmental reactivation approaches that seek to permissively modulate molecular checkpoints within existing odontogenic substrates. While whole-tooth bioengineering has demonstrated proof-of-concept in experimental models, their clinical translation remains constrained by morphogenetic complexity and early genetic specification. In contrast, increasing evidence identifies USAG-1, a dual BMP/Wnt antagonist, as a developmental gatekeeper regulating tooth number and progression. Preclinical studies indicate that anti-USAG-1 antibody administration can rescue tooth germs whose development stopped and induce supernumerary tooth formation in vivo, suggesting that, under restricted conditions, continuation of odontogenesis beyond embryonic checkpoints may be biologically achievable. However, such strategies depend on permissive genetic and temporal contexts therefore require careful consideration of safety, pediatric ethics and long-term craniofacial integration. By integrating developmental biology, human genetics, and regenerative medicine, this review delineates the biological boundaries that govern these strategies and highlights why future advances are more likely to arise from precise modulation of developmental constraints in carefully stratified patient populations than from de novo tooth reconstruction.</p>","PeriodicalId":21955,"journal":{"name":"Stem Cell Reviews and Reports","volume":" ","pages":"2657-2670"},"PeriodicalIF":4.9,"publicationDate":"2026-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147983321","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Mesenchymal Stromal Cell-Derived Extracellular Vesicles Mediate Mitochondrial Delivery in Injury: Mechanistic Insights, Evidentiary Tiers, and Translational Challenges.","authors":"Tingkun Ma, Yuan He, Jincui Yang, Peng Luo, Qiyi Shen, Junjie Yang, Ding Xu, Xiao Li, Chunchu Deng, Kelu Li, Biao Chen, Yulong Shi","doi":"10.1007/s12015-026-11170-0","DOIUrl":"10.1007/s12015-026-11170-0","url":null,"abstract":"<p><p>While mesenchymal stromal cell (MSC)-derived extracellular vesicles (MSC-EVs) offer a safer, cell-free alternative to stem cell transplantation, their specific role in rescuing recipient cell mitochondrial networks requires precise definition. This review clarifies that scientific landscape by systematically partitioning MSC-EV-mediated mitochondrial delivery into three rigorous, evidence-based categories: (i) the horizontal transfer of intact, bioenergetically active mitochondria, (ii) the lateral delivery of sub-organellar components such as mitochondrial DNA (mtDNA) and transcriptional proteins (e.g., TFAM), and (iii) indirect protective signaling that rejuvenates endogenous networks. Effectively integrated cargo within MSC-EV has been reported to restore mitochondrial membrane potential, contributing to the stabilization of electron transport chain complexes (I-IV), the reactive oxygen species (ROS) balance, and the tricarboxylic acid (TCA) cycle and NAD + /NADH balance to reverse bioenergetic collapse. Across diverse myocardial, pulmonary, hepatic, renal, and neurological injury models, this EV-associated delivery is associated with dampening of hyper-inflammation, enhances macrophage phagocytosis, and supports tissue barrier regeneration. Nevertheless, critical translational barriers remain, including significant EV heterogeneity, a lack of standardized high-purity isolation protocols in line with MISEV (Minimal Information for Studies of Extracellular Vesicles) guidelines, and unverified oncologic risks such as supporting tumor progression or chemoresistance through unintended metabolic rescue. In conclusion, large-scale clinical adoption requires prioritized, well-designed human trials with rigorous cargo characterization to firmly establish long-term safety, durability, and oncologic security.</p>","PeriodicalId":21955,"journal":{"name":"Stem Cell Reviews and Reports","volume":" ","pages":"2768-2787"},"PeriodicalIF":4.9,"publicationDate":"2026-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148266173","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"2-Methoxyestradiol Suppresses Stemness and Epithelial-Mesenchymal Transition in Drug-Resistant Esophageal Squamous Cell Carcinoma by Targeting the Snail Signaling Pathway in Cancer Stem Cells.","authors":"Jie Yan, Shuhua Han, Keqi Zhang, Linlin Li, Mingjing He, Haoqing Cao, Meiru Zhu, Bingjie Bi, Qiang Xu, Cong Wang","doi":"10.1007/s12015-026-11174-w","DOIUrl":"10.1007/s12015-026-11174-w","url":null,"abstract":"<p><p>Cancer stem cells (CSCs) and epithelial-mesenchymal transition (EMT) are critical contributors to tumor drug resistance, which represents a major obstacle to successful cancer therapy. 2-Methoxyestradiol (2ME2) is an endogenous metabolite of 17β-estradiol, and accumulating evidence has demonstrated that 2ME2 suppresses stemness and EMT in multiple cancer types. However, whether 2ME2 overcomes drug resistance remains unclear. In this study, 2ME2 was found to inhibit cell viability and increases susceptibility to paclitaxel in drug-resistant esophageal cancer cells. Besides, 2ME2 suppress CSC-like traits and cell migration. Mechanically, 2ME2 inhibited the activation of the TGFβ1/Smad signaling pathway, reduced Snail protein levels by promoting its degradation in paclitaxel-resistant esophageal squamous cell carcinoma cells. Importantly, Snail is at least partially involved in the inhibitory effect of 2ME2 on cell migration in drug-resistant cancer cells. Collectively, our results reveal that 2ME2 effectively attenuates CSC stemness and inhibits EMT to overcome paclitaxel resistance in esophageal cancer. Accordingly, further development of more potent 2ME2 analogs and optimized delivery systems in future preclinical studies is warranted, which may provide therapy strategy for resistant ESCC treatment.Clinical Trial Registration: Not applicable.</p>","PeriodicalId":21955,"journal":{"name":"Stem Cell Reviews and Reports","volume":" ","pages":"2938-2957"},"PeriodicalIF":4.9,"publicationDate":"2026-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148278890","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}