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Hepatic reprogramming occurs in a time-independent manner via an initial asymmetric division and continued mitotic activity. 肝脏重编程通过初始的不对称分裂和持续的有丝分裂活动以时间独立的方式发生。
IF 5.6 2区 医学
Stem Cell Reports Pub Date : 2026-08-27 DOI: 10.1016/j.stemcr.2026.103056
Nanako Goto, Shizuka Miura, Masaki Kawamata, Kenichi Horisawa, Ryoga Suzuki, Tomonori Miyata, Nao Taniguchi, Atsushi Suzuki
{"title":"Hepatic reprogramming occurs in a time-independent manner via an initial asymmetric division and continued mitotic activity.","authors":"Nanako Goto, Shizuka Miura, Masaki Kawamata, Kenichi Horisawa, Ryoga Suzuki, Tomonori Miyata, Nao Taniguchi, Atsushi Suzuki","doi":"10.1016/j.stemcr.2026.103056","DOIUrl":"https://doi.org/10.1016/j.stemcr.2026.103056","url":null,"abstract":"<p><p>Recent advancements in cellular reprogramming make it possible to alter cell fate, yet its mechanisms remain largely unclear. While previous studies have explored the link between cell division and reprogramming, it is still unknown why some cells reprogram under identical conditions, while others do not. In this study, we used the direct reprogramming of fibroblasts into induced hepatocyte-like cells (iHepCs) as a model to address this issue. Time-lapse imaging was performed throughout the entire reprogramming process, from the introduction of reprogramming factors to the completion of iHepC conversion. Spatiotemporal single-cell tracking revealed that the direct hepatic reprogramming follows a hybrid model, combining elite and stochastic models. Elite-like cells emerge from the earliest cell divisions, undergo random selection, and successfully reprogram a subset of their descendants. Moreover, cells that ultimately become iHepCs exhibited active division both before and after reprogramming. These results suggest that targeting active cell division may enhance reprogramming efficiency.</p>","PeriodicalId":21885,"journal":{"name":"Stem Cell Reports","volume":" ","pages":"103056"},"PeriodicalIF":5.6,"publicationDate":"2026-08-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148841140","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Short-term gonadal cultures are sufficient for germline transmission in a songbird. 短期性腺培养足以在鸣禽中进行种系传播。
IF 5.6 2区 医学
Stem Cell Reports Pub Date : 2026-08-20 DOI: 10.1016/j.stemcr.2026.103052
Matthew Biegler, Elijah Harter, Asha V Sidhu, Christina Szialta, Gillian Durham, Lotem Tchernichovski, Paul Collier, Ji-Dung Luo, Wei Wang, Ryan MacIsaac, Kirubel Belay, Thomas Carroll, Anna L Keyte, Erich D Jarvis
{"title":"Short-term gonadal cultures are sufficient for germline transmission in a songbird.","authors":"Matthew Biegler, Elijah Harter, Asha V Sidhu, Christina Szialta, Gillian Durham, Lotem Tchernichovski, Paul Collier, Ji-Dung Luo, Wei Wang, Ryan MacIsaac, Kirubel Belay, Thomas Carroll, Anna L Keyte, Erich D Jarvis","doi":"10.1016/j.stemcr.2026.103052","DOIUrl":"https://doi.org/10.1016/j.stemcr.2026.103052","url":null,"abstract":"<p><p>Primordial germ cells (PGCs) are reproductive stem cells that are valuable for avian biobanking and germline transmission. However, their long-term culture remains a challenge beyond a few poultry species. Here, we compare the transcriptomic impact and reproductive viability between short- and long-term chicken and zebra finch gonadal PGC culture protocols. Using single-cell transcriptomics, we identified rapid germline differentiation in zebra finch gonadal cultures compared to stable PGC identity in chicken, highlighting divergent signaling pathway responses to in vitro germline culture between species. These differentiation profiles were similarly found in low-serum zebra finch blood PGC cultures. Nonetheless, injections of these short-term zebra finch gonadal PGC cultures demonstrated sufficient gonadal reconstitution of host embryos to produce zebra finch germline chimeras and donor-derived offspring. This study demonstrates the minimal viability of short-term songbird gonadal cultures, and offers a roadmap to improve the longevity and self-renewal of non-poultry avian PGC cultures.</p>","PeriodicalId":21885,"journal":{"name":"Stem Cell Reports","volume":" ","pages":"103052"},"PeriodicalIF":5.6,"publicationDate":"2026-08-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148797986","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Development and validation of a long-term co-maturation protocol for human stem cell-derived microglia and neuronal networks. 人类干细胞衍生的小胶质细胞和神经网络长期共成熟方案的开发和验证。
IF 5.6 2区 医学
Stem Cell Reports Pub Date : 2026-08-20 DOI: 10.1016/j.stemcr.2026.103053
Annika Mordelt, Imke M E Schuurmans, Nicky Scheefhals, Marina P Hommersom, Koen Slottje, Kimberly Mast, Mara Graziani, Carlos O González, Klaas W Mulder, Laura J A Wingens, Dirk Schubert, Nael Nadif Kasri, Lot D de Witte
{"title":"Development and validation of a long-term co-maturation protocol for human stem cell-derived microglia and neuronal networks.","authors":"Annika Mordelt, Imke M E Schuurmans, Nicky Scheefhals, Marina P Hommersom, Koen Slottje, Kimberly Mast, Mara Graziani, Carlos O González, Klaas W Mulder, Laura J A Wingens, Dirk Schubert, Nael Nadif Kasri, Lot D de Witte","doi":"10.1016/j.stemcr.2026.103053","DOIUrl":"https://doi.org/10.1016/j.stemcr.2026.103053","url":null,"abstract":"<p><p>Microglia-neuron interactions play a key role in a variety of central nervous system disorders. Technologies using human induced pluripotent stem cells (hiPSCs) have been developed to model human brain cells with the goal to understand their function. To effectively study neuro-immune crosstalk and investigate microglial contributions to neuronal network development and function, both microglia and neurons should co-mature allowing for long-term interactions throughout their differentiation. Here, we present a co-maturation protocol that robustly generates glutamatergic neuronal networks containing hiPSC-derived microglia. We validated the long-term co-cultures using single-cell transcriptomics, imaging, and neuronal activity readouts. In this protocol, astrocytes were required for long-term survival of microglia and for their integration into neuronal networks. Our co-maturation approach induced the typical ramified microglia morphology and characteristic microglia-neuron interactions. Homeostatic markers such as P2RY12 and TMEM119 and neuronal remodeling-associated genes were upregulated compared to microglia monocultures, highlighting the necessity of the environment to generate and maintain the context-dependent microglia signature in vitro. In this manuscript, we include the full optimization process of our co-maturation approach, a comprehensive description of the protocol, practical guidelines, and troubleshooting tips. Our co-maturation model provides a powerful tool to assess the role of human microglia in modulating neuronal function and development in health and disease.</p>","PeriodicalId":21885,"journal":{"name":"Stem Cell Reports","volume":" ","pages":"103053"},"PeriodicalIF":5.6,"publicationDate":"2026-08-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148797767","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Brain organoids in Alzheimer disease and related tauopathies: Challenges and opportunities for translational readiness. 阿尔茨海默病和相关病变的脑类器官:转化准备的挑战和机遇。
IF 5.6 2区 医学
Stem Cell Reports Pub Date : 2026-08-20 DOI: 10.1016/j.stemcr.2026.103051
Anuj Guruacharya, Thomas Hartung, Roberta Souza Dos Reis, Natália Chermont Dos Santos Moreira, Liliana Attisano, Silvia Bolognin, Khalid Iqbal, Binita Rajbanshi
{"title":"Brain organoids in Alzheimer disease and related tauopathies: Challenges and opportunities for translational readiness.","authors":"Anuj Guruacharya, Thomas Hartung, Roberta Souza Dos Reis, Natália Chermont Dos Santos Moreira, Liliana Attisano, Silvia Bolognin, Khalid Iqbal, Binita Rajbanshi","doi":"10.1016/j.stemcr.2026.103051","DOIUrl":"10.1016/j.stemcr.2026.103051","url":null,"abstract":"<p><p>A major hurdle in Alzheimer disease research is the failure of mouse models to capture complexities of the human brain that contributes to repeated clinical trial failure. Although the recent US Food and Drug Administration (FDA) Modernization Act 2.0 has enabled non-animal preclinical pathways, brain organoid models of tauopathies remain nascent compared with other disease areas. Here, we identify three challenges for their translational readiness (maturity, disease-relevant cellular complexity, and pathological accuracy) and examine current achievements and emerging solutions. We propose a ten-metric benchmarking framework and discuss the opportunities and remaining challenges for translational readiness in tauopathy modeling.</p>","PeriodicalId":21885,"journal":{"name":"Stem Cell Reports","volume":" ","pages":"103051"},"PeriodicalIF":5.6,"publicationDate":"2026-08-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148797811","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
TDP-43 sustains satellite cells to maintain and regenerate skeletal muscle. TDP-43维持卫星细胞维持和再生骨骼肌。
IF 5.6 2区 医学
Stem Cell Reports Pub Date : 2026-08-20 DOI: 10.1016/j.stemcr.2026.103050
Theodore E Ewachiw, Tenaya K Vallery, Shloka Dhar, Hayden Clarkson, Tiffany Elston, Haileigh Gay, Bradley B Olwin
{"title":"TDP-43 sustains satellite cells to maintain and regenerate skeletal muscle.","authors":"Theodore E Ewachiw, Tenaya K Vallery, Shloka Dhar, Hayden Clarkson, Tiffany Elston, Haileigh Gay, Bradley B Olwin","doi":"10.1016/j.stemcr.2026.103050","DOIUrl":"10.1016/j.stemcr.2026.103050","url":null,"abstract":"<p><p>Skeletal muscle satellite cells (SCs), residing between the myofiber plasma membrane and the surrounding basement membrane, continue to maintain and repair skeletal muscle throughout life. Typically, quiescent SCs can transition into a reversible alert state (G<sub>Alert</sub>) that primes them for rapid activation to maintain or repair muscle. From G<sub>Alert</sub>, SCs can either re-enter quiescence or commit to the cell cycle, expand, and differentiate to fuse with existing regenerating myofibers. Exit from quiescence requires extensive post-transcriptional remodeling, including changes in RNA processing and RNA-binding protein activity. We show that TDP-43, an RNA-binding protein, is essential for SC maintenance and muscle repair. Conditional deletion of TDP-43 in SCs caused a consistent and progressive loss of G<sub>Alert</sub> SCs, even in uninjured muscle, leading to depletion of the SC pool. TDP-43 haploinsufficiency was sufficient to impair SC maintenance, indicating that both alleles are required. Integrative analysis suggests that TDP-43 supports the expression of stress response-associated transcripts during the quiescent-to- G<sub>Alert</sub> transition and that failure to mount this response contributes to SC apoptosis. Thus, we identified TDP-43 as a critical regulator of survival of SCs as these cells activate, and we establish that TDP-43 is required for the maintenance and repair of skeletal muscle.</p>","PeriodicalId":21885,"journal":{"name":"Stem Cell Reports","volume":" ","pages":"103050"},"PeriodicalIF":5.6,"publicationDate":"2026-08-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148797952","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
A human-specific non-coding RNA for EFHC1, an epilepsy-associated gene, regulates neural stem cell proliferation for cortical development. EFHC1(一种癫痫相关基因)的人类特异性非编码RNA调节神经干细胞的皮质发育增殖。
IF 5.6 2区 医学
Stem Cell Reports Pub Date : 2026-08-20 DOI: 10.1016/j.stemcr.2026.103049
Sota Nishida, Boyang An, Hayato Uchida, Shota Zenno, Takumi Nojima, Arisa Makimura, Fumihiro Morishita, Mizuki Honda, Takuya Imamura
{"title":"A human-specific non-coding RNA for EFHC1, an epilepsy-associated gene, regulates neural stem cell proliferation for cortical development.","authors":"Sota Nishida, Boyang An, Hayato Uchida, Shota Zenno, Takumi Nojima, Arisa Makimura, Fumihiro Morishita, Mizuki Honda, Takuya Imamura","doi":"10.1016/j.stemcr.2026.103049","DOIUrl":"https://doi.org/10.1016/j.stemcr.2026.103049","url":null,"abstract":"<p><p>Epilepsy is a prevalent brain disorder in humans but rarely occurs naturally in other species, highlighting the potential for human-specific mechanisms in its pathogenesis, and thus, current animal models fail to recapitulate human symptoms. Comparing RNA sequencing (RNA-seq) datasets from human and mouse neural stem cells (NSCs), we identified EFHC1, a juvenile myoclonic epilepsy gene, as exhibiting a human-biased expression. EFHC1 knockdown reduced human NSC proliferation, while its overexpression in mouse embryonic brains increased cortical NSC number. Mechanistically, EFHC1 prevented endoplasmic reticulum stress, thereby reducing inflammatory activation of p38 MAPK and promoting continuous proliferation of human NSCs. We also identified pancEFHC1, a bidirectional promoter-associated non-coding RNA (pancRNA), located at the human EFHC1 promoter. Knockdown of pancEFHC1 in human NSCs increased DNA methylation to reduce EFHC1 expression, with the resulting phenotype rescued by EFHC1 overexpression. We propose that the evolutionary acquisition of pancEFHC1 has introduced a complex regulatory mechanism for EFHC1 expression that allows distinguishing it in humans.</p>","PeriodicalId":21885,"journal":{"name":"Stem Cell Reports","volume":" ","pages":"103049"},"PeriodicalIF":5.6,"publicationDate":"2026-08-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148797769","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Metabolic reprogramming via LDHB confers resistance to lactate-induced dysfunction and enhanced antitumor activity in hiPSC-Derived NK cells. 通过LDHB的代谢重编程赋予hipsc来源的NK细胞抵抗乳酸诱导的功能障碍和增强的抗肿瘤活性。
IF 5.6 2区 医学
Stem Cell Reports Pub Date : 2026-08-13 DOI: 10.1016/j.stemcr.2026.103048
Zhishuai Zhang, Yuchan Mai, Jun Tang, Jiaying Ning, Yanjiao Qin, Jiaming Gu, Zhaozong Cao, Jian Liu, Tiancheng Zhou, Junwei Wang, Jeane L Pan, Jiaheng Chen, Yanling Zhu, Guangjin Pan
{"title":"Metabolic reprogramming via LDHB confers resistance to lactate-induced dysfunction and enhanced antitumor activity in hiPSC-Derived NK cells.","authors":"Zhishuai Zhang, Yuchan Mai, Jun Tang, Jiaying Ning, Yanjiao Qin, Jiaming Gu, Zhaozong Cao, Jian Liu, Tiancheng Zhou, Junwei Wang, Jeane L Pan, Jiaheng Chen, Yanling Zhu, Guangjin Pan","doi":"10.1016/j.stemcr.2026.103048","DOIUrl":"https://doi.org/10.1016/j.stemcr.2026.103048","url":null,"abstract":"<p><p>Natural Killer (NK) cells generally exhibit dysfunction in tumor microenvironment (TME), significantly limiting their efficacy in antitumor therapy. Tumor cells display enhanced glycolysis, leading to lactic acid (LA) secretion and accumulation in the TME. Using human-induced pluripotent stem cell (hiPSC)-derived NK cells (iNKs) as a model, we demonstrate that LA induces substantial iNK dysfunction, including reduced survival, impaired IFN-γ secretion, and diminished tumor-killing capacity due to severely compromised mitochondrial function. To overcome LA-induced dysfunction, we knocked in an expression cassette for lactate dehydrogenase B (LDHB) into hiPSCs (LDHB-hiPSCs), enabling conversion of cellular lactate to pyruvate. iNKs derived from LDHB-hiPSCs (LDHB-iNKs) largely resisted LA-induced dysfunction, exhibiting enhanced cytotoxicity and improved survival in high-LA tumor tissues. Importantly, LDHB-iNKs show superior suppression of solid tumor formation in vivo. Our study provides a novel strategy to enhance NK cell therapy against solid tumors by reshaping the metabolic pathways.</p>","PeriodicalId":21885,"journal":{"name":"Stem Cell Reports","volume":" ","pages":"103048"},"PeriodicalIF":5.6,"publicationDate":"2026-08-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148760398","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Genetic Engineering of Human Embryonic Stem Cells for Precise Cell Fate Tracing during Human Lineage Development. 人类胚胎干细胞基因工程用于人类谱系发育过程中细胞命运的精确追踪。
IF 5.6 2区 医学
Stem Cell Reports Pub Date : 2026-08-11 Epub Date: 2026-07-30 DOI: 10.1016/j.stemcr.2026.103054
Zhenyu Chen, Xudong Ren, Xiangjie Xu, Xiaojie Zhang, Yi Hui, Zhongliang Liu, Lei Shi, Yujiang Fang, Lin Ma, Yang Liu, Daniel Terheyden-Keighley, Ling Liu, Xiaoqing Zhang
{"title":"Genetic Engineering of Human Embryonic Stem Cells for Precise Cell Fate Tracing during Human Lineage Development.","authors":"Zhenyu Chen, Xudong Ren, Xiangjie Xu, Xiaojie Zhang, Yi Hui, Zhongliang Liu, Lei Shi, Yujiang Fang, Lin Ma, Yang Liu, Daniel Terheyden-Keighley, Ling Liu, Xiaoqing Zhang","doi":"10.1016/j.stemcr.2026.103054","DOIUrl":"10.1016/j.stemcr.2026.103054","url":null,"abstract":"","PeriodicalId":21885,"journal":{"name":"Stem Cell Reports","volume":" ","pages":"103054"},"PeriodicalIF":5.6,"publicationDate":"2026-08-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13476886/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148631531","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}
引用次数: 0
CCL5 exposure promotes acute and transient megakaryopoiesis and hematopoietic progenitor expansion. CCL5暴露促进急性和短暂巨核生成和造血祖细胞扩增。
IF 5.6 2区 医学
Stem Cell Reports Pub Date : 2026-08-11 Epub Date: 2026-07-16 DOI: 10.1016/j.stemcr.2026.103014
Maria N Barrachina, Dong H Lee, Virginia Camacho, Karen G Wang, Ethan Walsey, Estelle Carminita, Isabelle C Becker, Siobhan Branfield, Daniela Freire, Emma Nikols, Emma L Berdan, Blen Yohannes, Olivera Miladinovic, Julia Tilburg, Joseph E Italiano, Kellie R Machlus
{"title":"CCL5 exposure promotes acute and transient megakaryopoiesis and hematopoietic progenitor expansion.","authors":"Maria N Barrachina, Dong H Lee, Virginia Camacho, Karen G Wang, Ethan Walsey, Estelle Carminita, Isabelle C Becker, Siobhan Branfield, Daniela Freire, Emma Nikols, Emma L Berdan, Blen Yohannes, Olivera Miladinovic, Julia Tilburg, Joseph E Italiano, Kellie R Machlus","doi":"10.1016/j.stemcr.2026.103014","DOIUrl":"10.1016/j.stemcr.2026.103014","url":null,"abstract":"<p><p>During inflammation, megakaryocytes (MKs) can expand from hematopoietic stem cells, yet the specific driving factors remain unclear. We investigated whether C-C Motif Chemokine Ligand 5 (CCL5) influences this process in murine and human iPSC-derived bone marrow organoid (BMO) models. Acute CCL5 administration to mice increased hematopoietic stem and progenitor cell (HSPC) populations and increased MKs, including the expansion of MHC II-expressing MKs, characteristic of the immune MK subpopulation. Mechanistically, MK progenitors upregulated CCR1 and CCR5, and MKs showed increased phosphorylation of JAK1, SRC, and STAT1-5. Phenotypically, transcriptomic profiling revealed enhanced expression of genes associated with the cell cycle, inflammatory pathways, and mitochondrial metabolism in MKs isolated from CCL5-treated mice, which was functionally supported by increased mitochondrial activity. Similarly, in human BMOs, CCL5 treatment increased MK numbers. Together, these findings implicate CCL5 as a direct mediator of acute megakaryopoiesis and immune MK expansion during inflammation.</p>","PeriodicalId":21885,"journal":{"name":"Stem Cell Reports","volume":" ","pages":"103014"},"PeriodicalIF":5.6,"publicationDate":"2026-08-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13476898/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148472881","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}
引用次数: 0
GLP-1 regulates osteo-adipogenic fate of BMSCs via HIF-2-AKT signaling and supports trabecular bone in glucocorticoid-induced osteoporosis. GLP-1通过HIF-2-AKT信号调节骨髓间充质干细胞的成脂命运,并在糖皮质激素诱导的骨质疏松症中支持骨小梁。
IF 5.6 2区 医学
Stem Cell Reports Pub Date : 2026-08-11 Epub Date: 2026-07-09 DOI: 10.1016/j.stemcr.2026.103008
Zhe Yang, Xin Li, Niujian Wu, Ling Wang, Zhanjin Lu, Lingling Wang, Shisong Han, Hongyun Lu
{"title":"GLP-1 regulates osteo-adipogenic fate of BMSCs via HIF-2-AKT signaling and supports trabecular bone in glucocorticoid-induced osteoporosis.","authors":"Zhe Yang, Xin Li, Niujian Wu, Ling Wang, Zhanjin Lu, Lingling Wang, Shisong Han, Hongyun Lu","doi":"10.1016/j.stemcr.2026.103008","DOIUrl":"10.1016/j.stemcr.2026.103008","url":null,"abstract":"<p><p>Bone marrow mesenchymal stem cell (BMSC) lineage commitment contributes to metabolic bone diseases, but whether glucagon-like peptide-1 (GLP-1) regulates osteo-adipogenic fate remains unclear. Here, RNA sequencing was performed to identify potential pathways regulated by GLP-1 in BMSCs, followed by gain- and loss-of-function experiments. Furthermore, BMSC-specific Hif-2α knockout mice with glucocorticoid-induced osteoporosis were treated with semaglutide to evaluate skeletal effects. GLP-1 suppressed adipogenesis and promoted osteogenesis of BMSCs in a dose-dependent manner. Transcriptomic analysis identified PI3K-AKT and hypoxia signaling as major GLP-1-regulated pathways. Mechanistically, GLP-1 inhibited AKT activation during adipogenesis and reshaped AKT signaling dynamics during osteogenesis. Loss of HIF-2α largely abolished GLP-1-mediated regulation of AKT activity. In vivo, semaglutide improved trabecular bone mass in osteoporotic mice, whereas this bone-protective effect was markedly diminished in Hif-2α-knockout mice. Our findings suggest that GLP-1 modulates BMSC lineage commitment by inhibiting adipogenesis and enhancing osteogenesis through HIF-2α-associated regulation of AKT signaling.</p>","PeriodicalId":21885,"journal":{"name":"Stem Cell Reports","volume":" ","pages":"103008"},"PeriodicalIF":5.6,"publicationDate":"2026-08-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13476890/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148424394","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}
引用次数: 0
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