Pub Date : 2025-12-22DOI: 10.1016/j.stem.2025.12.001
Madison R Glass,Nana Matoba,Alvaro A Beltran,Niyanta K Patel,Tala M Farah,Karthik Eswar,Shivam Bhargava,Karen Huang,Ian Curtin,Sara Ahmed,Mary Srivastava,Emma Drake,Liam T Davis,Meghana Yeturi,Kexin Sun,Michael I Love,Jeremy M Simon,Tanya St John,Natasha Marrus,Juhi Pandey,Annette Estes,Stephen Dager,Robert T Schultz,Kelly Botteron,Alan Evans,Sun Hyung Kim,Martin Styner,Robert C McKinstry,D Louis Collins,Heather Volk,Kelly Benke,Lonnie Zwaigenbaum,Heather Hazlett,Adriana S Beltran,Jessica B Girault,Mark D Shen,Joseph Piven,Jason L Stein,
Induced pluripotent stem cell (iPSC)-derived human cortical organoids (hCOs) model neurogenesis on an individual's genetic background. The degree to which hCO phenotypes recapitulate the brain growth of the participants from whom they were derived is not well established. We generated up to 3 iPSC clones from each of 18 participants in the Infant Brain Imaging Study, who underwent longitudinal brain imaging during infancy. We identified consistent hCO morphology and cortical cell types across clones from the same participant. hCO cross-sectional area and production of hem/choroid plexus were associated with in vivo cortical growth rates. Cell-cycle-associated gene expression in early progenitors at the crux of fate-decision trajectories was correlated with cortical growth rates from 6 to 12 months of age and was enriched for microcephaly and neurodevelopmental disorder genes. Our data suggest the hCOs capture inter-individual variation in cortical cell types that influences infant cortical surface area expansion.
{"title":"Human cortical organoids recapitulate inter-individual variability in infant brain-growth trajectories.","authors":"Madison R Glass,Nana Matoba,Alvaro A Beltran,Niyanta K Patel,Tala M Farah,Karthik Eswar,Shivam Bhargava,Karen Huang,Ian Curtin,Sara Ahmed,Mary Srivastava,Emma Drake,Liam T Davis,Meghana Yeturi,Kexin Sun,Michael I Love,Jeremy M Simon,Tanya St John,Natasha Marrus,Juhi Pandey,Annette Estes,Stephen Dager,Robert T Schultz,Kelly Botteron,Alan Evans,Sun Hyung Kim,Martin Styner,Robert C McKinstry,D Louis Collins,Heather Volk,Kelly Benke,Lonnie Zwaigenbaum,Heather Hazlett,Adriana S Beltran,Jessica B Girault,Mark D Shen,Joseph Piven,Jason L Stein, ","doi":"10.1016/j.stem.2025.12.001","DOIUrl":"https://doi.org/10.1016/j.stem.2025.12.001","url":null,"abstract":"Induced pluripotent stem cell (iPSC)-derived human cortical organoids (hCOs) model neurogenesis on an individual's genetic background. The degree to which hCO phenotypes recapitulate the brain growth of the participants from whom they were derived is not well established. We generated up to 3 iPSC clones from each of 18 participants in the Infant Brain Imaging Study, who underwent longitudinal brain imaging during infancy. We identified consistent hCO morphology and cortical cell types across clones from the same participant. hCO cross-sectional area and production of hem/choroid plexus were associated with in vivo cortical growth rates. Cell-cycle-associated gene expression in early progenitors at the crux of fate-decision trajectories was correlated with cortical growth rates from 6 to 12 months of age and was enriched for microcephaly and neurodevelopmental disorder genes. Our data suggest the hCOs capture inter-individual variation in cortical cell types that influences infant cortical surface area expansion.","PeriodicalId":9665,"journal":{"name":"Cell stem cell","volume":"45 1","pages":""},"PeriodicalIF":23.9,"publicationDate":"2025-12-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145813558","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
The sympathetic ganglia are essential components of the nervous system that regulate various aspects of involuntary body functions. Recapitulating sympathetic ganglion development with three-dimensional (3D) organoids is challenging and has not been achieved. Here, we report a method to differentiate human pluripotent stem cells into 3D neural organoids that resemble peripheral sympathetic ganglia, producing both neurons and glial cells of the ganglia in a self-organized manner. We developed an organoid system to construct functional connections between the sympathetic ganglia and one of their peripheral targets, the heart, by fusing human sympathetic ganglion organoids (hSGOs) and heart-forming organoids. Notably, this system enables the evaluation of signaling controls (i.e., nerve growth factor [NGF] signaling) on human sympathetic-to-cardiac innervation and reveals the reciprocal impacts between the sympathetic and cardiac lineages during their co-development. Our study provides a physiologically relevant platform for understanding the development of human sympathetic ganglia, their crosstalk with peripheral targets, and related diseases.
{"title":"Human PSC-derived organoids model sympathetic ganglion development and its functional crosstalk with the heart","authors":"Yantong Liu, Jinkui Zhu, Xiaoxiang Lu, Xuran Zhuang, Jianfeng Wei, Linlin Jiang, Wei Zhou, Wei Pang, Yao Yin, Ziling Chen, Yajing Cao, Qinzhi Zhang, Sisi Chen, Siyuan Chu, Xinrui Zhang, Yangfei Xiang","doi":"10.1016/j.stem.2025.11.003","DOIUrl":"https://doi.org/10.1016/j.stem.2025.11.003","url":null,"abstract":"The sympathetic ganglia are essential components of the nervous system that regulate various aspects of involuntary body functions. Recapitulating sympathetic ganglion development with three-dimensional (3D) organoids is challenging and has not been achieved. Here, we report a method to differentiate human pluripotent stem cells into 3D neural organoids that resemble peripheral sympathetic ganglia, producing both neurons and glial cells of the ganglia in a self-organized manner. We developed an organoid system to construct functional connections between the sympathetic ganglia and one of their peripheral targets, the heart, by fusing human sympathetic ganglion organoids (hSGOs) and heart-forming organoids. Notably, this system enables the evaluation of signaling controls (i.e., nerve growth factor [NGF] signaling) on human sympathetic-to-cardiac innervation and reveals the reciprocal impacts between the sympathetic and cardiac lineages during their co-development. Our study provides a physiologically relevant platform for understanding the development of human sympathetic ganglia, their crosstalk with peripheral targets, and related diseases.","PeriodicalId":9665,"journal":{"name":"Cell stem cell","volume":"29 1","pages":""},"PeriodicalIF":23.9,"publicationDate":"2025-12-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145732400","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-12-04DOI: 10.1016/j.stem.2025.10.013
Tao Tan, Xiao Lu, Tianqing Li, Jingkuan Wei, Hongmei Wang, Weizhi Ji
Recent advances in human embryo culture and revised guidelines from the International Society for Stem Cell Research (ISSCR) give grounds for extending the 14-day limit. To prepare for any possible future change in China’s regulation, we propose a path toward cautious extension with strict oversight, balancing scientific progress with ethical responsibility.
{"title":"An exploratory proposal for a revision to the 14-day rule in the regulatory context of China","authors":"Tao Tan, Xiao Lu, Tianqing Li, Jingkuan Wei, Hongmei Wang, Weizhi Ji","doi":"10.1016/j.stem.2025.10.013","DOIUrl":"https://doi.org/10.1016/j.stem.2025.10.013","url":null,"abstract":"Recent advances in human embryo culture and revised guidelines from the International Society for Stem Cell Research (ISSCR) give grounds for extending the 14-day limit. To prepare for any possible future change in China’s regulation, we propose a path toward cautious extension with strict oversight, balancing scientific progress with ethical responsibility.","PeriodicalId":9665,"journal":{"name":"Cell stem cell","volume":"219 1","pages":""},"PeriodicalIF":23.9,"publicationDate":"2025-12-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145664516","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-12-04DOI: 10.1016/j.stem.2025.10.014
Yanxia Rao, Yunshang Bai, Xiaoyu Li, Bingying Du, Bo Peng
Microglia are indispensable for the central nervous system (CNS) development and homeostasis, and mutations in microglia can cause microgliopathies. Correcting these mutations holds therapeutic potential, but conventional gene therapies cannot yet achieve the CNS-wide delivery required for meaningful treatment. Microglia replacement has emerged as a groundbreaking paradigm that removes pathogenic microglia and introduces healthy donor cells. Over the past 5 years (2020–2025), the field has advanced rapidly from first achieving efficient replacement in animals to first-in-human clinical interventions. Here, we summarize microgliopathies as therapeutic targets and trace the historical and technical evolution from the pre-replacement era of low-engraftment approaches to efficient strategies enabling widespread replacement. We outline the mechanistic principles and current methods that underpin efficient replacement. We highlight therapeutic applications ranging from gene correction to engineered “Trojan horse” microglia and explore potential ability enhancement. Finally, we discuss the potential risks and future directions for safe, scalable, and ethically governed clinical translation.
{"title":"The evolution of microglia replacement: A new paradigm for CNS disease therapy","authors":"Yanxia Rao, Yunshang Bai, Xiaoyu Li, Bingying Du, Bo Peng","doi":"10.1016/j.stem.2025.10.014","DOIUrl":"https://doi.org/10.1016/j.stem.2025.10.014","url":null,"abstract":"Microglia are indispensable for the central nervous system (CNS) development and homeostasis, and mutations in microglia can cause microgliopathies. Correcting these mutations holds therapeutic potential, but conventional gene therapies cannot yet achieve the CNS-wide delivery required for meaningful treatment. Microglia replacement has emerged as a groundbreaking paradigm that removes pathogenic microglia and introduces healthy donor cells. Over the past 5 years (2020–2025), the field has advanced rapidly from first achieving efficient replacement in animals to first-in-human clinical interventions. Here, we summarize microgliopathies as therapeutic targets and trace the historical and technical evolution from the pre-replacement era of low-engraftment approaches to efficient strategies enabling widespread replacement. We outline the mechanistic principles and current methods that underpin efficient replacement. We highlight therapeutic applications ranging from gene correction to engineered “Trojan horse” microglia and explore potential ability enhancement. Finally, we discuss the potential risks and future directions for safe, scalable, and ethically governed clinical translation.","PeriodicalId":9665,"journal":{"name":"Cell stem cell","volume":"142 1","pages":""},"PeriodicalIF":23.9,"publicationDate":"2025-12-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145664518","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-12-04DOI: 10.1016/j.stem.2025.10.010
Shih-Lei (Ben) Lai, Yu-Jen Hung, Rubén Marín-Juez
Adult mammalian hearts exhibit limited regenerative capacity. Fan et al.1 report that neonatal cardiomyocyte-derived clusterin competes for macrophage Toll-like receptor 4 to suppress inflammation and induces reparative polarization. This cardio-immune dialogue activates BMP2 signaling to stimulate cardiomyocyte proliferation, reframing inflammation as a cooperative driver of heart repair.
{"title":"When the heart calls for help: Clusterin reprograms immunity to enable regeneration","authors":"Shih-Lei (Ben) Lai, Yu-Jen Hung, Rubén Marín-Juez","doi":"10.1016/j.stem.2025.10.010","DOIUrl":"https://doi.org/10.1016/j.stem.2025.10.010","url":null,"abstract":"Adult mammalian hearts exhibit limited regenerative capacity. Fan et al.<span><span><sup>1</sup></span></span> report that neonatal cardiomyocyte-derived clusterin competes for macrophage Toll-like receptor 4 to suppress inflammation and induces reparative polarization. This cardio-immune dialogue activates BMP2 signaling to stimulate cardiomyocyte proliferation, reframing inflammation as a cooperative driver of heart repair.","PeriodicalId":9665,"journal":{"name":"Cell stem cell","volume":"53 1","pages":""},"PeriodicalIF":23.9,"publicationDate":"2025-12-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145664514","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Through a comprehensive analysis of stem cell clinical research in China, we reveal robust yet uneven translational linkages between IITs and INDs and propose governance reforms to reduce redundancy, enhance efficiency, and better align exploratory research with regulatory and industrial pathways.
{"title":"Optimizing translational efficiency in stem cell clinical research","authors":"Yi Hao, Qianwen Chen, Jiayu Yin, Lulu Ding, Xue Pang, Yaojin Peng","doi":"10.1016/j.stem.2025.11.002","DOIUrl":"https://doi.org/10.1016/j.stem.2025.11.002","url":null,"abstract":"Through a comprehensive analysis of stem cell clinical research in China, we reveal robust yet uneven translational linkages between IITs and INDs and propose governance reforms to reduce redundancy, enhance efficiency, and better align exploratory research with regulatory and industrial pathways.","PeriodicalId":9665,"journal":{"name":"Cell stem cell","volume":"202 1","pages":""},"PeriodicalIF":23.9,"publicationDate":"2025-12-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145664517","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-12-04DOI: 10.1016/j.stem.2025.10.011
Wei Pang, Yangfei Xiang
In this issue of Cell Stem Cell, Wang et al.1 generate human nucleus basalis of Meynert organoids (hnbMOs), establish a human-specific cholinergic projection system in transplanted assembloids, and identify projection deficits in Down syndrome-derived assembloids. This study provides a valuable model for investigating nbM-related neural circuits and neurological disorders.
{"title":"Unlocking human brain networks by assembling circuits in vitro and in vivo","authors":"Wei Pang, Yangfei Xiang","doi":"10.1016/j.stem.2025.10.011","DOIUrl":"https://doi.org/10.1016/j.stem.2025.10.011","url":null,"abstract":"In this issue of <em>Cell Stem Cell</em>, Wang et al.<span><span><sup>1</sup></span></span> generate human nucleus basalis of Meynert organoids (hnbMOs), establish a human-specific cholinergic projection system in transplanted assembloids, and identify projection deficits in Down syndrome-derived assembloids. This study provides a valuable model for investigating nbM-related neural circuits and neurological disorders.","PeriodicalId":9665,"journal":{"name":"Cell stem cell","volume":"31 1","pages":""},"PeriodicalIF":23.9,"publicationDate":"2025-12-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145664515","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-11-24DOI: 10.1016/j.stem.2025.10.012
Tasleem Arif, Jiajing Qiu, Hossein Khademian, Anusree Lohithakshan, Anagha Menon, Vijay Menon, Mary Slavinsky, Maxime Batignes, Miao Lin, Robert Sebra, Kristin G. Beaumont, Deanna L. Benson, Nikolaos Tzavaras, Mickaël M. Ménager, Saghi Ghaffari
Aging impairs hematopoietic stem cells (HSCs), driving clonal hematopoiesis, myeloid malignancies, and immune decline. The role of lysosomes in HSC aging—beyond their passive mediation of autophagy—is unclear. We show that lysosomes in aged HSCs are hyperacidic, depleted, damaged, and aberrantly activated. Single-cell transcriptomics and functional analyses reveal that suppression of hyperactivated lysosomes using a vacuolar ATPase (v-ATPase) inhibitor restores lysosomal integrity and metabolic and epigenetic homeostasis in old HSCs. This intervention reduces inflammatory and interferon-driven programs by improving lysosomal processing of mitochondrial DNA and attenuating cyclic GMP-AMP synthase-stimulator of interferon gene (cGAS-STING) signaling. Strikingly, ex vivo lysosomal inhibition boosts old HSCs’ in vivo repopulation capacity by over eightfold and improves their self-renewal. Thus, lysosomal dysfunction emerges as a key driver of HSC aging. Targeting hyperactivated lysosomes reinstates a youthful state in old HSCs, offering a promising strategy to restore hematopoietic function in the elderly.
{"title":"Reversing lysosomal dysfunction restores youthful state in aged hematopoietic stem cells","authors":"Tasleem Arif, Jiajing Qiu, Hossein Khademian, Anusree Lohithakshan, Anagha Menon, Vijay Menon, Mary Slavinsky, Maxime Batignes, Miao Lin, Robert Sebra, Kristin G. Beaumont, Deanna L. Benson, Nikolaos Tzavaras, Mickaël M. Ménager, Saghi Ghaffari","doi":"10.1016/j.stem.2025.10.012","DOIUrl":"https://doi.org/10.1016/j.stem.2025.10.012","url":null,"abstract":"Aging impairs hematopoietic stem cells (HSCs), driving clonal hematopoiesis, myeloid malignancies, and immune decline. The role of lysosomes in HSC aging—beyond their passive mediation of autophagy—is unclear. We show that lysosomes in aged HSCs are hyperacidic, depleted, damaged, and aberrantly activated. Single-cell transcriptomics and functional analyses reveal that suppression of hyperactivated lysosomes using a vacuolar ATPase (v-ATPase) inhibitor restores lysosomal integrity and metabolic and epigenetic homeostasis in old HSCs. This intervention reduces inflammatory and interferon-driven programs by improving lysosomal processing of mitochondrial DNA and attenuating cyclic GMP-AMP synthase-stimulator of interferon gene (cGAS-STING) signaling. Strikingly, <em>ex vivo</em> lysosomal inhibition boosts old HSCs’ <em>in vivo</em> repopulation capacity by over eightfold and improves their self-renewal. Thus, lysosomal dysfunction emerges as a key driver of HSC aging. Targeting hyperactivated lysosomes reinstates a youthful state in old HSCs, offering a promising strategy to restore hematopoietic function in the elderly.","PeriodicalId":9665,"journal":{"name":"Cell stem cell","volume":"1 1","pages":""},"PeriodicalIF":23.9,"publicationDate":"2025-11-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145583757","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-11-24DOI: 10.1016/j.stem.2025.11.001
Jessica Pham, Shuvro P. Nandi, Larisa Balaian, Claire Engstrom, Patrick Chang, Karla Mack, Inge van der Werf, Emma Klacking, Jenna Sneifer, Neha Katragadda, Kendale Wirtjes, Antonio Ruiz, Daisy Chilin-Fuentes, Elsa Molina, Pinar Mesci, Jana Stoudemire, Sheldon R. Morris, Thomas Whisenant, Ludmil B. Alexandrov, Catriona H.M. Jamieson
{"title":"Space-associated stem cell hallmarks of aging and resilience in astronauts","authors":"Jessica Pham, Shuvro P. Nandi, Larisa Balaian, Claire Engstrom, Patrick Chang, Karla Mack, Inge van der Werf, Emma Klacking, Jenna Sneifer, Neha Katragadda, Kendale Wirtjes, Antonio Ruiz, Daisy Chilin-Fuentes, Elsa Molina, Pinar Mesci, Jana Stoudemire, Sheldon R. Morris, Thomas Whisenant, Ludmil B. Alexandrov, Catriona H.M. Jamieson","doi":"10.1016/j.stem.2025.11.001","DOIUrl":"https://doi.org/10.1016/j.stem.2025.11.001","url":null,"abstract":"","PeriodicalId":9665,"journal":{"name":"Cell stem cell","volume":"168 1","pages":""},"PeriodicalIF":23.9,"publicationDate":"2025-11-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145583718","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-11-18DOI: 10.1016/j.stem.2025.10.009
Qing Li, Marina T. Nikolova, Gangyu Zhang, Igor Cervenka, Federica Valigi, Dominik Burri, Evelia Plantier, Andrea Mazzoleni, Anaïs Lamouline, Juerg Schwaller, Barbara Treutlein, Ivan Martin, Andrés García-García
Endosteal bone marrow (BM) niches are crucial to sustain non-steady-state hematopoiesis but are challenging to be modeled in their cellular and molecular complexity in standardized, human settings. We report a developmentally guided approach to generate a macro-scale organotypic model of BM endosteal niches (engineered vascularized osteoblastic niche [eVON]) based on human induced pluripotent stem cells and porous hydroxyapatite scaffolds. The eVON contains long-lasting vascular networks covered by pericytes and neural fibers within an osteogenic matrix. Key niche signals (CXCL12, KITLG, and vascular endothelial growth factor A [VEGFA]) are expressed in human-specific patterns. The system supports hematopoiesis in vitro and preserves hematopoietic stem and progenitor cell (HSPC) multilineage repopulation capacity in vivo. eVON perturbations at cellular (removing vasculature) and molecular (deregulating VEGF-A and CXCL12 signaling) levels enabled the investigation of the contribution of endosteal vasculature to myelopoiesis. The eVON faithfully captures phenotypic, structural, and functional features of human endosteal BM, enabling the study of pathophysiological interactions with hematopoietic cells.
{"title":"Macro-scale, scaffold-assisted model of the human bone marrow endosteal niche using hiPSC-vascularized osteoblastic organoids","authors":"Qing Li, Marina T. Nikolova, Gangyu Zhang, Igor Cervenka, Federica Valigi, Dominik Burri, Evelia Plantier, Andrea Mazzoleni, Anaïs Lamouline, Juerg Schwaller, Barbara Treutlein, Ivan Martin, Andrés García-García","doi":"10.1016/j.stem.2025.10.009","DOIUrl":"https://doi.org/10.1016/j.stem.2025.10.009","url":null,"abstract":"Endosteal bone marrow (BM) niches are crucial to sustain non-steady-state hematopoiesis but are challenging to be modeled in their cellular and molecular complexity in standardized, human settings. We report a developmentally guided approach to generate a macro-scale organotypic model of BM endosteal niches (engineered vascularized osteoblastic niche [eVON]) based on human induced pluripotent stem cells and porous hydroxyapatite scaffolds. The eVON contains long-lasting vascular networks covered by pericytes and neural fibers within an osteogenic matrix. Key niche signals (<em>CXCL12</em>, <em>KITLG</em>, and vascular endothelial growth factor A [<em>VEGFA</em>]) are expressed in human-specific patterns. The system supports hematopoiesis <em>in vitro</em> and preserves hematopoietic stem and progenitor cell (HSPC) multilineage repopulation capacity <em>in vivo</em>. eVON perturbations at cellular (removing vasculature) and molecular (deregulating VEGF-A and CXCL12 signaling) levels enabled the investigation of the contribution of endosteal vasculature to myelopoiesis. The eVON faithfully captures phenotypic, structural, and functional features of human endosteal BM, enabling the study of pathophysiological interactions with hematopoietic cells.","PeriodicalId":9665,"journal":{"name":"Cell stem cell","volume":"120 1","pages":""},"PeriodicalIF":23.9,"publicationDate":"2025-11-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145536149","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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