Cell stem cell最新文献

Glycolytic activity instructs germ layer proportions through regulation of Nodal and Wnt signaling

IF 23.9 1区医学

Cell stem cell Pub Date : 2025-04-16 DOI: 10.1016/j.stem.2025.03.011

Kristina S. Stapornwongkul, Elisa Hahn, Patryk Poliński, Laura Salamó Palau, Krisztina Arató, LiAng Yao, Kate Williamson, Nicola Gritti, Kerim Anlas, Mireia Osuna Lopez, Kiran R. Patil, Idse Heemskerk, Miki Ebisuya, Vikas Trivedi

{"title":"Glycolytic activity instructs germ layer proportions through regulation of Nodal and Wnt signaling","authors":"Kristina S. Stapornwongkul, Elisa Hahn, Patryk Poliński, Laura Salamó Palau, Krisztina Arató, LiAng Yao, Kate Williamson, Nicola Gritti, Kerim Anlas, Mireia Osuna Lopez, Kiran R. Patil, Idse Heemskerk, Miki Ebisuya, Vikas Trivedi","doi":"10.1016/j.stem.2025.03.011","DOIUrl":"https://doi.org/10.1016/j.stem.2025.03.011","url":null,"abstract":"Metabolic pathways can influence cell fate decisions, yet their regulative role during embryonic development remains poorly understood. Here, we demonstrate an instructive role of glycolytic activity in regulating signaling pathways involved in mesoderm and endoderm specification. Using a mouse embryonic stem cell (mESC)-based in vitro model for gastrulation, we found that glycolysis inhibition increases ectodermal cell fates at the expense of mesodermal and endodermal lineages. We demonstrate that this relationship is dose dependent, enabling metabolic control of germ layer proportions through exogenous glucose levels. We further show that glycolysis acts as an upstream regulator of Nodal and Wnt signaling and that its influence on cell fate specification can be decoupled from its effects on growth. Finally, we confirm the generality of our findings using a human gastrulation model. Our work underscores the dependence of signaling pathways on metabolic conditions and provides mechanistic insight into the nutritional regulation of cell fate decision-making.","PeriodicalId":9665,"journal":{"name":"Cell stem cell","volume":"47 1","pages":""},"PeriodicalIF":23.9,"publicationDate":"2025-04-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143837079","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}

引用次数: 0

Integrated molecular-phenotypic profiling reveals metabolic control of morphological variation in a stem-cell-based embryo model

IF 23.9 1区医学

Cell stem cell Pub Date : 2025-04-16 DOI: 10.1016/j.stem.2025.03.012

Alba Villaronga-Luque, Ryan G. Savill, Natalia López-Anguita, Adriano Bolondi, Sumit Garai, Seher Ipek Gassaloglu, Roua Rouatbi, Kathrin Schmeisser, Aayush Poddar, Lisa Bauer, Tiago Alves, Sofia Traikov, Jonathan Rodenfels, Triantafyllos Chavakis, Aydan Bulut-Karslioglu, Jesse V. Veenvliet

{"title":"Integrated molecular-phenotypic profiling reveals metabolic control of morphological variation in a stem-cell-based embryo model","authors":"Alba Villaronga-Luque, Ryan G. Savill, Natalia López-Anguita, Adriano Bolondi, Sumit Garai, Seher Ipek Gassaloglu, Roua Rouatbi, Kathrin Schmeisser, Aayush Poddar, Lisa Bauer, Tiago Alves, Sofia Traikov, Jonathan Rodenfels, Triantafyllos Chavakis, Aydan Bulut-Karslioglu, Jesse V. Veenvliet","doi":"10.1016/j.stem.2025.03.012","DOIUrl":"https://doi.org/10.1016/j.stem.2025.03.012","url":null,"abstract":"Considerable phenotypic variation under identical culture conditions limits the potential of stem-cell-based embryo models (SEMs) in basic and applied research. The biological processes causing this seemingly stochastic variation remain unclear. Here, we investigated the roots of phenotypic variation by parallel recording of transcriptomic states and morphological history in individual structures modeling embryonic trunk formation. Machine learning and integration of time-resolved single-cell RNA sequencing with imaging-based phenotypic profiling identified early features predictive of phenotypic end states. Leveraging this predictive power revealed that early imbalance of oxidative phosphorylation and glycolysis results in aberrant morphology and a neural lineage bias, which we confirmed by metabolic measurements. Accordingly, metabolic interventions improved phenotypic end states. Collectively, our work establishes divergent metabolic states as drivers of phenotypic variation and offers a broadly applicable framework to chart and predict phenotypic variation in organoids and SEMs. The strategy can be used to identify and control underlying biological processes, ultimately increasing reproducibility.","PeriodicalId":9665,"journal":{"name":"Cell stem cell","volume":"1 1","pages":""},"PeriodicalIF":23.9,"publicationDate":"2025-04-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143837080","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}

引用次数: 0

Harnessing human iPSC-microglia for CNS-wide delivery of disease-modifying proteins

IF 23.9 1区医学

Cell stem cell Pub Date : 2025-04-14 DOI: 10.1016/j.stem.2025.03.009

Jean Paul Chadarevian, Hayk Davtyan, Alina L. Chadarevian, Jasmine Nguyen, Joia K. Capocchi, Lauren Le, Adrian Escobar, Talar Chadarevian, Kimiya Mansour, Ekaterina Deynega, Michael Mgerian, Christina Tu, Sepideh Kiani Shabestari, William Carlen-Jones, Ghazaleh Eskandari-Sedighi, Jonathan Hasselmann, Robert C. Spitale, Mathew Blurton-Jones

{"title":"Harnessing human iPSC-microglia for CNS-wide delivery of disease-modifying proteins","authors":"Jean Paul Chadarevian, Hayk Davtyan, Alina L. Chadarevian, Jasmine Nguyen, Joia K. Capocchi, Lauren Le, Adrian Escobar, Talar Chadarevian, Kimiya Mansour, Ekaterina Deynega, Michael Mgerian, Christina Tu, Sepideh Kiani Shabestari, William Carlen-Jones, Ghazaleh Eskandari-Sedighi, Jonathan Hasselmann, Robert C. Spitale, Mathew Blurton-Jones","doi":"10.1016/j.stem.2025.03.009","DOIUrl":"https://doi.org/10.1016/j.stem.2025.03.009","url":null,"abstract":"Widespread delivery of therapeutic proteins to the brain remains challenging. To determine whether human induced pluripotent stem cell (iPSC)-microglia (iMG) could enable brain-wide and pathology-responsive delivery of therapeutic cargo, we utilized CRISPR gene editing to engineer iMG to express the Aβ-degrading enzyme neprilysin under control of the plaque-responsive promoter, CD9. To further determine whether increased engraftment enhances efficacy, we utilized a CSF1R-inhibitor resistance approach. Interestingly, both localized and brain-wide engraftment in Alzheimer’s disease (AD) mice reduced multiple biochemical measures of pathology. However, within the plaque-dense subiculum, reductions in plaque load, dystrophic neurites, and astrogliosis and preservation of neuronal density were only achieved following widespread microglial engraftment. Lastly, we examined chimeric models of breast cancer brain metastases and demyelination, demonstrating that iMG adopt diverse transcriptional responses to differing neuropathologies, which could be harnessed to enable widespread and pathology-responsive delivery of therapeutics to the CNS.","PeriodicalId":9665,"journal":{"name":"Cell stem cell","volume":"42 1","pages":""},"PeriodicalIF":23.9,"publicationDate":"2025-04-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143827152","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}

引用次数: 0

An erythroid-biased FOShi hematopoietic multipotent progenitor subpopulation contributes to adaptation to chronic hypoxia 偏红细胞的 FOShi 造血多能祖细胞亚群有助于适应慢性缺氧

IF 23.9 1区医学

Cell stem cell Pub Date : 2025-04-11 DOI: 10.1016/j.stem.2025.03.010

Weili Liu, Xiaoru Zhang, Jinhua Liu, Lingling Pu, Lanlan Ai, Hongbao Xu, Guangrui Wang, Ding Wang, Xiaona Song, Yingnan Zhang, Ling Zhang, Jie Gao, Xiaoling Cheng, Xinxing Wang, Jingyuan Tong, Xiaowei Xie, Fang Dong, Yingchi Zhang, Ping Zhu, Zhaoli Chen, Lihong Shi

{"title":"An erythroid-biased FOShi hematopoietic multipotent progenitor subpopulation contributes to adaptation to chronic hypoxia","authors":"Weili Liu, Xiaoru Zhang, Jinhua Liu, Lingling Pu, Lanlan Ai, Hongbao Xu, Guangrui Wang, Ding Wang, Xiaona Song, Yingnan Zhang, Ling Zhang, Jie Gao, Xiaoling Cheng, Xinxing Wang, Jingyuan Tong, Xiaowei Xie, Fang Dong, Yingchi Zhang, Ping Zhu, Zhaoli Chen, Lihong Shi","doi":"10.1016/j.stem.2025.03.010","DOIUrl":"https://doi.org/10.1016/j.stem.2025.03.010","url":null,"abstract":"Hypoxia imposes notable stress on organisms and even causes tissue damage; however, the cellular and molecular mechanisms underlying hypoxic adaptation and maladaptation are elusive. Here, we performed single-cell RNA sequencing to analyze hematopoietic stem and progenitor cells (HSPCs) and erythroid cells in a mouse model of high-altitude polycythemia (HAPC) mimicking long-term high-altitude hypoxia exposure. We identified a distinct erythroid-biased multipotent progenitor subset, FOShi MPP, characterized by a unique responsiveness to interferon (IFN) signaling, which expands under hypoxia conditions. This subset rapidly responds to hypoxia during re-ascent by sustaining low methylation of erythroid-priming genes, suggesting a memory function in HSPCs for faster acclimatization. Additionally, erythroid cells in HAPC mice had active metabolic and autophagic activity, as well as abundant CD47 expression that prevented the phagocytosis of erythrocytes. Finally, CD47 blockade and/or IFNα treatments alleviated erythrocytosis in HAPC mice. These approaches might constitute promising therapeutic strategies for HAPC.","PeriodicalId":9665,"journal":{"name":"Cell stem cell","volume":"25 1","pages":""},"PeriodicalIF":23.9,"publicationDate":"2025-04-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143820084","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}

引用次数: 0

Activating innate immune responses repolarizes hPSC-derived CAR macrophages to improve anti-tumor activity 激活先天性免疫反应可使 hPSC 衍生的 CAR 巨噬细胞重新极化，从而提高抗肿瘤活性

IF 23.9 1区医学

Cell stem cell Pub Date : 2025-04-11 DOI: 10.1016/j.stem.2025.03.013

Jun Shen, Shuzhen Lyu, Yingxi Xu, Shuo Zhang, Li Li, Jinze Li, Junli Mou, Leling Xie, Kejing Tang, Wei Wen, Xuemei Peng, Ying Yang, Yu Shi, Xinjie Li, Min Wang, Xin Li, Jianxiang Wang, Tao Cheng

引用次数: 0

A cloaked human stem-cell-derived neural graft capable of functional integration and immune evasion in rodent models

IF 23.9 1区医学

Cell stem cell Pub Date : 2025-04-09 DOI: 10.1016/j.stem.2025.03.008

Chiara Pavan, Kathryn C. Davidson, Natalie Payne, Stefano Frausin, Cameron P.J. Hunt, Niamh Moriarty, Miguel Á. Berrocal Rubio, Zahra Elahi, Andrew T. Quattrocchi, Kwaku Dad Abu-Bonsrah, Le Wang, William Clow, Huijuan Yang, Marc Pellegrini, Christine A. Wells, Lachlan H. Thompson, Andras Nagy, Clare L. Parish

{"title":"A cloaked human stem-cell-derived neural graft capable of functional integration and immune evasion in rodent models","authors":"Chiara Pavan, Kathryn C. Davidson, Natalie Payne, Stefano Frausin, Cameron P.J. Hunt, Niamh Moriarty, Miguel Á. Berrocal Rubio, Zahra Elahi, Andrew T. Quattrocchi, Kwaku Dad Abu-Bonsrah, Le Wang, William Clow, Huijuan Yang, Marc Pellegrini, Christine A. Wells, Lachlan H. Thompson, Andras Nagy, Clare L. Parish","doi":"10.1016/j.stem.2025.03.008","DOIUrl":"https://doi.org/10.1016/j.stem.2025.03.008","url":null,"abstract":"Human pluripotent stem cell (hPSC)-derived therapies are a realistic possibility for numerous disorders, including Parkinson’s disease. While generating replacement neurons is achievable, immunosuppressive drug challenges, to prevent rejection, remain. Here we adopted a hPSC line (termed H1-FS-8IM), engineered to overexpress 8 immunomodulatory transgenes, to enable transplant immune evasion. In co-cultures, H1-FS-8IM PSC-derived midbrain neurons evaded rejection by T lymphocytes, natural killer cells, macrophages, and dendritic cells. In humanized mice, allogeneic H1-FS-8IM neural grafts evaded rejection, while control hPSC-derived neural grafts evoked activation of human immune cells, elevated inflammatory cytokines in blood and cerebrospinal fluid, and caused spleen and lymph node enlargement. H1-FS-8IM neural grafts retained functionality, reversing motor deficits in Parkinsonian rats. Additional incorporation of a suicide gene into the H1-FS-8IM hPSC line enabled proliferative cell elimination within grafts. Findings demonstrate feasibility of generating a population-wide applicable, safe, off-the-shelf cell product, suitable for treating diseases for which cell-based therapies are a viable option.","PeriodicalId":9665,"journal":{"name":"Cell stem cell","volume":"43 1","pages":""},"PeriodicalIF":23.9,"publicationDate":"2025-04-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143806109","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}

引用次数: 0

Intestinal secretory differentiation reflects niche-driven phenotypic and epigenetic plasticity of a common signal-responsive terminal cell

IF 23.9 1区医学

Cell stem cell Pub Date : 2025-04-08 DOI: 10.1016/j.stem.2025.03.005

Swarnabh Bhattacharya, Guodong Tie, Pratik N.P. Singh, Ermanno Malagola, Onur Eskiocak, Ruiyang He, Judith Kraiczy, Wei Gu, Yakov Perlov, Aybuke Alici-Garipcan, Semir Beyaz, Timothy C. Wang, Qiao Zhou, Ramesh A. Shivdasani

{"title":"Intestinal secretory differentiation reflects niche-driven phenotypic and epigenetic plasticity of a common signal-responsive terminal cell","authors":"Swarnabh Bhattacharya, Guodong Tie, Pratik N.P. Singh, Ermanno Malagola, Onur Eskiocak, Ruiyang He, Judith Kraiczy, Wei Gu, Yakov Perlov, Aybuke Alici-Garipcan, Semir Beyaz, Timothy C. Wang, Qiao Zhou, Ramesh A. Shivdasani","doi":"10.1016/j.stem.2025.03.005","DOIUrl":"https://doi.org/10.1016/j.stem.2025.03.005","url":null,"abstract":"Enterocytes and four classic secretory cell types derive from intestinal epithelial stem cells. Based on morphology, location, and canonical markers, goblet and Paneth cells are considered distinct secretory types. Here, we report high overlap in their transcripts and sites of accessible chromatin, in marked contrast to those of their enteroendocrine or tuft cell siblings. Mouse and human goblet and Paneth cells express extraordinary fractions of few antimicrobial genes, which reflect specific responses to local niches. Wnt signaling retains some ATOH1+ secretory cells in crypt bottoms, where the absence of BMP signaling potently induces Paneth features. Cells that migrate away from crypt bottoms encounter BMPs and thereby acquire goblet properties. These phenotypes and underlying accessible cis-elements interconvert in post-mitotic cells. Thus, goblet and Paneth properties represent alternative phenotypic manifestations of a common signal-responsive terminal cell type. These findings reveal exquisite niche-dependent cell plasticity and cis-regulatory dynamics in likely response to antimicrobial needs.","PeriodicalId":9665,"journal":{"name":"Cell stem cell","volume":"59 1","pages":""},"PeriodicalIF":23.9,"publicationDate":"2025-04-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143797998","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}

引用次数: 0

Engineered heart tissue patches: A milestone in cardiac regenerative medicine

IF 23.9 1区医学

Cell stem cell Pub Date : 2025-04-03 DOI: 10.1016/j.stem.2025.02.012

Alain van Mil, Jasmijn Janssen, Eva van Rooij

引用次数: 0

Progress and challenges in developing allogeneic cell therapies

IF 23.9 1区医学

Cell stem cell Pub Date : 2025-04-03 DOI: 10.1016/j.stem.2025.03.004

Tobias Deuse, Sonja Schrepfer

引用次数: 0

The clones have STRACK: Tracing responses to leukemic mutations