Cell stem cellPub Date : 2024-05-20DOI: 10.1016/j.stem.2024.04.022
Kun Zhang, Ping Wan, Liren Wang, Zhen Wang, Fangzhi Tan, Jie Li, Xiaolong Ma, Jin Cen, Xiang Yuan, Yang Liu, Zhen Sun, Xi Cheng, Yuanhua Liu, Xuhao Liu, Jiazhi Hu, Guisheng Zhong, Dali Li, Qiang Xia, Lijian Hui
{"title":"Efficient expansion and CRISPR-Cas9-mediated gene correction of patient-derived hepatocytes for treatment of inherited liver diseases","authors":"Kun Zhang, Ping Wan, Liren Wang, Zhen Wang, Fangzhi Tan, Jie Li, Xiaolong Ma, Jin Cen, Xiang Yuan, Yang Liu, Zhen Sun, Xi Cheng, Yuanhua Liu, Xuhao Liu, Jiazhi Hu, Guisheng Zhong, Dali Li, Qiang Xia, Lijian Hui","doi":"10.1016/j.stem.2024.04.022","DOIUrl":"https://doi.org/10.1016/j.stem.2024.04.022","url":null,"abstract":"<p>Cell-based <em>ex vivo</em> gene therapy in solid organs, especially the liver, has proven technically challenging. Here, we report a feasible strategy for the clinical application of hepatocyte therapy. We first generated high-quality autologous hepatocytes through the large-scale expansion of patient-derived hepatocytes. Moreover, the proliferating patient-derived hepatocytes, together with the AAV2.7m8 variant identified through screening, enabled CRISPR-Cas9-mediated targeted integration efficiently, achieving functional correction of pathogenic mutations in FAH or OTC. Importantly, these edited hepatocytes repopulated the injured mouse liver at high repopulation levels and underwent maturation, successfully treating mice with tyrosinemia following transplantation. Our study combines <em>ex vivo</em> large-scale cell expansion and gene editing in patient-derived transplantable hepatocytes, which holds potential for treating human liver diseases.</p>","PeriodicalId":9665,"journal":{"name":"Cell stem cell","volume":"20 1","pages":""},"PeriodicalIF":23.9,"publicationDate":"2024-05-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141069215","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}
Cell stem cellPub Date : 2024-05-16DOI: 10.1016/j.stem.2024.04.021
Shiqi Li, Sikai Ling, Dawei Wang, Xiaoyuan Wang, Fangyuan Hao, Liufan Yin, Zhongtao Yuan, Lin Liu, Lin Zhang, Yu Li, Yingnian Chen, Le Luo, Ying Dai, Lihua Zhang, Lvzhe Chen, Dongjie Deng, Wei Tang, Sujiang Zhang, Sanbin Wang, Yujia Cai
{"title":"Modified lentiviral globin gene therapy for pediatric β0/β0 transfusion-dependent β-thalassemia: A single-center, single-arm pilot trial","authors":"Shiqi Li, Sikai Ling, Dawei Wang, Xiaoyuan Wang, Fangyuan Hao, Liufan Yin, Zhongtao Yuan, Lin Liu, Lin Zhang, Yu Li, Yingnian Chen, Le Luo, Ying Dai, Lihua Zhang, Lvzhe Chen, Dongjie Deng, Wei Tang, Sujiang Zhang, Sanbin Wang, Yujia Cai","doi":"10.1016/j.stem.2024.04.021","DOIUrl":"https://doi.org/10.1016/j.stem.2024.04.021","url":null,"abstract":"<p>β<sup>0</sup>/β<sup>0</sup> thalassemia is the most severe type of transfusion-dependent β-thalassemia (TDT) and is still a challenge facing lentiviral gene therapy. Here, we report the interim analysis of a single-center, single-arm pilot trial (NCT05015920) evaluating the safety and efficacy of a β-globin expression-optimized and insulator-engineered lentivirus-modified cell product (BD211) in β<sup>0</sup>/β<sup>0</sup> TDT. Two female children were enrolled, infused with BD211, and followed up for an average of 25.5 months. Engraftment of genetically modified hematopoietic stem and progenitor cells was successful and sustained in both patients. No unexpected safety issues occurred during conditioning or after infusion. Both patients achieved transfusion independence for over 22 months. The treatment extended the lifespan of red blood cells by over 42 days. Single-cell DNA/RNA-sequencing analysis of the dynamic changes of gene-modified cells, transgene expression, and oncogene activation showed no notable adverse effects. Optimized lentiviral gene therapy may safely and effectively treat all β-thalassemia.</p>","PeriodicalId":9665,"journal":{"name":"Cell stem cell","volume":"193 1","pages":""},"PeriodicalIF":23.9,"publicationDate":"2024-05-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140949869","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}
Cell stem cellPub Date : 2024-05-15DOI: 10.1016/j.stem.2024.04.017
Suzan Stelloo, Maria Teresa Alejo-Vinogradova, Charlotte A.G.H. van Gelder, Dick W. Zijlmans, Marek J. van Oostrom, Juan Manuel Valverde, Lieke A. Lamers, Teja Rus, Paula Sobrevals Alcaraz, Tilman Schäfers, Cristina Furlan, Pascal W.T.C. Jansen, Marijke P.A. Baltissen, Katharina F. Sonnen, Boudewijn Burgering, Maarten A.F.M. Altelaar, Harmjan R. Vos, Michiel Vermeulen
{"title":"Deciphering lineage specification during early embryogenesis in mouse gastruloids using multilayered proteomics","authors":"Suzan Stelloo, Maria Teresa Alejo-Vinogradova, Charlotte A.G.H. van Gelder, Dick W. Zijlmans, Marek J. van Oostrom, Juan Manuel Valverde, Lieke A. Lamers, Teja Rus, Paula Sobrevals Alcaraz, Tilman Schäfers, Cristina Furlan, Pascal W.T.C. Jansen, Marijke P.A. Baltissen, Katharina F. Sonnen, Boudewijn Burgering, Maarten A.F.M. Altelaar, Harmjan R. Vos, Michiel Vermeulen","doi":"10.1016/j.stem.2024.04.017","DOIUrl":"https://doi.org/10.1016/j.stem.2024.04.017","url":null,"abstract":"<p>Gastrulation is a critical stage in embryonic development during which the germ layers are established. Advances in sequencing technologies led to the identification of gene regulatory programs that control the emergence of the germ layers and their derivatives. However, proteome-based studies of early mammalian development are scarce. To overcome this, we utilized gastruloids and a multilayered mass spectrometry-based proteomics approach to investigate the global dynamics of (phospho) protein expression during gastruloid differentiation. Our findings revealed many proteins with temporal expression and unique expression profiles for each germ layer, which we also validated using single-cell proteomics technology. Additionally, we profiled enhancer interaction landscapes using P300 proximity labeling, which revealed numerous gastruloid-specific transcription factors and chromatin remodelers. Subsequent degron-based perturbations combined with single-cell RNA sequencing (scRNA-seq) identified a critical role for ZEB2 in mouse and human somitogenesis. Overall, this study provides a rich resource for developmental and synthetic biology communities endeavoring to understand mammalian embryogenesis.</p>","PeriodicalId":9665,"journal":{"name":"Cell stem cell","volume":"33 1","pages":""},"PeriodicalIF":23.9,"publicationDate":"2024-05-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140942786","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}
Cell stem cellPub Date : 2024-05-15DOI: 10.1016/j.stem.2024.04.019
Lan Dao, Zhen You, Lu Lu, Tianyang Xu, Avijite Kumer Sarkar, Hui Zhu, Miao Liu, Riccardo Calandrelli, George Yoshida, Pei Lin, Yifei Miao, Sarah Mierke, Srijan Kalva, Haining Zhu, Mingxia Gu, Sudhakar Vadivelu, Sheng Zhong, L. Frank Huang, Ziyuan Guo
{"title":"Modeling blood-brain barrier formation and cerebral cavernous malformations in human PSC-derived organoids","authors":"Lan Dao, Zhen You, Lu Lu, Tianyang Xu, Avijite Kumer Sarkar, Hui Zhu, Miao Liu, Riccardo Calandrelli, George Yoshida, Pei Lin, Yifei Miao, Sarah Mierke, Srijan Kalva, Haining Zhu, Mingxia Gu, Sudhakar Vadivelu, Sheng Zhong, L. Frank Huang, Ziyuan Guo","doi":"10.1016/j.stem.2024.04.019","DOIUrl":"https://doi.org/10.1016/j.stem.2024.04.019","url":null,"abstract":"<p>The human blood-brain barrier (hBBB) is a highly specialized structure that regulates passage across blood and central nervous system (CNS) compartments. Despite its critical physiological role, there are no reliable <em>in vitro</em> models that can mimic hBBB development and function. Here, we constructed hBBB assembloids from brain and blood vessel organoids derived from human pluripotent stem cells. We validated the acquisition of blood-brain barrier (BBB)-specific molecular, cellular, transcriptomic, and functional characteristics and uncovered an extensive neuro-vascular crosstalk with a spatial pattern within hBBB assembloids. When we used patient-derived hBBB assembloids to model cerebral cavernous malformations (CCMs), we found that these assembloids recapitulated the cavernoma anatomy and BBB breakdown observed in patients. Upon comparison of phenotypes and transcriptome between patient-derived hBBB assembloids and primary human cavernoma tissues, we uncovered CCM-related molecular and cellular alterations. Taken together, we report hBBB assembloids that mimic the core properties of the hBBB and identify a potentially underlying cause of CCMs.</p>","PeriodicalId":9665,"journal":{"name":"Cell stem cell","volume":"33 1","pages":""},"PeriodicalIF":23.9,"publicationDate":"2024-05-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140942880","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}
Cell stem cellPub Date : 2024-05-15DOI: 10.1016/j.stem.2024.04.020
Paul V. Dellorusso, Melissa A. Proven, Fernando J. Calero-Nieto, Xiaonan Wang, Carl A. Mitchell, Felix Hartmann, Meelad Amouzgar, Patricia Favaro, Andrew DeVilbiss, James W. Swann, Theodore T. Ho, Zhiyu Zhao, Sean C. Bendall, Sean Morrison, Berthold Göttgens, Emmanuelle Passegué
{"title":"Autophagy counters inflammation-driven glycolytic impairment in aging hematopoietic stem cells","authors":"Paul V. Dellorusso, Melissa A. Proven, Fernando J. Calero-Nieto, Xiaonan Wang, Carl A. Mitchell, Felix Hartmann, Meelad Amouzgar, Patricia Favaro, Andrew DeVilbiss, James W. Swann, Theodore T. Ho, Zhiyu Zhao, Sean C. Bendall, Sean Morrison, Berthold Göttgens, Emmanuelle Passegué","doi":"10.1016/j.stem.2024.04.020","DOIUrl":"https://doi.org/10.1016/j.stem.2024.04.020","url":null,"abstract":"<p>Autophagy is central to the benefits of longevity signaling programs and to hematopoietic stem cell (HSC) response to nutrient stress. With age, a subset of HSCs increases autophagy flux and preserves regenerative capacity, but the signals triggering autophagy and maintaining the functionality of autophagy-activated old HSCs (oHSCs) remain unknown. Here, we demonstrate that autophagy is an adaptive cytoprotective response to chronic inflammation in the aging murine bone marrow (BM) niche. We find that inflammation impairs glucose uptake and suppresses glycolysis in oHSCs through Socs3-mediated inhibition of AKT/FoxO-dependent signaling, with inflammation-mediated autophagy engagement preserving functional quiescence by enabling metabolic adaptation to glycolytic impairment. Moreover, we show that transient autophagy induction via a short-term fasting/refeeding paradigm normalizes glycolytic flux and significantly boosts oHSC regenerative potential. Our results identify inflammation-driven glucose hypometabolism as a key driver of HSC dysfunction with age and establish autophagy as a targetable node to reset oHSC regenerative capacity.</p>","PeriodicalId":9665,"journal":{"name":"Cell stem cell","volume":"192 1","pages":""},"PeriodicalIF":23.9,"publicationDate":"2024-05-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140942948","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}
Cell stem cellPub Date : 2024-05-15DOI: 10.1016/j.stem.2024.04.018
Tengku Ibrahim Maulana, Claudia Teufel, Madalena Cipriano, Julia Roosz, Lisa Lazarevski, Francijna E. van den Hil, Lukas Scheller, Valeria Orlova, André Koch, Michael Hudecek, Miriam Alb, Peter Loskill
{"title":"Breast cancer-on-chip for patient-specific efficacy and safety testing of CAR-T cells","authors":"Tengku Ibrahim Maulana, Claudia Teufel, Madalena Cipriano, Julia Roosz, Lisa Lazarevski, Francijna E. van den Hil, Lukas Scheller, Valeria Orlova, André Koch, Michael Hudecek, Miriam Alb, Peter Loskill","doi":"10.1016/j.stem.2024.04.018","DOIUrl":"https://doi.org/10.1016/j.stem.2024.04.018","url":null,"abstract":"<p>Physiologically relevant human models that recapitulate the challenges of solid tumors and the tumor microenvironment (TME) are highly desired in the chimeric antigen receptor (CAR)-T cell field. We developed a breast cancer-on-chip model with an integrated endothelial barrier that enables the transmigration of perfused immune cells, their infiltration into the tumor, and concomitant monitoring of cytokine release during perfused culture over a period of up to 8 days. Here, we exemplified its use for investigating CAR-T cell efficacy and the ability to control the immune reaction with a pharmacological on/off switch. Additionally, we integrated primary breast cancer organoids to study patient-specific CAR-T cell efficacy. The modular architecture of our tumor-on-chip paves the way for studying the role of other cell types in the TME and thus provides the potential for broad application in bench-to-bedside translation as well as acceleration of the preclinical development of CAR-T cell products.</p>","PeriodicalId":9665,"journal":{"name":"Cell stem cell","volume":"47 1","pages":""},"PeriodicalIF":23.9,"publicationDate":"2024-05-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140942766","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}
Cell stem cellPub Date : 2024-05-10DOI: 10.1016/j.stem.2024.04.015
Pratik N.P. Singh, Wei Gu, Shariq Madha, Allen W. Lynch, Paloma Cejas, Ruiyang He, Swarnabh Bhattacharya, Miguel Muñoz Gomez, Matthew G. Oser, Myles Brown, Henry W. Long, Clifford A. Meyer, Qiao Zhou, Ramesh A. Shivdasani
{"title":"Transcription factor dynamics, oscillation, and functions in human enteroendocrine cell differentiation","authors":"Pratik N.P. Singh, Wei Gu, Shariq Madha, Allen W. Lynch, Paloma Cejas, Ruiyang He, Swarnabh Bhattacharya, Miguel Muñoz Gomez, Matthew G. Oser, Myles Brown, Henry W. Long, Clifford A. Meyer, Qiao Zhou, Ramesh A. Shivdasani","doi":"10.1016/j.stem.2024.04.015","DOIUrl":"https://doi.org/10.1016/j.stem.2024.04.015","url":null,"abstract":"<p>Enteroendocrine cells (EECs) secrete serotonin (enterochromaffin [EC] cells) or specific peptide hormones (non-EC cells) that serve vital metabolic functions. The basis for terminal EEC diversity remains obscure. By forcing activity of the transcription factor (TF) NEUROG3 in 2D cultures of human intestinal stem cells, we replicated physiologic EEC differentiation and examined transcriptional and <em>cis</em>-regulatory dynamics that culminate in discrete cell types. Abundant EEC precursors expressed stage-specific genes and TFs. Before expressing pre-terminal NEUROD1, post-mitotic precursors oscillated between transcriptionally distinct <em>ASCL1</em><sup><em>+</em></sup> and <em>HES6</em><sup><em>hi</em></sup> cell states. Loss of either factor accelerated EEC differentiation substantially and disrupted EEC individuality; ASCL1 or NEUROD1 deficiency had opposing consequences on EC and non-EC cell features. These TFs mainly bind <em>cis</em>-elements that are accessible in undifferentiated stem cells, and they tailor subsequent expression of TF combinations that underlie discrete EEC identities. Thus, early TF oscillations retard EEC maturation to enable accurate diversity within a medically important cell lineage.</p>","PeriodicalId":9665,"journal":{"name":"Cell stem cell","volume":"15 1","pages":""},"PeriodicalIF":23.9,"publicationDate":"2024-05-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140903336","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}
Cell stem cellPub Date : 2024-05-10DOI: 10.1016/j.stem.2024.04.016
Mahliyah Adkins-Threats, Sumimasa Arimura, Yang-Zhe Huang, Margarita Divenko, Sarah To, Heather Mao, Yongji Zeng, Jenie Y. Hwang, Joseph R. Burclaff, Shilpa Jain, Jason C. Mills
{"title":"Metabolic regulator ERRγ governs gastric stem cell differentiation into acid-secreting parietal cells","authors":"Mahliyah Adkins-Threats, Sumimasa Arimura, Yang-Zhe Huang, Margarita Divenko, Sarah To, Heather Mao, Yongji Zeng, Jenie Y. Hwang, Joseph R. Burclaff, Shilpa Jain, Jason C. Mills","doi":"10.1016/j.stem.2024.04.016","DOIUrl":"https://doi.org/10.1016/j.stem.2024.04.016","url":null,"abstract":"<p>Parietal cells (PCs) produce gastric acid to kill pathogens and aid digestion. Dysregulated PC census is common in disease, yet how PCs differentiate is unclear. Here, we identify the PC progenitors arising from isthmal stem cells, using mouse models and human gastric cells, and show that they preferentially express cell-metabolism regulator and orphan nuclear receptor Estrogen-related receptor gamma (<em>Esrrg</em>, encoding ERRγ). <em>Esrrg</em> expression facilitated the tracking of stepwise molecular, cellular, and ultrastructural stages of PC differentiation. <em>Esrrg</em><sup><em>P2ACreERT2</em></sup> lineage tracing revealed that <em>Esrrg</em> expression commits progenitors to differentiate into mature PCs. scRNA-seq indicated the earliest <em>Esrrg</em>+ PC progenitors preferentially express SMAD4 and SP1 transcriptional targets and the GTPases regulating acid-secretion signal transduction. As progenitors matured, ERRγ-dependent metabolic transcripts predominated. Organoid and mouse studies validated the requirement of ERRγ for PC differentiation. Our work chronicles stem cell differentiation along a single lineage <em>in vivo</em> and suggests ERRγ as a therapeutic target for PC-related disorders.</p>","PeriodicalId":9665,"journal":{"name":"Cell stem cell","volume":"15 1","pages":""},"PeriodicalIF":23.9,"publicationDate":"2024-05-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140903341","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}
Cell stem cellPub Date : 2024-05-08DOI: 10.1016/j.stem.2024.04.012
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
{"title":"Activating innate immune responses repolarizes hPSC-derived CAR macrophages to improve anti-tumor activity","authors":"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","doi":"10.1016/j.stem.2024.04.012","DOIUrl":"https://doi.org/10.1016/j.stem.2024.04.012","url":null,"abstract":"<p>Generation of chimeric antigen receptor macrophages (CAR-Ms) from human pluripotent stem cells (hPSCs) offers new prospects for cancer immunotherapy but is currently challenged by low differentiation efficiency and limited function. Here, we develop a highly efficient monolayer-based system that can produce around 6,000 macrophages from a single hPSC within 3 weeks. Based on CAR structure screening, we generate hPSC-CAR-Ms with stable CAR expression and potent tumoricidal activity <em>in vitro</em>. To overcome the loss of tumoricidal activity of hPSC-CAR-Ms <em>in vivo</em>, we use interferon-γ and monophosphoryl lipid A to activate an innate immune response that repolarizes the hPSC-CAR-Ms to tumoricidal macrophages. Moreover, through combined activation of T cells by hPSC-CAR-Ms, we demonstrate that activating a collaborative innate-adaptive immune response can further enhance the anti-tumor effect of hPSC-CAR-Ms <em>in vivo</em>. Collectively, our study provides feasible methodologies that significantly improve the production and function of hPSC-CAR-Ms to support their translation into clinical applications.</p>","PeriodicalId":9665,"journal":{"name":"Cell stem cell","volume":"86 1","pages":""},"PeriodicalIF":23.9,"publicationDate":"2024-05-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140890135","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}
Cell stem cellPub Date : 2024-05-07DOI: 10.1016/j.stem.2024.04.014
Catarina Martins-Costa, Andrea Wiegers, Vincent A. Pham, Jaydeep Sidhaye, Balint Doleschall, Maria Novatchkova, Thomas Lendl, Marielle Piber, Angela Peer, Paul Möseneder, Marlene Stuempflen, Siu Yu A. Chow, Rainer Seidl, Daniela Prayer, Romana Höftberger, Gregor Kasprian, Yoshiho Ikeuchi, Nina S. Corsini, Jürgen A. Knoblich
{"title":"ARID1B controls transcriptional programs of axon projection in an organoid model of the human corpus callosum","authors":"Catarina Martins-Costa, Andrea Wiegers, Vincent A. Pham, Jaydeep Sidhaye, Balint Doleschall, Maria Novatchkova, Thomas Lendl, Marielle Piber, Angela Peer, Paul Möseneder, Marlene Stuempflen, Siu Yu A. Chow, Rainer Seidl, Daniela Prayer, Romana Höftberger, Gregor Kasprian, Yoshiho Ikeuchi, Nina S. Corsini, Jürgen A. Knoblich","doi":"10.1016/j.stem.2024.04.014","DOIUrl":"https://doi.org/10.1016/j.stem.2024.04.014","url":null,"abstract":"<p>Mutations in <em>ARID1B</em>, a member of the mSWI/SNF complex, cause severe neurodevelopmental phenotypes with elusive mechanisms in humans. The most common structural abnormality in the brain of ARID1B patients is agenesis of the corpus callosum (ACC), characterized by the absence of an interhemispheric white matter tract that connects distant cortical regions. Here, we find that neurons expressing SATB2, a determinant of callosal projection neuron (CPN) identity, show impaired maturation in <em>ARID1B</em><sup><em>+/−</em></sup> neural organoids. Molecularly, a reduction in chromatin accessibility of genomic regions targeted by TCF-like, NFI-like, and ARID-like transcription factors drives the differential expression of genes required for corpus callosum (CC) development. Through an <em>in vitro</em> model of the CC tract, we demonstrate that this transcriptional dysregulation impairs the formation of long-range axonal projections, causing structural underconnectivity. Our study uncovers new functions of the mSWI/SNF during human corticogenesis, identifying cell-autonomous axonogenesis defects in SATB2<sup>+</sup> neurons as a cause of ACC in ARID1B patients.</p>","PeriodicalId":9665,"journal":{"name":"Cell stem cell","volume":"23 1","pages":""},"PeriodicalIF":23.9,"publicationDate":"2024-05-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140846070","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}
求助内容：
应助结果提醒方式：
京公网安备 11010802042870号
