{"title":"IGF2BP1 restricts the induction of human primordial germ cell fate in an m6A-dependent manner","authors":"Jin Zhang, Yashi Gu, Lingling Tong, Boshi Feng, Shenghua Dong, Qizhe Shao, Yanxi Chen, Huanchang Tu, Ziqi Wang, Yueqi Wang, Xiang Li, Honglin Yu, Ziying Lin, Xueting Wang, Zhenfu Li, Zhipeng Ai, Yangquan Xiang, Zhiwei Jiang, Zixin Jin, Zhengyi Li, Di Chen","doi":"10.1016/j.stem.2025.05.001","DOIUrl":"https://doi.org/10.1016/j.stem.2025.05.001","url":null,"abstract":"Primordial germ cells (PGCs) are specified early during embryogenesis and establish the germ cell lineage for transmitting genetic and epigenetic information from parents to offspring. However, whether <em>N</em><sup>6</sup>-methyladenosine (m<sup>6</sup>A)-mediated epigenetic regulation is involved in the specification of PGCs remains elusive. In this study, we report that a knockout of m<sup>6</sup>A writers or overexpression of m<sup>6</sup>A erasers leads to an increased percentage of human PGC-like cells (hPGCLCs) induced from embryonic stem cells using a 3D aggregate system. We identify the m<sup>6</sup>A reader IGF2BP1 as the key factor for restricting hPGCLC fate induction by stabilizing OTX2 mRNAs in an m<sup>6</sup>A-dependent manner. In turn, OTX2 protein suppresses the function of TFAP2C via histone variant MacroH2A.1 during germ cell lineage specification. We also observe a similar role of Igf2bp1 in zebrafish in the induction of PGC fate. In summary, we identify an m<sup>6</sup>A-IGF2BP1-OTX2-MacroH2A.1-TFAP2C signaling axis that restricts the specification of human germ cell fate.","PeriodicalId":9665,"journal":{"name":"Cell stem cell","volume":"14 1","pages":""},"PeriodicalIF":23.9,"publicationDate":"2025-05-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144145860","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 : 2025-05-22DOI: 10.1016/j.stem.2025.04.012
Maria Sirenko, Soobeom Lee, Zhengxi Sun, Ronan Chaligne, Sanam Loghavi, Georgios Asimomitis, Charlotte K. Brierley, Elsa Bernard, Sheng F. Cai, Robert M. Myers, Bettina Nadorp, Junya Sango, Morgan Lallo, Max F. Levine, Dylan Domenico, Juan E. Arango Ossa, Juan S. Medina-Martinez, Kamal Menghrajani, Audrey Lasry, Alice S. Mims, Elli Papaemmanuil
{"title":"Deconvoluting clonal and cellular architecture in IDH-mutant acute myeloid leukemia","authors":"Maria Sirenko, Soobeom Lee, Zhengxi Sun, Ronan Chaligne, Sanam Loghavi, Georgios Asimomitis, Charlotte K. Brierley, Elsa Bernard, Sheng F. Cai, Robert M. Myers, Bettina Nadorp, Junya Sango, Morgan Lallo, Max F. Levine, Dylan Domenico, Juan E. Arango Ossa, Juan S. Medina-Martinez, Kamal Menghrajani, Audrey Lasry, Alice S. Mims, Elli Papaemmanuil","doi":"10.1016/j.stem.2025.04.012","DOIUrl":"https://doi.org/10.1016/j.stem.2025.04.012","url":null,"abstract":"Isocitrate dehydrogenase 1/2 (<em>IDH</em>) mutations are early initiating events in acute myeloid leukemia (AML). The complex clonal architecture and cellular heterogeneity in <em>IDH-</em>mutant AML underlies the heterogeneous clinical presentation and outcomes. Integrating single-cell genotyping and transcriptomics, we demonstrate a stem-like and inflammatory phenotype of <em>IDH</em>-mutant AML and identify clone-specific programs associated with <em>NPM1</em>, <em>NRAS</em>, and <em>SRSF2</em> co-mutations. Furthermore, these clones had distinct responses to treatment with combination IDH inhibitors and chemotherapy, including elimination, reconstitution of myeloid differentiation, or retention within progenitor populations. At relapse after IDH inhibitor monotherapy, we identify upregulated stemness, inflammation, mitochondrial metabolism, and anti-apoptotic factors, as well as downregulated major histocompatibility complex (MHC) class II antigen presentation. At the pre-leukemic stage, we observe upregulation of <em>IDH2</em>-associated pathways, including inflammation. We deliver a detailed phenotyping of <em>IDH</em>-mutant AML and a framework for dissecting contributions of recurrently mutated genes in AML at diagnosis and following therapy, with implications for precision medicine.","PeriodicalId":9665,"journal":{"name":"Cell stem cell","volume":"15 1","pages":""},"PeriodicalIF":23.9,"publicationDate":"2025-05-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144114404","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 : 2025-05-21DOI: 10.1016/j.stem.2025.04.010
Wei-Chien Yuan, Andrew S. Earl, Sai Ma, Karel Alcedo, Jacquelyn O. Russell, Fabiana M. Duarte, Yen-Ting Chu, Pei-Chi Chang, Hsin-Yi Chen, Hsin-Hui Chi, Qian Zhu, Alejo E. Rodriguez-Fraticelli, Sachin H. Patel, Yu-Ru Lee, Jason D. Buenrostro, Fernando D. Camargo
{"title":"HBO1 functions as an epigenetic barrier to hepatocyte plasticity and reprogramming during liver injury","authors":"Wei-Chien Yuan, Andrew S. Earl, Sai Ma, Karel Alcedo, Jacquelyn O. Russell, Fabiana M. Duarte, Yen-Ting Chu, Pei-Chi Chang, Hsin-Yi Chen, Hsin-Hui Chi, Qian Zhu, Alejo E. Rodriguez-Fraticelli, Sachin H. Patel, Yu-Ru Lee, Jason D. Buenrostro, Fernando D. Camargo","doi":"10.1016/j.stem.2025.04.010","DOIUrl":"https://doi.org/10.1016/j.stem.2025.04.010","url":null,"abstract":"Hepatocytes can reprogram into biliary epithelial cells (BECs) during liver injury, but the underlying epigenetic mechanisms remain poorly understood. Here, we define the chromatin dynamics of this process using single-cell ATAC-seq and identify YAP/TEAD activation as a key driver of chromatin remodeling. An <em>in vivo</em> CRISPR screen highlights the histone acetyltransferase HBO1 as a critical barrier to reprogramming. HBO1 is recruited by YAP to target loci, where it promotes histone H3 lysine 14 acetylation (H3K14ac) and engages the chromatin reader zinc-finger MYND-type containing 8 (ZMYND8) to suppress YAP/TEAD-driven transcription. Loss of HBO1 accelerates chromatin remodeling, enhances YAP binding, and enables a more complete hepatocyte-to-BEC transition. Our findings position HBO1 as an epigenetic brake that restrains YAP-mediated reprogramming, suggesting that targeting HBO1 may enhance hepatocyte plasticity for liver regeneration.","PeriodicalId":9665,"journal":{"name":"Cell stem cell","volume":"15 1","pages":""},"PeriodicalIF":23.9,"publicationDate":"2025-05-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144103992","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 : 2025-05-14DOI: 10.1016/j.stem.2025.04.011
Tao Luo, Cong Liu, Tao Cheng, Guo-Qin Zhao, Ying Huang, Jing-Yun Luan, Junyu Guo, Xiang Liu, Yi-Fan Wang, Yang Dong, Yu Xiao, Enhui He, Rui-Zhen Sun, Xiuyu Chen, Jiekai Chen, Jun Ma, Sean Megason, Junfeng Ji, Peng-Fei Xu
{"title":"Establishing dorsal-ventral patterning in human neural tube organoids with synthetic organizers","authors":"Tao Luo, Cong Liu, Tao Cheng, Guo-Qin Zhao, Ying Huang, Jing-Yun Luan, Junyu Guo, Xiang Liu, Yi-Fan Wang, Yang Dong, Yu Xiao, Enhui He, Rui-Zhen Sun, Xiuyu Chen, Jiekai Chen, Jun Ma, Sean Megason, Junfeng Ji, Peng-Fei Xu","doi":"10.1016/j.stem.2025.04.011","DOIUrl":"https://doi.org/10.1016/j.stem.2025.04.011","url":null,"abstract":"Precise dorsal-ventral (D-V) patterning of the neural tube (NT) is essential for the development and function of the central nervous system. However, existing models for studying NT D-V patterning and related human diseases remain inadequate. Here, we present organizers derived from pluripotent stem cell aggregate fusion (“ORDER”), a method that establishes opposing BMP and SHH gradients within neural ectodermal cell aggregates. Using this approach, we generated NT organoids with ordered D-V patterning from both zebrafish and human pluripotent stem cells (hPSCs). Single-cell transcriptomic analysis revealed that the synthetic human NT organoids (hNTOs) closely resemble the human embryonic spinal cord at Carnegie stage 12 (CS12) and exhibit greater similarity to human NT than to mouse models. Furthermore, using the hNTO model, we demonstrated the critical role of WNT signaling in regulating intermediate progenitors, modeled TCTN2-related D-V patterning defects, and identified a rescue strategy.","PeriodicalId":9665,"journal":{"name":"Cell stem cell","volume":"4 1","pages":""},"PeriodicalIF":23.9,"publicationDate":"2025-05-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143946269","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 : 2025-05-08DOI: 10.1016/j.stem.2025.04.008
Min Shi, Brittney Crouse, Nambirajan Sundaram, Naomi Pode Shakked, Konrad Thorner, Nathaniel M. King, Parna Dutta, Lioba Ester, Weitao Zhang, Vinothini Govindarajah, Raphael Kopan, Cristina Cebrian, Christopher N. Mayhew, Michael A. Helmrath, Joseph V. Bonventre, Kyle W. McCracken
{"title":"Integrating collecting systems in human kidney organoids through fusion of distal nephron to ureteric bud","authors":"Min Shi, Brittney Crouse, Nambirajan Sundaram, Naomi Pode Shakked, Konrad Thorner, Nathaniel M. King, Parna Dutta, Lioba Ester, Weitao Zhang, Vinothini Govindarajah, Raphael Kopan, Cristina Cebrian, Christopher N. Mayhew, Michael A. Helmrath, Joseph V. Bonventre, Kyle W. McCracken","doi":"10.1016/j.stem.2025.04.008","DOIUrl":"https://doi.org/10.1016/j.stem.2025.04.008","url":null,"abstract":"Kidneys maintain homeostasis through an array of parallel nephrons, which fuse during development to a system of collecting ducts (CDs), establishing the essential luminal pathway for excretion of metabolic waste. Human kidney organoids derived from pluripotent stem cells (human pluripotent stem cells [hPSCs]) generate nephrons that lack CDs and terminate as blind-ended tubules, limiting their functional potential. Here, we describe a developmentally inspired hPSC differentiation system that addresses this deficiency through assembly of induced nephrogenic mesenchyme with ureteric bud (UB) progenitors, leading to a CD network functionally integrated in kidney organoids through fusion with the distal tubule. The nephron fusion occurs stereotypically and is regulated by proximal-distal nephron patterning, which can be modulated through temporal manipulation of developmental pathways. This work provides a platform for interrogating the principles and mechanisms underlying nephron-UB fusion and a framework for engineering unobstructed nephrons with collecting systems, an important step toward <em>de novo</em> generation of functional kidney tissue.","PeriodicalId":9665,"journal":{"name":"Cell stem cell","volume":"187 6 1","pages":""},"PeriodicalIF":23.9,"publicationDate":"2025-05-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143920773","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}
{"title":"3D reconstruction of a human Carnegie stage 9 embryo provides a snapshot of early body plan formation","authors":"Yang Yuan, Xiaoyan Wang, Xiaodi Yan, Nannan He, Xiaojian Lu, Jingyu Yang, Xinwei Xie, Huiyao Yuan, Naixin Chen, Yinbo Liu, Hongan Ren, Runzhao Zhang, Lina Cui, Pengcheng Ren, Sirui Lin, Shuhan Cheng, Xiaolong Yang, Yifei Guo, Rong Li, Tianyi Yan, Leqian Yu","doi":"10.1016/j.stem.2025.04.007","DOIUrl":"https://doi.org/10.1016/j.stem.2025.04.007","url":null,"abstract":"The Carnegie stage 9 (CS9) embryo is a pivotal phase signifying the conclusion of gastrulation and the onset of early organogenesis, crucial for initiating major organ system development. Utilizing spatial transcriptomics, we analyzed an intact CS9 human embryo in a spatially detailed manner. Through the examination of 75 transverse cryosections, we digitally reconstructed a 3D model, allowing us to identify diverse cell types, including those from brain and spine regions, the primitive gut tube, distinct somite formation stages, somatic mesoderm, splanchnic mesoderm, etc. Notably, we observed two distinct trajectories of hindbrain development, pinpointed the isthmic organizer at the midbrain-hindbrain boundary, delineated the bi-layered structure of neuromesodermal progenitor (NMP) cells, and described the early aorta formation and primordial germ cells (PGCs) presence in the aorta-gonad-mesonephros (AGM) region. This study provides key insights into the transcriptomic and spatial intricacies shaping the human body plan.","PeriodicalId":9665,"journal":{"name":"Cell stem cell","volume":"35 1","pages":""},"PeriodicalIF":23.9,"publicationDate":"2025-05-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143920494","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 : 2025-05-01DOI: 10.1016/j.stem.2025.04.006
Soraya Scuderi, Tae-Yun Kang, Alexandre Jourdon, Alex Nelson, Liang Yang, Feinan Wu, George M. Anderson, Jessica Mariani, Livia Tomasini, Vivekananda Sarangi, Alexej Abyzov, Andre Levchenko, Flora M. Vaccarino
{"title":"Specification of human brain regions with orthogonal gradients of WNT and SHH in organoids reveals patterning variations across cell lines","authors":"Soraya Scuderi, Tae-Yun Kang, Alexandre Jourdon, Alex Nelson, Liang Yang, Feinan Wu, George M. Anderson, Jessica Mariani, Livia Tomasini, Vivekananda Sarangi, Alexej Abyzov, Andre Levchenko, Flora M. Vaccarino","doi":"10.1016/j.stem.2025.04.006","DOIUrl":"https://doi.org/10.1016/j.stem.2025.04.006","url":null,"abstract":"The repertoire of neurons and their progenitors depends on their location along the antero-posterior and dorso-ventral axes of the neural tube. To model these axes, we designed the Dual Orthogonal-Morphogen Assisted Patterning System (Duo-MAPS) diffusion device to expose spheres of induced pluripotent stem cells (iPSCs) to concomitant orthogonal gradients of a posteriorizing and a ventralizing morphogen, activating WNT and SHH signaling, respectively. Comparison with single-cell transcriptomes from the fetal human brain revealed that Duo-MAPS-patterned organoids generated an extensive diversity of neuronal lineages from the forebrain, midbrain, and hindbrain. WNT and SHH crosstalk translated into early patterns of gene expression programs associated with the generation of specific brain lineages with distinct functional networks. Human iPSC lines showed substantial interindividual and line-to-line variations in their response to morphogens, highlighting that genetic and epigenetic variations may influence regional specification. Morphogen gradients promise to be a key approach to model the brain in its entirety.","PeriodicalId":9665,"journal":{"name":"Cell stem cell","volume":"24 1","pages":""},"PeriodicalIF":23.9,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143893292","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 : 2025-05-01DOI: 10.1016/j.stem.2025.03.015
Riccardo Barrile, Magdalena Kasendra
{"title":"Shaping intestinal organoids: Engineering crypt curvature to guide stem cell niches","authors":"Riccardo Barrile, Magdalena Kasendra","doi":"10.1016/j.stem.2025.03.015","DOIUrl":"https://doi.org/10.1016/j.stem.2025.03.015","url":null,"abstract":"Yavitt et al.<span><span><sup>1</sup></span></span> introduce a photodegradable hydrogel platform to control crypt curvature in intestinal organoids, revealing how epithelial morphology directs Paneth cell localization. This innovative approach advances organoid engineering, providing a reproducible method to study stem cell niche interactions and model intestinal development and disease.","PeriodicalId":9665,"journal":{"name":"Cell stem cell","volume":"273 1","pages":""},"PeriodicalIF":23.9,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143893296","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 : 2025-05-01DOI: 10.1016/j.stem.2025.04.004
Timothy Chai, Julie Y. Chen, Kyle M. Loh
{"title":"Dopaminergic neurons entering the brain under the immunological cover of darkness","authors":"Timothy Chai, Julie Y. Chen, Kyle M. Loh","doi":"10.1016/j.stem.2025.04.004","DOIUrl":"https://doi.org/10.1016/j.stem.2025.04.004","url":null,"abstract":"The ability to transplant immunologically foreign cells into an animal without immune suppression would be transformative. Pavan et al. show that human pluripotent stem cell-derived dopaminergic neuron progenitors engineered to express eight immune-evasive proteins can engraft in humanized mice and a rat model of Parkinson’s disease without recourse to immune suppression.<span><span><sup>1</sup></span></span>","PeriodicalId":9665,"journal":{"name":"Cell stem cell","volume":"68 1","pages":""},"PeriodicalIF":23.9,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143893295","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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