Cell stem cellPub Date : 2024-09-24DOI: 10.1016/j.stem.2024.09.004
Dylan Siriwardena, Clara Munger, Christopher Penfold, Timo N. Kohler, Antonia Weberling, Madeleine Linneberg-Agerholm, Erin Slatery, Anna L. Ellermann, Sophie Bergmann, Stephen J. Clark, Thomas M. Rawlings, Joshua M. Brickman, Wolf Reik, Jan J. Brosens, Magdalena Zernicka-Goetz, Erika Sasaki, Rüdiger Behr, Florian Hollfelder, Thorsten E. Boroviak
{"title":"Marmoset and human trophoblast stem cells differ in signaling requirements and recapitulate divergent modes of trophoblast invasion","authors":"Dylan Siriwardena, Clara Munger, Christopher Penfold, Timo N. Kohler, Antonia Weberling, Madeleine Linneberg-Agerholm, Erin Slatery, Anna L. Ellermann, Sophie Bergmann, Stephen J. Clark, Thomas M. Rawlings, Joshua M. Brickman, Wolf Reik, Jan J. Brosens, Magdalena Zernicka-Goetz, Erika Sasaki, Rüdiger Behr, Florian Hollfelder, Thorsten E. Boroviak","doi":"10.1016/j.stem.2024.09.004","DOIUrl":"https://doi.org/10.1016/j.stem.2024.09.004","url":null,"abstract":"Early human trophoblast development has remained elusive due to the inaccessibility of the early conceptus. Non-human primate models recapitulate many features of human development and allow access to early postimplantation stages. Here, we tracked the pre- to postimplantation transition of the trophoblast lineage in superficially implanting marmoset embryos <em>in vivo</em>. We differentiated marmoset naive pluripotent stem cells into trophoblast stem cells (TSCs), which exhibited trophoblast-specific transcriptome, methylome, differentiation potential, and long-term self-renewal. Notably, human TSC culture conditions failed to support marmoset TSC derivation, instead inducing an extraembryonic mesoderm-like fate in marmoset cells. We show that combined MEK, TGF-β/NODAL, and histone deacetylase inhibition stabilizes a periimplantation trophoblast-like identity in marmoset TSCs. By contrast, these conditions differentiated human TSCs toward extravillous trophoblasts. Our work presents a paradigm to harness the evolutionary divergence in implantation strategies to elucidate human trophoblast development and invasion.","PeriodicalId":9665,"journal":{"name":"Cell stem cell","volume":"5 1","pages":""},"PeriodicalIF":23.9,"publicationDate":"2024-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142313579","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 : 2024-09-20DOI: 10.1016/j.stem.2024.08.010
Ahmad Al Shihabi, Peyton J. Tebon, Huyen Thi Lam Nguyen, Jomjit Chantharasamee, Sara Sartini, Ardalan Davarifar, Alexandra Y. Jensen, Miranda Diaz-Infante, Hannah Cox, Alfredo Enrique Gonzalez, Summer Norris, Jantzen Sperry, Jonathan Nakashima, Nasrin Tavanaie, Helena Winata, Sorel T. Fitz-Gibbon, Takafumi N. Yamaguchi, Jae H. Jeong, Sarah Dry, Arun S. Singh, Alice Soragni
{"title":"The landscape of drug sensitivity and resistance in sarcoma","authors":"Ahmad Al Shihabi, Peyton J. Tebon, Huyen Thi Lam Nguyen, Jomjit Chantharasamee, Sara Sartini, Ardalan Davarifar, Alexandra Y. Jensen, Miranda Diaz-Infante, Hannah Cox, Alfredo Enrique Gonzalez, Summer Norris, Jantzen Sperry, Jonathan Nakashima, Nasrin Tavanaie, Helena Winata, Sorel T. Fitz-Gibbon, Takafumi N. Yamaguchi, Jae H. Jeong, Sarah Dry, Arun S. Singh, Alice Soragni","doi":"10.1016/j.stem.2024.08.010","DOIUrl":"https://doi.org/10.1016/j.stem.2024.08.010","url":null,"abstract":"<p>Sarcomas are rare malignancies with over 100 distinct histological subtypes. Their rarity and heterogeneity pose significant challenges to identifying effective therapies, and approved regimens show varied responses. Novel, personalized approaches to therapy are needed to improve patient outcomes. Patient-derived tumor organoids (PDTOs) model tumor behavior across an array of malignancies. We leverage PDTOs to characterize the landscape of drug resistance and sensitivity in sarcoma, collecting 194 specimens from 126 patients spanning 24 distinct sarcoma subtypes. Our high-throughput organoid screening pipeline tested single agents and combinations, with results available within a week from surgery. Drug sensitivity correlated with clinical features such as tumor subtype, treatment history, and disease trajectory. PDTO screening can facilitate optimal drug selection and mirror patient outcomes in sarcoma. We could identify at least one FDA-approved or NCCN-recommended effective regimen for 59% of the specimens, demonstrating the potential of our pipeline to provide actionable treatment information.</p>","PeriodicalId":9665,"journal":{"name":"Cell stem cell","volume":"5 1","pages":""},"PeriodicalIF":23.9,"publicationDate":"2024-09-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142246740","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 : 2024-09-12DOI: 10.1016/j.stem.2024.08.009
Holly M. Poling, Nambirajan Sundaram, Garrett W. Fisher, Akaljot Singh, Joseph R. Shiley, Kalpana Nattamai, Vinothini Govindarajah, Alexander R. Cortez, Maksym O. Krutko, Séverine Ménoret, Ignacio Anegon, Magdalena Kasendra, James M. Wells, Christopher N. Mayhew, Takanori Takebe, Maxime M. Mahe, Michael A. Helmrath
{"title":"Human pluripotent stem cell-derived organoids repair damaged bowel in vivo","authors":"Holly M. Poling, Nambirajan Sundaram, Garrett W. Fisher, Akaljot Singh, Joseph R. Shiley, Kalpana Nattamai, Vinothini Govindarajah, Alexander R. Cortez, Maksym O. Krutko, Séverine Ménoret, Ignacio Anegon, Magdalena Kasendra, James M. Wells, Christopher N. Mayhew, Takanori Takebe, Maxime M. Mahe, Michael A. Helmrath","doi":"10.1016/j.stem.2024.08.009","DOIUrl":"https://doi.org/10.1016/j.stem.2024.08.009","url":null,"abstract":"<p>The fundamental goal of tissue engineering is to functionally restore or improve damaged tissues or organs. Here we address this in the small bowel using an <em>in vivo</em> xenograft preclinical acute damage model. We investigated the therapeutic capacity of human intestinal organoids (HIOs), which are generated from human pluripotent stem cells (hPSCs), to repair damaged small bowel. We hypothesized that the HIO’s cellular complexity would allow it to sustain transmural engraftment. To test this, we developed a rodent injury model where, through luminal delivery, we demonstrated that fragmented HIOs engraft, proliferate, and persist throughout the bowel following repair. Not only was restitution of the mucosal layer observed, but significant incorporation was also observed in the muscularis and vascular endothelium. Further analysis characterized sustained cell type presence within the regenerated regions, retention of proximal regionalization, and the neo-epithelia’s function. These findings demonstrate the therapeutic importance of mesenchyme for intestinal injury repair.</p>","PeriodicalId":9665,"journal":{"name":"Cell stem cell","volume":"63 1","pages":""},"PeriodicalIF":23.9,"publicationDate":"2024-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142171402","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 : 2024-09-10DOI: 10.1016/j.stem.2024.08.008
Jiuru Li, Alexandra Wiesinger, Lianne Fokkert, Priscilla Bakker, Dylan K. de Vries, Anke J. Tijsen, Yigal M. Pinto, Arie O. Verkerk, Vincent M. Christoffels, Gerard J.J. Boink, Harsha D. Devalla
{"title":"Modeling the atrioventricular conduction axis using human pluripotent stem cell-derived cardiac assembloids","authors":"Jiuru Li, Alexandra Wiesinger, Lianne Fokkert, Priscilla Bakker, Dylan K. de Vries, Anke J. Tijsen, Yigal M. Pinto, Arie O. Verkerk, Vincent M. Christoffels, Gerard J.J. Boink, Harsha D. Devalla","doi":"10.1016/j.stem.2024.08.008","DOIUrl":"https://doi.org/10.1016/j.stem.2024.08.008","url":null,"abstract":"<p>The atrioventricular (AV) conduction axis provides electrical continuity between the atrial and ventricular chambers. The “nodal” cardiomyocytes populating this region (AV canal in the embryo, AV node from fetal stages onward) propagate impulses slowly, ensuring sequential contraction of the chambers. Dysfunction of AV nodal tissue causes severe disturbances in rhythm and contraction, and human models that capture its salient features are limited. Here, we report an approach for the reproducible generation of AV canal cardiomyocytes (AVCMs) with <em>in vivo</em>-like gene expression and electrophysiological profiles. We created the so-called “assembloids” composed of atrial, AVCM, and ventricular spheroids, which effectively recapitulated unidirectional conduction and the “fast-slow-fast” activation pattern typical for the vertebrate heart. We utilized these systems to reveal intracellular calcium mishandling as the basis of <em>LMNA</em>-associated AV conduction block. In sum, our study introduces novel cell differentiation and tissue construction strategies to facilitate the study of complex disorders affecting heart rhythm.</p>","PeriodicalId":9665,"journal":{"name":"Cell stem cell","volume":"5 1","pages":""},"PeriodicalIF":23.9,"publicationDate":"2024-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142161041","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 : 2024-09-05DOI: 10.1016/j.stem.2024.08.003
Joseph Festa, Sophie Trefely
{"title":"Acetate to the rescue: Acetyl-CoA facilitates placental development","authors":"Joseph Festa, Sophie Trefely","doi":"10.1016/j.stem.2024.08.003","DOIUrl":"https://doi.org/10.1016/j.stem.2024.08.003","url":null,"abstract":"<p>While the placenta regulates nutritional exchange between mother and fetus, Yu et al. reveal that human placental development is itself nutrient-sensitive. They elucidate entwined metabolic and epigenetic transitions driving syncytialization and pinpoint a requirement for the metabolite acetyl-CoA, which is sensitive to glucose metabolism.</p>","PeriodicalId":9665,"journal":{"name":"Cell stem cell","volume":"4 1","pages":""},"PeriodicalIF":23.9,"publicationDate":"2024-09-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142138215","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 : 2024-09-05DOI: 10.1016/j.stem.2024.07.005
Fuguo Liu, Rizwan Romee
{"title":"A one-way street recognition approach to mediate allogeneic immune cell therapies","authors":"Fuguo Liu, Rizwan Romee","doi":"10.1016/j.stem.2024.07.005","DOIUrl":"https://doi.org/10.1016/j.stem.2024.07.005","url":null,"abstract":"<p>CD54 and CD58 are adhesion proteins that mediate efficient immune synapse formation. Hammer et al. now show that the abrogation of these molecules in T and NK cells prevents their immune rejection while maintaining their effector function. These findings should significantly help advance our efforts to generate “off-the-shelf” allogeneic products.</p>","PeriodicalId":9665,"journal":{"name":"Cell stem cell","volume":"14 1","pages":""},"PeriodicalIF":23.9,"publicationDate":"2024-09-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142138213","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 : 2024-09-03DOI: 10.1016/j.stem.2024.08.005
Zan Lv, Zixin Liu, Kuo Liu, Xiuyu Lin, Wenjuan Pu, Yan Li, Huan Zhao, Ying Xi, Pengfei Sui, Andrew E. Vaughan, Astrid Gillich, Bin Zhou
{"title":"Alveolar regeneration by airway secretory-cell-derived p63+ progenitors","authors":"Zan Lv, Zixin Liu, Kuo Liu, Xiuyu Lin, Wenjuan Pu, Yan Li, Huan Zhao, Ying Xi, Pengfei Sui, Andrew E. Vaughan, Astrid Gillich, Bin Zhou","doi":"10.1016/j.stem.2024.08.005","DOIUrl":"https://doi.org/10.1016/j.stem.2024.08.005","url":null,"abstract":"<p>Lung injury activates epithelial stem or progenitor cells for alveolar repair and regeneration. Unraveling the origin and fate of injury-induced progenitors is crucial for elucidating lung repair mechanisms. Here, we report that p63-expressing progenitors emerge upon bleomycin-induced mouse lung injury. Single-cell RNA sequencing and clonal analysis reveal that these p63<sup>+</sup> progenitors proliferate rapidly and differentiate into alveolar type 1 and type 2 cells through different trajectories. Dual recombinase-mediated sequential genetic-lineage tracing demonstrates that p63<sup>+</sup> progenitors originate from airway secretory cells and subsequently generate alveolar cells. Functionally, p63 activation is essential for efficient alveolar regeneration from secretory cells post injury. Our study identifies secretory-cell-derived p63<sup>+</sup> progenitors as contributors to alveolar repair, suggesting a potential therapeutic avenue for lung regeneration following injury.</p>","PeriodicalId":9665,"journal":{"name":"Cell stem cell","volume":"48 1","pages":""},"PeriodicalIF":23.9,"publicationDate":"2024-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142123910","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 : 2024-09-03DOI: 10.1016/j.stem.2024.08.007
Liuliu Yang, Yuling Han, Tuo Zhang, Xue Dong, Jian Ge, Aadita Roy, Jiajun Zhu, Tiankun Lu, J. Jeya Vandana, Neranjan de Silva, Catherine C. Robertson, Jenny Z. Xiang, Chendong Pan, Yanjie Sun, Jianwen Que, Todd Evans, Chengyang Liu, Wei Wang, Ali Naji, Stephen C.J. Parker, Shuibing Chen
{"title":"Human vascularized macrophage-islet organoids to model immune-mediated pancreatic β cell pyroptosis upon viral infection","authors":"Liuliu Yang, Yuling Han, Tuo Zhang, Xue Dong, Jian Ge, Aadita Roy, Jiajun Zhu, Tiankun Lu, J. Jeya Vandana, Neranjan de Silva, Catherine C. Robertson, Jenny Z. Xiang, Chendong Pan, Yanjie Sun, Jianwen Que, Todd Evans, Chengyang Liu, Wei Wang, Ali Naji, Stephen C.J. Parker, Shuibing Chen","doi":"10.1016/j.stem.2024.08.007","DOIUrl":"https://doi.org/10.1016/j.stem.2024.08.007","url":null,"abstract":"<p>There is a paucity of human models to study immune-mediated host damage. Here, we utilized the GeoMx spatial multi-omics platform to analyze immune cell changes in COVID-19 pancreatic autopsy samples, revealing an accumulation of proinflammatory macrophages. Single-cell RNA sequencing (scRNA-seq) analysis of human islets exposed to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) or coxsackievirus B4 (CVB4) viruses identified activation of proinflammatory macrophages and β cell pyroptosis. To distinguish viral versus proinflammatory-macrophage-mediated β cell pyroptosis, we developed human pluripotent stem cell (hPSC)-derived vascularized macrophage-islet (VMI) organoids. VMI organoids exhibited enhanced marker expression and function in both β cells and endothelial cells compared with separately cultured cells. Notably, proinflammatory macrophages within VMI organoids induced β cell pyroptosis. Mechanistic investigations highlighted TNFSF12-TNFRSF12A involvement in proinflammatory-macrophage-mediated β cell pyroptosis. This study established hPSC-derived VMI organoids as a valuable tool for studying immune-cell-mediated host damage and uncovered the mechanism of β cell damage during viral exposure.</p>","PeriodicalId":9665,"journal":{"name":"Cell stem cell","volume":"149 1","pages":""},"PeriodicalIF":23.9,"publicationDate":"2024-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142123926","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 : 2024-09-03DOI: 10.1016/j.stem.2024.08.006
Dongchang Zhao, Visweswaran Ravikumar, Tyler J. Leach, Daniel Kraushaar, Emma Lauder, Lu Li, Yaping Sun, Katherine Oravecz-Wilson, Evan T. Keller, Fengju Chen, Laure Maneix, Robert R. Jenq, Robert Britton, Katherine Y. King, Ana E. Santibanez, Chad J. Creighton, Arvind Rao, Pavan Reddy
{"title":"Inflammation-induced epigenetic imprinting regulates intestinal stem cells","authors":"Dongchang Zhao, Visweswaran Ravikumar, Tyler J. Leach, Daniel Kraushaar, Emma Lauder, Lu Li, Yaping Sun, Katherine Oravecz-Wilson, Evan T. Keller, Fengju Chen, Laure Maneix, Robert R. Jenq, Robert Britton, Katherine Y. King, Ana E. Santibanez, Chad J. Creighton, Arvind Rao, Pavan Reddy","doi":"10.1016/j.stem.2024.08.006","DOIUrl":"https://doi.org/10.1016/j.stem.2024.08.006","url":null,"abstract":"<p>It remains unknown whether and how intestinal stem cells (ISCs) adapt to inflammatory exposure and whether the adaptation leaves scars that will affect their subsequent regeneration. We investigated the consequences of inflammation on Lgr5<sup>+</sup> ISCs in well-defined clinically relevant models of acute gastrointestinal graft-versus-host disease (GI GVHD). Utilizing single-cell transcriptomics, as well as organoid, metabolic, epigenomic, and <em>in vivo</em> models, we found that Lgr5<sup>+</sup> ISCs undergo metabolic changes that lead to the accumulation of succinate, which reprograms their epigenome. These changes reduced the ability of ISCs to differentiate and regenerate <em>ex vivo</em> in serial organoid cultures and also <em>in vivo</em> following serial transplantation. Furthermore, ISCs demonstrated a reduced capacity for <em>in vivo</em> regeneration despite resolution of the initial inflammatory exposure, demonstrating the persistence of the maladaptive impact induced by the inflammatory encounter. Thus, inflammation imprints the epigenome of ISCs in a manner that persists and affects their sensitivity to adapt to future stress or challenges.</p>","PeriodicalId":9665,"journal":{"name":"Cell stem cell","volume":"16 1","pages":""},"PeriodicalIF":23.9,"publicationDate":"2024-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142123911","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 : 2024-08-28DOI: 10.1016/j.stem.2024.08.004
{"title":"Generation of human region-specific brain organoids with medullary spinal trigeminal nuclei","authors":"","doi":"10.1016/j.stem.2024.08.004","DOIUrl":"https://doi.org/10.1016/j.stem.2024.08.004","url":null,"abstract":"Brain organoids with nucleus-specific identities provide unique platforms for studying human brain development and diseases at a finer resolution. Des…","PeriodicalId":9665,"journal":{"name":"Cell stem cell","volume":"28 1","pages":""},"PeriodicalIF":23.9,"publicationDate":"2024-08-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142090517","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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