Cell stem cellPub Date : 2025-04-03DOI: 10.1016/j.stem.2025.03.003
Nissim Benvenisty, Jonathan S. Draper, Paul J. Gokhale, Lyn Healy, Zoe Hewitt, Deborah Hursh, Adam Hodgson, Tenneille E. Ludwig, Nancy Mah, Sarah E. McClelland, Milena Mennecozzi, Florian T. Merkle, Joanne C. Mountford, Martin Pera, Alessandro Prigione, Tristan A. Rodriguez, Andrea Rossi, Foad J. Rouhani, Kourosh Saeb-Parsy, Lucia Selfa Aspiroz, Ivana Barbaric
{"title":"A call to action for deciphering genetic variants in human pluripotent stem cells for cell therapy","authors":"Nissim Benvenisty, Jonathan S. Draper, Paul J. Gokhale, Lyn Healy, Zoe Hewitt, Deborah Hursh, Adam Hodgson, Tenneille E. Ludwig, Nancy Mah, Sarah E. McClelland, Milena Mennecozzi, Florian T. Merkle, Joanne C. Mountford, Martin Pera, Alessandro Prigione, Tristan A. Rodriguez, Andrea Rossi, Foad J. Rouhani, Kourosh Saeb-Parsy, Lucia Selfa Aspiroz, Ivana Barbaric","doi":"10.1016/j.stem.2025.03.003","DOIUrl":"https://doi.org/10.1016/j.stem.2025.03.003","url":null,"abstract":"Human pluripotent stem cell (hPSC)-based therapies offer promise but pose potential risks due to culture-acquired genetic variants, some of which have been linked with cancer. An international workshop addressed these concerns, highlighting the need for improved strategies to stratify variants and chart a path toward definitive guidelines in hPSC-based therapy.","PeriodicalId":9665,"journal":{"name":"Cell stem cell","volume":"44 1","pages":""},"PeriodicalIF":23.9,"publicationDate":"2025-04-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143766847","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 : 2025-04-03DOI: 10.1016/j.stem.2025.03.007
Petter Brodin
{"title":"Tonsils weigh in on flu-specific immunity","authors":"Petter Brodin","doi":"10.1016/j.stem.2025.03.007","DOIUrl":"https://doi.org/10.1016/j.stem.2025.03.007","url":null,"abstract":"Wagoner et al.<span><span><sup>1</sup></span></span> use human tonsil organoids to uncover key immune mechanisms driving influenza vaccine responses. They identify Th1 cell frequencies as a critical predictor of neutralizing antibody responses to inactivated vaccines, providing new insights into vaccine effectiveness and paving the way for more targeted vaccine development in the future.","PeriodicalId":9665,"journal":{"name":"Cell stem cell","volume":"58 1","pages":""},"PeriodicalIF":23.9,"publicationDate":"2025-04-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143766842","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 : 2025-04-03DOI: 10.1016/j.stem.2025.02.014
Chiyeol Choi, Tae-Hee Kim
{"title":"A robust ingredient makes human gut stem cell niches on a dish","authors":"Chiyeol Choi, Tae-Hee Kim","doi":"10.1016/j.stem.2025.02.014","DOIUrl":"https://doi.org/10.1016/j.stem.2025.02.014","url":null,"abstract":"Human intestinal organoids (HIOs) generated from induced pluripotent stem cells (iPSCs) are utilized for disease modeling but they lack a full complement of niche components. Childs et al.<span><span><sup>1</sup></span></span> demonstrate that EPIREGULIN-driven HIOs mature into functional, neuromuscular, and vascularized niches, establishing a powerful platform for human gut physiology and disease research.","PeriodicalId":9665,"journal":{"name":"Cell stem cell","volume":"23 1","pages":""},"PeriodicalIF":23.9,"publicationDate":"2025-04-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143766920","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 : 2025-03-31DOI: 10.1016/j.stem.2025.03.002
Colleen E. O’Connor, Fan Zhang, Anna Neufeld, Olivia Prado, Susana P. Simmonds, Chelsea L. Fortin, Fredrik Johansson, Jonathan Mene, Sarah H. Saxton, Irina Kopyeva, Nicole E. Gregorio, Zachary James, Cole A. DeForest, Elizabeth C. Wayne, Daniela M. Witten, Kelly R. Stevens
{"title":"Bioprinted platform for parallelized screening of engineered microtissues in vivo","authors":"Colleen E. O’Connor, Fan Zhang, Anna Neufeld, Olivia Prado, Susana P. Simmonds, Chelsea L. Fortin, Fredrik Johansson, Jonathan Mene, Sarah H. Saxton, Irina Kopyeva, Nicole E. Gregorio, Zachary James, Cole A. DeForest, Elizabeth C. Wayne, Daniela M. Witten, Kelly R. Stevens","doi":"10.1016/j.stem.2025.03.002","DOIUrl":"https://doi.org/10.1016/j.stem.2025.03.002","url":null,"abstract":"Human engineered tissues hold great promise for therapeutic tissue regeneration and repair. Yet, development of these technologies often stalls at the stage of <em>in vivo</em> studies due to the complexity of engineered tissue formulations, which are often composed of diverse cell populations and material elements, along with the tedious nature of <em>in vivo</em> experiments. We introduce a “plug and play” platform called parallelized host apposition for screening tissues <em>in vivo</em> (PHAST). PHAST enables parallelized <em>in vivo</em> testing of 43 three-dimensional microtissues in a single 3D-printed device. Using PHAST, we screen microtissue formations with varying cellular and material components and identify formulations that support vascular graft-host inosculation and engineered liver tissue function <em>in vivo</em>. Our studies reveal that the cellular population(s) that should be included in engineered tissues for optimal <em>in vivo</em> performance is material dependent. PHAST could thus accelerate development of human tissue therapies for clinical regeneration and repair.","PeriodicalId":9665,"journal":{"name":"Cell stem cell","volume":"48 1","pages":""},"PeriodicalIF":23.9,"publicationDate":"2025-03-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143737205","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":"Vagal pathway activation links chronic stress to decline in intestinal stem cell function","authors":"Guoying Zhang, Yannan Lian, Qingguo Li, Shudi Zhou, Lili Zhang, Liting Chen, Junzhe Tang, Hailong Liu, Ni Li, Qiang Pan, Yongqiang Gu, Naiheng Lin, Hanling Wang, Xuege Wang, Jiacheng Guo, Wei Zhang, Zige Jin, Beitao Xu, Xiao Su, Moubin Lin, Jun Qin","doi":"10.1016/j.stem.2025.02.016","DOIUrl":"https://doi.org/10.1016/j.stem.2025.02.016","url":null,"abstract":"Chronic stress adversely affects intestinal health, but the specific neural pathways linking the brain to intestinal tissue are not fully understood. Here, we show that chronic stress-induced activation of the central amygdala-dorsal motor nucleus of the vagus (CeA-DMV) pathway accelerates premature aging and impairs the stemness of intestinal stem cells (ISCs). This pathway influences ISC function independently of the microbiota, the hypothalamic-pituitary-adrenal (HPA) axis, the immune response, and the sympathetic nervous system (SNS). Under chronic stress, DMV-mediated vagal activation prompts cholinergic enteric neurons to release acetylcholine (ACh), which engages ISCs via the M3 muscarinic acetylcholine receptor (CHRM3). This interaction activates the p38 mitogen-activated protein kinase (MAPK) pathway, triggering growth arrest and mitochondrial fragmentation, thereby accelerating an aging-like decline in ISCs. Together, our findings provide insights into an alternative neural mechanism that links stress to intestinal dysfunction. Strategies targeting the DMV-associated vagal pathway represent potential therapeutic approaches for stress-induced intestinal diseases.","PeriodicalId":9665,"journal":{"name":"Cell stem cell","volume":"21 1","pages":""},"PeriodicalIF":23.9,"publicationDate":"2025-03-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143666286","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 : 2025-03-21DOI: 10.1016/j.stem.2025.02.017
Vanessa Lopez-Pajares, Aparna Bhaduri, Yang Zhao, Gayatri Gowrishankar, Laura K.H. Donohue, Margaret G. Guo, Zurab Siprashvili, Weili Miao, Duy T. Nguyen, Xue Yang, Albert M. Li, Alan Sheng-Hwa Tung, Ronald L. Shanderson, Marten C.G. Winge, Lindsey M. Meservey, Suhas Srinivasan, Robin M. Meyers, Angela Guerrero, Andrew L. Ji, Omar S. Garcia, Paul A. Khavari
{"title":"Glucose modulates IRF6 transcription factor dimerization to enable epidermal differentiation","authors":"Vanessa Lopez-Pajares, Aparna Bhaduri, Yang Zhao, Gayatri Gowrishankar, Laura K.H. Donohue, Margaret G. Guo, Zurab Siprashvili, Weili Miao, Duy T. Nguyen, Xue Yang, Albert M. Li, Alan Sheng-Hwa Tung, Ronald L. Shanderson, Marten C.G. Winge, Lindsey M. Meservey, Suhas Srinivasan, Robin M. Meyers, Angela Guerrero, Andrew L. Ji, Omar S. Garcia, Paul A. Khavari","doi":"10.1016/j.stem.2025.02.017","DOIUrl":"https://doi.org/10.1016/j.stem.2025.02.017","url":null,"abstract":"Non-energetic roles for glucose are largely unclear, as is the interplay between transcription factors (TFs) and ubiquitous biomolecules. Metabolomic analyses uncovered elevation of intracellular glucose during differentiation of diverse cell types. Human and mouse tissue engineered with glucose sensors detected a glucose gradient that peaked in the outermost differentiated layers of the epidermis. Free glucose accumulation was essential for epidermal differentiation and required the SGLT1 glucose transporter. Glucose affinity chromatography uncovered glucose binding to diverse regulatory proteins, including the IRF6 TF. Direct glucose binding enabled IRF6 dimerization, DNA binding, genomic localization, and induction of IRF6 target genes, including essential pro-differentiation TFs GRHL1, GRHL3, HOPX, and PRDM1. These data identify a role for glucose as a gradient morphogen that modulates protein multimerization in cellular differentiation.","PeriodicalId":9665,"journal":{"name":"Cell stem cell","volume":"34 1","pages":""},"PeriodicalIF":23.9,"publicationDate":"2025-03-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143666285","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 : 2025-03-20DOI: 10.1016/j.stem.2025.02.015
Gerrald A. Lodewijk, Sayaka Kozuki, Clara J. Han, Benjamin R. Topacio, Seungho Lee, Lily Nixon, Abolfazl Zargari, Gavin Knight, Randolph Ashton, Lei S. Qi, S. Ali Shariati
{"title":"Self-organization of mouse embryonic stem cells into reproducible pre-gastrulation embryo models via CRISPRa programming","authors":"Gerrald A. Lodewijk, Sayaka Kozuki, Clara J. Han, Benjamin R. Topacio, Seungho Lee, Lily Nixon, Abolfazl Zargari, Gavin Knight, Randolph Ashton, Lei S. Qi, S. Ali Shariati","doi":"10.1016/j.stem.2025.02.015","DOIUrl":"https://doi.org/10.1016/j.stem.2025.02.015","url":null,"abstract":"Embryonic stem cells (ESCs) can self-organize into structures with spatial and molecular similarities to natural embryos. During development, embryonic and extraembryonic cells differentiate through activation of endogenous regulatory elements while co-developing via cell-cell interactions. However, engineering regulatory elements to self-organize ESCs into embryo models remains underexplored. Here, we demonstrate that CRISPR activation (CRISPRa) of two regulatory elements near Gata6 and Cdx2 generates embryonic patterns resembling pre-gastrulation mouse embryos. Live single-cell imaging revealed that self-patterning occurs through orchestrated collective movement driven by cell-intrinsic fate induction. In 3D, CRISPRa-programmed embryo models (CPEMs) exhibit morphological and transcriptomic similarity to pre-gastrulation mouse embryos. CPEMs allow versatile perturbations, including dual Cdx2-Elf5 activation to enhance trophoblast differentiation and lineage-specific activation of laminin and matrix metalloproteinases, uncovering their roles in basement membrane remodeling and embryo model morphology. Our findings demonstrate that minimal intrinsic epigenome editing can self-organize ESCs into programmable pre-gastrulation embryo models with robust lineage-specific perturbation capabilities.","PeriodicalId":9665,"journal":{"name":"Cell stem cell","volume":"34 1","pages":""},"PeriodicalIF":23.9,"publicationDate":"2025-03-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143660412","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 : 2025-03-20DOI: 10.1016/j.stem.2025.02.013
Thomas H. Ambrosi, Sahar Taheri, Kun Chen, Rahul Sinha, Yuting Wang, Ethan J. Hunt, L. Henry Goodnough, Matthew P. Murphy, Holly M. Steininger, Malachia Y. Hoover, Franco Felix, Kelly C. Weldon, Lauren S. Koepke, Jan Sokol, Daniel Dan Liu, Liming Zhao, Stephanie D. Conley, Wan-Jin Lu, Maurizio Morri, Norma F. Neff, Charles K.F. Chan
{"title":"Human skeletal development and regeneration are shaped by functional diversity of stem cells across skeletal sites","authors":"Thomas H. Ambrosi, Sahar Taheri, Kun Chen, Rahul Sinha, Yuting Wang, Ethan J. Hunt, L. Henry Goodnough, Matthew P. Murphy, Holly M. Steininger, Malachia Y. Hoover, Franco Felix, Kelly C. Weldon, Lauren S. Koepke, Jan Sokol, Daniel Dan Liu, Liming Zhao, Stephanie D. Conley, Wan-Jin Lu, Maurizio Morri, Norma F. Neff, Charles K.F. Chan","doi":"10.1016/j.stem.2025.02.013","DOIUrl":"https://doi.org/10.1016/j.stem.2025.02.013","url":null,"abstract":"The skeleton is one of the most structurally and compositionally diverse organ systems in the human body, depending on unique cellular dynamisms. Here, we integrate prospective isolation of human skeletal stem cells (hSSCs; CD45<sup>−</sup>CD235a<sup>−</sup>TIE2<sup>−</sup>CD31<sup>−</sup>CD146<sup>−</sup>PDPN<sup>+</sup>CD73<sup>+</sup>CD164<sup>+</sup>) from ten skeletal sites with functional assays and single-cell RNA sequencing (scRNA-seq) analysis to identify chondrogenic, osteogenic, stromal, and fibrogenic subtypes of hSSCs during development and their linkage to skeletal phenotypes. We map the distinct composition of hSSC subtypes across multiple skeletal sites and demonstrate their unique <em>in vivo</em> clonal dynamics. We find that age-related changes in bone formation and regeneration disorders stem from a pathological fibroblastic shift in the hSSC pool. Utilizing a Boolean algorithm, we uncover gene regulatory networks that dictate differences in the ability of hSSCs to generate specific skeletal tissues. Importantly, hSSC lineage dynamics are pharmacologically malleable, providing a new strategy to treat aberrant hSSC diversity central to aging and skeletal maladies.","PeriodicalId":9665,"journal":{"name":"Cell stem cell","volume":"91 1","pages":""},"PeriodicalIF":23.9,"publicationDate":"2025-03-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143660422","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 : 2025-03-19DOI: 10.1016/j.stem.2025.02.011
Yachen Shen, Samuel Zheng Hao Wong, Tong Ma, Feng Zhang, Qing Wang, Riki Kawaguchi, Daniel H. Geschwind, Jeremy Wang, Chuan He, Guo-li Ming, Hongjun Song
{"title":"m6A deficiency impairs hypothalamic neurogenesis of feeding-related neurons in mice and human organoids and leads to adult obesity in mice","authors":"Yachen Shen, Samuel Zheng Hao Wong, Tong Ma, Feng Zhang, Qing Wang, Riki Kawaguchi, Daniel H. Geschwind, Jeremy Wang, Chuan He, Guo-li Ming, Hongjun Song","doi":"10.1016/j.stem.2025.02.011","DOIUrl":"https://doi.org/10.1016/j.stem.2025.02.011","url":null,"abstract":"N<sup>6</sup>-methyladenosine (m<sup>6</sup>A), the most prevalent internal modification on mRNAs, plays important roles in the nervous system. Whether neurogenesis in the hypothalamus, a region critical for controlling appetite, is regulated by m<sup>6</sup>A signaling, especially in humans, remains unclear. Here, we showed that deletion of m<sup>6</sup>A writer Mettl14 in the mouse embryonic hypothalamus led to adult obesity, with impaired glucose-insulin homeostasis and increased energy intake. Mechanistically, deletion of Mettl14 leads to hypothalamic arcuate nucleus neurogenesis deficits with reduced generation of feeding-related neurons and dysregulation of neurogenesis-related m<sup>6</sup>A-tagged transcripts. Deletion of m<sup>6</sup>A writer Mettl3 or m<sup>6</sup>A reader Ythdc1 shared similar phenotypes. METTL14 or YTHDC1 knockdown also led to reduced generation of feeding-related neurons in human brain subregion-specific arcuate nucleus organoids. Our studies reveal a conserved role of m<sup>6</sup>A signaling in arcuate nucleus neurogenesis in mice and human organoids and shed light on the developmental basis of epitranscriptomic regulation of food intake and energy homeostasis.","PeriodicalId":9665,"journal":{"name":"Cell stem cell","volume":"59 1","pages":""},"PeriodicalIF":23.9,"publicationDate":"2025-03-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143653845","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 : 2025-03-17DOI: 10.1016/j.stem.2025.02.010
Hongwei Cai, Chunhui Tian, Lei Chen, Yang Yang, Alfred Xuyang Sun, Kyle McCracken, Jason Tchieu, Mingxia Gu, Ken Mackie, Feng Guo
{"title":"Vascular network-inspired diffusible scaffolds for engineering functional midbrain organoids","authors":"Hongwei Cai, Chunhui Tian, Lei Chen, Yang Yang, Alfred Xuyang Sun, Kyle McCracken, Jason Tchieu, Mingxia Gu, Ken Mackie, Feng Guo","doi":"10.1016/j.stem.2025.02.010","DOIUrl":"https://doi.org/10.1016/j.stem.2025.02.010","url":null,"abstract":"Organoids, 3D organ-like tissue cultures derived from stem cells, show promising potential for developmental biology, drug discovery, and regenerative medicine. However, the function and phenotype of current organoids, especially neural organoids, are still limited by insufficient diffusion of oxygen, nutrients, metabolites, signaling molecules, and drugs. Herein, we present vascular network-inspired diffusible (VID) scaffolds to mimic physiological diffusion physics for generating functional organoids and phenotyping their drug response. Specifically, the VID scaffolds, 3D-printed meshed tubular channel networks, successfully engineer human midbrain organoids almost without necrosis and hypoxia in commonly used well plates. Compared with conventional organoids, these engineered organoids develop more physiologically relevant features and functions, including midbrain-specific identity, oxygen metabolism, neuronal maturation, and network activity. Moreover, these engineered organoids also better recapitulate pharmacological responses, such as neural activity changes to fentanyl exposure, compared with conventional organoids with significant diffusion limits. This platform may provide insights for organoid development and therapeutic innovation.","PeriodicalId":9665,"journal":{"name":"Cell stem cell","volume":"25 1","pages":""},"PeriodicalIF":23.9,"publicationDate":"2025-03-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143635602","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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