Cell stem cellPub Date : 2026-03-05Epub Date: 2026-02-12DOI: 10.1016/j.stem.2026.01.006
Martti Maimets, Mikhail Nikolaev, Cecilia Lövkvist, Fabien Bertillot, Hjalte List Larsen, Raul Bardini Bressan, Antonios Georgantzoglou, Nikolce Gjorevski, Eirini Filidou, Maureen Zøylner, Stine Lind Hansen, Astrid M Baattrup, Isidora Banjac, Jordi Guiu, Sara A Wickström, Matthias P Lutolf, Kim B Jensen
{"title":"Engineered intestinal crypt geometry uncovers YAP1-dependent fetal-to-adult transition.","authors":"Martti Maimets, Mikhail Nikolaev, Cecilia Lövkvist, Fabien Bertillot, Hjalte List Larsen, Raul Bardini Bressan, Antonios Georgantzoglou, Nikolce Gjorevski, Eirini Filidou, Maureen Zøylner, Stine Lind Hansen, Astrid M Baattrup, Isidora Banjac, Jordi Guiu, Sara A Wickström, Matthias P Lutolf, Kim B Jensen","doi":"10.1016/j.stem.2026.01.006","DOIUrl":"10.1016/j.stem.2026.01.006","url":null,"abstract":"<p><p>During morphogenesis, the intestine undergoes significant structural remodeling, transitioning from a simple tube of immature epithelium into a complex crypt-villus architecture housing mature cell types. However, the relationship between these structural changes and epithelial maturation has remained enigmatic. Using engineered scaffolds that replicate crypt-like geometries, we establish a robust platform for guiding the morphogenesis and differentiation of fetal intestinal cells into mature engineered tissues that mimic their in vivo counterparts. Mechanistically, tissue maturation is driven by cell crowding, leading to reduced YAP1 activation. Modulating YAP signaling in both engineered tissues and the developing mouse intestine alters epithelial lineage specification. These findings uncover a geometry-dependent mechanism that links tissue architecture to cell fate transitions. Our work provides a platform for modeling aspects of intestinal development and offers insights for refining stem cell differentiation protocols and regenerative strategies for intestinal disorders.</p>","PeriodicalId":93928,"journal":{"name":"Cell stem cell","volume":" ","pages":"487-501.e7"},"PeriodicalIF":20.4,"publicationDate":"2026-03-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12979008/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146196224","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Cell stem cellPub Date : 2026-03-05Epub Date: 2026-02-13DOI: 10.1016/j.stem.2026.01.007
Takeshi Uenaka, Alan Napole, Aninda Dibya Saha, Duo Sun, Angelina Singavarapu, Elizabeth Calzada, Jiahui Chen, Lena Erlebach, Amanda McQuade, Daniel M Ramos, Alessandra Rigamonti, Lisa Salazar, Avi J Samelson, Kamilla Sedov, Natalie J Welsh, Katleen Wild, Qianxin Wu, Ernest Arenas, Andrew R Bassett, Martin Kampmann, Deborah Kronenberg-Versteeg, Florian T Merkle, Birgitt Schüle, Leslie M Thompson, William C Skarnes, Michael E Ward, Marius Wernig
{"title":"Prevention of transgene silencing during human pluripotent stem cell differentiation.","authors":"Takeshi Uenaka, Alan Napole, Aninda Dibya Saha, Duo Sun, Angelina Singavarapu, Elizabeth Calzada, Jiahui Chen, Lena Erlebach, Amanda McQuade, Daniel M Ramos, Alessandra Rigamonti, Lisa Salazar, Avi J Samelson, Kamilla Sedov, Natalie J Welsh, Katleen Wild, Qianxin Wu, Ernest Arenas, Andrew R Bassett, Martin Kampmann, Deborah Kronenberg-Versteeg, Florian T Merkle, Birgitt Schüle, Leslie M Thompson, William C Skarnes, Michael E Ward, Marius Wernig","doi":"10.1016/j.stem.2026.01.007","DOIUrl":"10.1016/j.stem.2026.01.007","url":null,"abstract":"<p><p>Transgenes are often silenced upon differentiation of pluripotent stem cells using conventional expression systems. Here, we developed the TK4 PiggyBac vector to conduct a comparative analysis to evaluate the impact of various promoters, transcriptional regulatory elements, insulators, and genomic integration sites on transgene silencing during neuronal differentiation. Our findings reveal that specific combinations of CAG and Ubc promoters with the Woodchuck hepatitis virus post-transcriptional regulatory element (WPRE) can prevent transgene silencing during differentiation, whereas chromatin insulators have less impact on sustained expression. Three novel safe harbor loci, distant from known genes, as well as the citrate lyase beta-like (CLYBL) locus, similarly support the prevention of transgene silencing. Remarkably, the TK4 vector showed complete resistance to silencing across various neuronal and microglial differentiation protocols, as independently confirmed by seven laboratories. This construct will be highly useful for assays requiring stable transgene expression during differentiation and holds potential for broad applications in various research fields.</p>","PeriodicalId":93928,"journal":{"name":"Cell stem cell","volume":" ","pages":"517-530.e8"},"PeriodicalIF":20.4,"publicationDate":"2026-03-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146198381","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Cell stem cellPub Date : 2026-02-05DOI: 10.1016/j.stem.2026.01.004
Giulia Schiroli, Pietro Genovese
{"title":"A 3D \"nichoid\" boost for gene-engineered blood stem cells.","authors":"Giulia Schiroli, Pietro Genovese","doi":"10.1016/j.stem.2026.01.004","DOIUrl":"https://doi.org/10.1016/j.stem.2026.01.004","url":null,"abstract":"<p><p>Midena et al.<sup>1</sup> employ a nanoengineered 3D \"nichoid\" substrate that mechanically supports CD34<sup>+</sup> hematopoietic stem and progenitor cells (HSPCs) during ex vivo manipulation, reducing culture-associated stress and improving engraftment and polyclonal output after gene editing or lentiviral gene addition. The work spotlights mechanobiology as a manufacturing lever for improving HSPC gene therapies.</p>","PeriodicalId":93928,"journal":{"name":"Cell stem cell","volume":"33 2","pages":"167-169"},"PeriodicalIF":20.4,"publicationDate":"2026-02-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146133716","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Cell stem cellPub Date : 2026-02-05DOI: 10.1016/j.stem.2026.01.005
Fang Fang, Renee A Reijo Pera
{"title":"Nurturing eggs with hiPSC-derived cells to improve outcomes in in vitro fertilization.","authors":"Fang Fang, Renee A Reijo Pera","doi":"10.1016/j.stem.2026.01.005","DOIUrl":"https://doi.org/10.1016/j.stem.2026.01.005","url":null,"abstract":"<p><p>Clinical success of in vitro maturation (IVM) for fertility treatment is currently limited by the lack of a reliable source of ovarian support cells (OSCs) to nurture oocytes. Kramme et al. develop \"Fertilo,\" a scalable, clinical-grade hiPSC-derived OSC product that significantly enhances oocyte maturation and improves clinical reproductive outcomes.<sup>1</sup>.</p>","PeriodicalId":93928,"journal":{"name":"Cell stem cell","volume":"33 2","pages":"173-175"},"PeriodicalIF":20.4,"publicationDate":"2026-02-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146133763","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Cell stem cellPub Date : 2026-02-05DOI: 10.1016/j.stem.2026.01.002
Mingxin Zhang, Xi Wu, Di Liu, Huaxing Li, Xulin Li, Wuqi Yang, Jialin Ye, Liyuan Hou, Shiyang Wang, Ning Ning, Hanfu Zhang, Yuhua Tian, Lu Yu, Kaichun Wu, Liping Wang, Maksim V Plikus, Cong Lv, Feng Wang, Zhengquan Yu
{"title":"Sleep disturbance triggers aberrant activation of vagus circuitry and induces intestinal stem cell dysfunction.","authors":"Mingxin Zhang, Xi Wu, Di Liu, Huaxing Li, Xulin Li, Wuqi Yang, Jialin Ye, Liyuan Hou, Shiyang Wang, Ning Ning, Hanfu Zhang, Yuhua Tian, Lu Yu, Kaichun Wu, Liping Wang, Maksim V Plikus, Cong Lv, Feng Wang, Zhengquan Yu","doi":"10.1016/j.stem.2026.01.002","DOIUrl":"https://doi.org/10.1016/j.stem.2026.01.002","url":null,"abstract":"<p><p>Sleep disturbances are associated with pathogenesis of numerous chronic disorders, including chronic gastrointestinal diseases. However, the mechanism that transmits sleep disturbance-induced aberrant neural signaling from the brain to the gut remains elusive. We show that acute sleep deprivation (SD) impairs intestinal stem cell (ISC) function, leading to shortening of crypt-villus architecture and Paneth cell loss. We identified the dorsal motor nucleus of vagus (DMV) as the SD-sensitive central nervous system center that transmits sleep effects to the gut. SD aberrantly activates DMV neurons, driving excessive acetylcholine release from the vagus nerve into the gut. Acetylcholine triggers 5-hydroxytryptamine (5-HT) release by enterochromaffin cells and suppresses its reuptake via muscarinic receptors, thereby causing a spike in 5-HT levels. Elevated 5-HT induces excessive oxidative stress in ISCs through its receptor HTR4, promoting gut pathologies. Overall, we reveal an SD-responsive neural circuit that controls ISCs and identify therapeutic strategies for mitigating SD-related gut diseases.</p>","PeriodicalId":93928,"journal":{"name":"Cell stem cell","volume":"33 2","pages":"306-324.e8"},"PeriodicalIF":20.4,"publicationDate":"2026-02-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146133823","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Cell stem cellPub Date : 2026-02-05DOI: 10.1016/j.stem.2026.01.003
Rohan Palanki, Emily Fitzgerald, Alexandre J Poirier, Michael J Mitchell
{"title":"Editing the skin in place: In vivo genome correction of rare skin disease.","authors":"Rohan Palanki, Emily Fitzgerald, Alexandre J Poirier, Michael J Mitchell","doi":"10.1016/j.stem.2026.01.003","DOIUrl":"https://doi.org/10.1016/j.stem.2026.01.003","url":null,"abstract":"<p><p>In this issue, Apaydin and Sadhnani et al. report in situ genome editing of human skin to correct a common disease-causing mutation underlying autosomal recessive congenital ichthyosis (ARCI).<sup>1</sup> They combine a base editor, transient barrier modulation, and topical mRNA-lipid nanoparticle administration to restore clinically meaningful levels of transglutaminase 1 activity.</p>","PeriodicalId":93928,"journal":{"name":"Cell stem cell","volume":"33 2","pages":"170-172"},"PeriodicalIF":20.4,"publicationDate":"2026-02-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146133760","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Cell stem cellPub Date : 2026-01-08DOI: 10.1016/j.stem.2025.12.010
Ross D Jones, Kevin Salim, Laura N Stankiewicz, John M Edgar, Lorna Leon, Jana K Gillies, Ali Murtaza, Lauren J Durland, Divy Raval, Charles Lau, Thristan Paulo B Taberna, Han Hsuan Hsu, Carla Zimmerman, Yale S Michaels, Fabio M V Rossi, Megan K Levings, Peter W Zandstra
{"title":"Tunable differentiation of human CD4<sup>+</sup> and CD8<sup>+</sup> T cells from pluripotent stem cells.","authors":"Ross D Jones, Kevin Salim, Laura N Stankiewicz, John M Edgar, Lorna Leon, Jana K Gillies, Ali Murtaza, Lauren J Durland, Divy Raval, Charles Lau, Thristan Paulo B Taberna, Han Hsuan Hsu, Carla Zimmerman, Yale S Michaels, Fabio M V Rossi, Megan K Levings, Peter W Zandstra","doi":"10.1016/j.stem.2025.12.010","DOIUrl":"https://doi.org/10.1016/j.stem.2025.12.010","url":null,"abstract":"<p><p>Allogeneic T cell therapies are a highly desirable option to circumvent the cost and complexity of using autologous T cells to treat diseases. Allogeneic CD8<sup>+</sup> T cells can be made from pluripotent stem cells (PSCs), but deriving CD4<sup>+</sup> T cells from PSCs has remained a significant challenge. Using feeder- and serum-free conditions, we found that CD4<sup>+</sup> vs. CD8<sup>+</sup> T cell commitment from PSCs can be controlled by fine-tuning the dynamics of Notch and T cell receptor (TCR) signaling delivered to CD4<sup>+</sup>CD8<sup>+</sup> double-positive T cells. Notch signaling negatively impacts CD4<sup>+</sup> T cell commitment, and its timed removal allows generation of clonally diverse and expandable CD4<sup>+</sup> T cells from PSCs. The resulting CD4<sup>+</sup> T cells respond to cytokine-mediated polarization by differentiating into Th1, Th2, or Th17 cells, recapitulating canonical helper cell function. These findings represent a significant step toward using PSC-derived CD4<sup>+</sup> T cells as a low-cost, off-the-shelf cell therapy.</p>","PeriodicalId":93928,"journal":{"name":"Cell stem cell","volume":"33 1","pages":"73-90.e14"},"PeriodicalIF":20.4,"publicationDate":"2026-01-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145947060","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Cell stem cellPub Date : 2026-01-08Epub Date: 2025-12-30DOI: 10.1016/j.stem.2025.12.004
Ferdi Ridvan Kiral, Woo Sub Yang, Onur Iyilikci, Xiaona Lu, Jonghun Kim, Mu Seog Choe, Cynthia Lo, Mei Zhong, Kun-Yong Kim, Yong-Hui Jiang, In-Hyun Park
{"title":"Generation of human pineal gland organoids with melatonin production for disease modeling.","authors":"Ferdi Ridvan Kiral, Woo Sub Yang, Onur Iyilikci, Xiaona Lu, Jonghun Kim, Mu Seog Choe, Cynthia Lo, Mei Zhong, Kun-Yong Kim, Yong-Hui Jiang, In-Hyun Park","doi":"10.1016/j.stem.2025.12.004","DOIUrl":"10.1016/j.stem.2025.12.004","url":null,"abstract":"<p><p>The pineal gland regulates circadian rhythms through melatonin production, yet human studies are limited by poor tissue access. To overcome this, we developed human pineal gland organoids (hPGOs) from pluripotent stem cells, modeling pineal development and function. Single-cell RNA sequencing revealed distinct mature and developing pinealocyte populations with transcriptomic profiles closely resembling the in vivo pineal gland. hPGOs produce melatonin, express adrenergic receptors, and respond to noradrenaline, mimicking physiological regulation. To model disease-related impairments, we generated hPGOs from Angelman syndrome (AS) patient-derived iPSCs, which exhibit disrupted pinealocyte differentiation and markedly reduced melatonin synthesis, reflecting AS-related developmental pathology. Additionally, transplanted hPGOs restored circulating melatonin in pinealectomized mice, demonstrating their potential for cell-therapy approaches. These findings establish hPGOs as a robust platform for probing pineal development, circadian regulation, and their disruption in neurodevelopmental and sleep-related disorders.</p>","PeriodicalId":93928,"journal":{"name":"Cell stem cell","volume":" ","pages":"91-107.e9"},"PeriodicalIF":20.4,"publicationDate":"2026-01-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12925488/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145879369","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Cell stem cellPub Date : 2026-01-08Epub Date: 2025-12-29DOI: 10.1016/j.stem.2025.12.007
Ryoma Endo, Shinya Sugimoto, Yutaro Kuwashima, Mami Matano, Hikaru Hanyu, Sirirat Takahashi, Hirochika Kato, Taku Tanaka, Andreas Michael Sihombing, Koji Shirosaki, Yoshiko Hatano, Yuki Sugiura, Takanori Kanai, Motoshi Wada, Toshiro Sato
{"title":"Niche-preserving transplantation promotes functional engraftment of intestinal organoids in rat short bowel syndrome.","authors":"Ryoma Endo, Shinya Sugimoto, Yutaro Kuwashima, Mami Matano, Hikaru Hanyu, Sirirat Takahashi, Hirochika Kato, Taku Tanaka, Andreas Michael Sihombing, Koji Shirosaki, Yoshiko Hatano, Yuki Sugiura, Takanori Kanai, Motoshi Wada, Toshiro Sato","doi":"10.1016/j.stem.2025.12.007","DOIUrl":"10.1016/j.stem.2025.12.007","url":null,"abstract":"<p><p>Short bowel syndrome (SBS) is a life-threatening condition in which outcomes often critically depend on ileal function, the only intestinal segment specialized for bile acid uptake and efficient fat absorption. However, whether restoring ileal epithelium-specific nutrient absorption can ameliorate SBS has remained unknown. Here, we demonstrate a niche-preserving transplantation strategy enabling highly efficient engraftment of intestinal organoids into the rat small intestine. Clearing luminal mucus with N-acetylcysteine facilitates ethylenediaminetetraacetic acid (EDTA)-based epithelial detachment, enabling removal of Lgr5<sup>+</sup> stem cells while preserving the stromal niche. This preconditioning increased the engrafted area and enabled the generation of an ilealized jejunum that improved body-weight trajectories and survival in rat SBS. Furthermore, the engrafted epithelia endowed the jejunum with bile acid absorption capacity. These findings provide in vivo evidence for stem cell niche theory, showing that the niche is essential to accommodate donor stem cells, and establish ilealized jejunum as a path toward autologous, region-targeted therapy for SBS.</p>","PeriodicalId":93928,"journal":{"name":"Cell stem cell","volume":" ","pages":"157-165.e6"},"PeriodicalIF":20.4,"publicationDate":"2026-01-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145866914","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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