Cell stem cellPub Date : 2026-10-16DOI: 10.1016/j.stem.2026.09.011
Jingqiang Wang, Aurelien Pelissier, Jeffrey S H Lin, Clément Quintard, Anna Tamakhina, Jun Wang, Jie Jiao, Nicolas Werschler, Meilin An, Ivona Kozieradzki, James D Johnson, Josef M Penninger
{"title":"Organotypic vascularization improves maturation of human stem cell-derived islets and restores normoglycemia in diabetic mice.","authors":"Jingqiang Wang, Aurelien Pelissier, Jeffrey S H Lin, Clément Quintard, Anna Tamakhina, Jun Wang, Jie Jiao, Nicolas Werschler, Meilin An, Ivona Kozieradzki, James D Johnson, Josef M Penninger","doi":"10.1016/j.stem.2026.09.011","DOIUrl":"https://doi.org/10.1016/j.stem.2026.09.011","url":null,"abstract":"<p><p>Human pluripotent stem cells-derived pancreatic islet organoids (PIOs) hold promise for treating type 1 diabetes, but poor post-transplant survival due to inadequate vascularization remains a major challenge. Here, we generated vascularized PIOs (VPIOs) by co-culturing PIOs with blood vessel organoids (BVOs), resulting in integrated structures with BVOs-derived capillary networks that penetrate into the islet structures. These blood vessels structurally exhibit fenestrations characteristic of islet-specific endothelium and carry a molecular signature of organotypic vasculature. β cells within the VPIOs display partially enhanced maturation and greater resistance to hypoxia and endoplasmic reticulum stress. Following subcutaneous transplantation into diabetic mice, VPIOs exhibit markedly improved survival, establish vascular connections with the host circulation, and restore long-term normoglycemia. Our work presents a strategy for generating vascularized islet organoids that enhances β cell maturation and tissue-specific blood vessel specification in vitro and, critically, improves graft survival and function in vivo.</p>","PeriodicalId":93928,"journal":{"name":"Cell stem cell","volume":" ","pages":""},"PeriodicalIF":20.4,"publicationDate":"2026-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149208348","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}
{"title":"IGF2 acts downstream of Hippo signaling to regulate organ growth and restore liver regeneration in aging.","authors":"Zhenxing Zhong, Ruxin Jin, Yiting Zhong, Yawen Fu, Rui Zhu, Li Zhang, Zhihan Jiao, Fanhui Zhou, Lingdu Meng, Jiajie Zhu, Lingyan Zhang, Jian Wu, Rui Dong, Huirong Yang, Yanhui Xu, Kun-Liang Guan, Fei Lan, Yu Wang, Fa-Xing Yu","doi":"10.1016/j.stem.2026.08.006","DOIUrl":"10.1016/j.stem.2026.08.006","url":null,"abstract":"<p><p>Precise regulation of organ size is essential for proper function, yet the underlying logic remains unclear. Here, we identify a Hippo-IGF2 signaling axis as a regulator of organ growth. During mouse liver development, Igf2 is highly expressed in fetal and neonatal hepatocytes to fuel rapid growth but is directly silenced by the Hippo signaling pathway at the postnatal stage, enforcing growth arrest and determining liver size. In contrast, chronic liver injury inactivates Hippo signaling and induces Igf2 expression, which is essential for regeneration. Notably, this regenerative response is defective in aged mice but can be restored by ectopic Igf2 expression. As a hormone, circulating IGF2 can compensate for local deficiencies in response to organ-restricted perturbations, whereas whole-body Hippo activation or Igf2 deletion results in small mice with miniature organs. Hence, the Hippo-IGF2 axis is a general regulator of growth and organ size during development and regeneration.</p>","PeriodicalId":93928,"journal":{"name":"Cell stem cell","volume":" ","pages":"1695-1712.e9"},"PeriodicalIF":20.4,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148893172","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 : 2026-10-01Epub Date: 2026-08-25DOI: 10.1016/j.stem.2026.07.017
Huaigeng Xu, Chisato Kamei, Deniz Gökbuget, Jacob Du, Mercedes Barrero, Li Wang, Yoshihiro Iwamoto, Jason Mark Soriano, Krystal Godding, Bo Wang, Serena S Kwek, Gabriel I Nistor, Hans S Keirstead, Lawrence Fong, Shin Kaneko, Karin M L Gaensler, Robert Blelloch
{"title":"Engineered human iPSC-derived dendritic cells dressed with tumor MHC complexes as a cancer vaccine.","authors":"Huaigeng Xu, Chisato Kamei, Deniz Gökbuget, Jacob Du, Mercedes Barrero, Li Wang, Yoshihiro Iwamoto, Jason Mark Soriano, Krystal Godding, Bo Wang, Serena S Kwek, Gabriel I Nistor, Hans S Keirstead, Lawrence Fong, Shin Kaneko, Karin M L Gaensler, Robert Blelloch","doi":"10.1016/j.stem.2026.07.017","DOIUrl":"10.1016/j.stem.2026.07.017","url":null,"abstract":"<p><p>Autologous-derived dendritic cells (DCs) are a promising source for cell-based cancer vaccines. However, their therapeutic potential is challenged by the number and quality produced and the diversity of antigens presented. To address these limitations, we present an approach that involves differentiating universal MHC-deficient human-induced pluripotent stem cells (hiPSCs) into CCR7<sup>+</sup> migratory DCs. These DCs are subsequently \"dressed\" with the full repertoire of MHC-antigen complexes derived from tumor cell membranes, transforming an allogeneic substrate into a personalized cancer vaccine product. The resulting \"TumorDressed\" DCs effectively activate T cells against tumor antigens. Their function is diminished when CD80/86 is deleted but significantly enhanced by the loss of PD-L1/2. PD-L1/2-null TumorDressed DCs demonstrate robust priming of anti-tumor T cell-mediated cytotoxicity both in vitro and in vivo, including against primary hematologic and solid tumors with matching patient T cells. These findings provide proof of concept for a universal, scalable, adaptable, and off-the-shelf DC cancer vaccine platform.</p>","PeriodicalId":93928,"journal":{"name":"Cell stem cell","volume":" ","pages":"1625-1642.e10"},"PeriodicalIF":20.4,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148820586","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 : 2026-09-03Epub Date: 2026-08-25DOI: 10.1016/j.stem.2026.07.012
Bérénice Dugué, Pia Wanner, Mayra L Ruiz Tejada Segura, Mohamed Saad, Lucas Greven, Katrin Götz, Carmen Schalla, Stijn Fuchs, Gerjanne Vroeg In de Wei, Hélène F E Gleitz, Anna Katharina Galyga, Jessica Ellen Pritchard, Tobias Schlangen, Niklas Lutterbach, Salim Atakhanov, Lina Schmidt, Marie Parrens, Armelle Peyrat, Damien Luque Paz, Marie-Christine Copin, Alexandre Guy, Victor-Emmanuel Brett, Olivier Mansier, Susanne Schmitz, Paul Wanek, Bella Banjanin, Stephani Schmitz, Martina Crysandt, Marian C Clahsen-van Groningen, Konnie M Hebeda, Sascha Dietrich, Harald Voehringer, Matthias Meyer-Bender, Kristin Séré, Chloé James, Adam Benabid, Ivan Costa, Charles Dussiau, Rebekka K Schneider
{"title":"Spatial profiling of the spleen in mouse and human myelofibrosis reveals complement-driven immune-stromal interactions as a therapeutic target.","authors":"Bérénice Dugué, Pia Wanner, Mayra L Ruiz Tejada Segura, Mohamed Saad, Lucas Greven, Katrin Götz, Carmen Schalla, Stijn Fuchs, Gerjanne Vroeg In de Wei, Hélène F E Gleitz, Anna Katharina Galyga, Jessica Ellen Pritchard, Tobias Schlangen, Niklas Lutterbach, Salim Atakhanov, Lina Schmidt, Marie Parrens, Armelle Peyrat, Damien Luque Paz, Marie-Christine Copin, Alexandre Guy, Victor-Emmanuel Brett, Olivier Mansier, Susanne Schmitz, Paul Wanek, Bella Banjanin, Stephani Schmitz, Martina Crysandt, Marian C Clahsen-van Groningen, Konnie M Hebeda, Sascha Dietrich, Harald Voehringer, Matthias Meyer-Bender, Kristin Séré, Chloé James, Adam Benabid, Ivan Costa, Charles Dussiau, Rebekka K Schneider","doi":"10.1016/j.stem.2026.07.012","DOIUrl":"10.1016/j.stem.2026.07.012","url":null,"abstract":"<p><p>Splenomegaly is a defining feature of myelofibrosis, yet the contribution of splenic mesenchymal stroma to disease progression remains unclear. We combined spatial and single-nucleus transcriptomics of patient spleens with spatial and single-cell transcriptomics, as well as imaging analyses, of murine spleens to map extramedullary hematopoiesis niches. Activated red pulp reticular cells localize near hematopoietic stem and progenitor cells, and early disease is characterized by marginal zone disruption with lymphoid depletion preceding stromal remodeling. Trajectory analyses reveal a shift in reticular cells from hematopoiesis-supportive to inflammatory and pro-fibrotic states, driven by macrophage- and megakaryocyte-derived signals that activate complement and induce tumor necrosis factor α (TNF-α), transforming growth factor β (TGF-β), extracellular matrix, and Thbs1 programs. Non-hematopoietic complement component C3 deficiency or pharmacological C3 inhibition suppresses these pathways, restores splenic architecture, and reduces splenomegaly and bone marrow fibrosis. These findings identify complement-dependent stromal reprogramming as a mechanism governing hematopoietic niches and as a targetable axis in myelofibrosis.</p>","PeriodicalId":93928,"journal":{"name":"Cell stem cell","volume":" ","pages":"1477-1494.e14"},"PeriodicalIF":20.4,"publicationDate":"2026-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148820519","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 : 2026-09-03Epub Date: 2026-08-25DOI: 10.1016/j.stem.2026.08.002
Rebecca Austin, Madeline H Kowalski, Xiaoli Wang, Ziyan Lin, Bettina Nadorp, Nicholas Ward, Pier Edoardo Rovatti, Audrey Lasry, Zhengxi Sun, Julia Rojo-Tomillo, Giovanni Gambi, Tejas Patel, Hua Zhou, M D Babu Mia, Eduardo Esteva, Igor Dolgalev, Valeria Mezzano, Suhita Ray, Sergei Doulatov, Tatyana Gindin, Sanam Loghavi, Bethan Psaila, Aristotelis Tsirigos, Rahul Satija, Iannis Aifantis, Ronald Hoffman
{"title":"Splenic extramedullary hematopoiesis in myelofibrosis is shaped by transcriptomic and epigenetic dysregulation.","authors":"Rebecca Austin, Madeline H Kowalski, Xiaoli Wang, Ziyan Lin, Bettina Nadorp, Nicholas Ward, Pier Edoardo Rovatti, Audrey Lasry, Zhengxi Sun, Julia Rojo-Tomillo, Giovanni Gambi, Tejas Patel, Hua Zhou, M D Babu Mia, Eduardo Esteva, Igor Dolgalev, Valeria Mezzano, Suhita Ray, Sergei Doulatov, Tatyana Gindin, Sanam Loghavi, Bethan Psaila, Aristotelis Tsirigos, Rahul Satija, Iannis Aifantis, Ronald Hoffman","doi":"10.1016/j.stem.2026.08.002","DOIUrl":"10.1016/j.stem.2026.08.002","url":null,"abstract":"<p><p>Myelofibrosis (MF) is a chronic, progressive myeloproliferative neoplasm characterized by bone marrow fibrosis, ineffective blood cell production, and neoplastic extramedullary hematopoiesis (EMH) occurring primarily within the spleen. To explore the molecular mechanisms underlying splenic EMH, we performed single-cell transcriptional and chromatin profiling of cells from MF spleens that had been surgically removed. We demonstrate significant expansion of hematopoietic stem and progenitor cells, coupled with aberrant differentiation toward the erythroid and megakaryocytic lineages, associated with a significant enrichment of inflammatory pathways with enhanced NF-κB signaling and IFN responses, as well as dysregulation of the inferred function of differentiation-defining transcription factors. Finally, we report a significant remodeling of the immune microenvironment in MF spleens, characterized by emergence of dysfunctional T cell subsets and inflammatory memory B cells, suggesting the concomitant establishment of a pro-inflammatory and immune-tolerant tumor microenvironment within the spleen that influences hematopoietic cell differentiation and impairs tumor immune surveillance.</p>","PeriodicalId":93928,"journal":{"name":"Cell stem cell","volume":" ","pages":"1495-1513.e13"},"PeriodicalIF":20.4,"publicationDate":"2026-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148820513","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 : 2026-09-03Epub Date: 2026-08-11DOI: 10.1016/j.stem.2026.07.011
Yuanhang He, Abbas Jalili, Carter B Jones, Haoting He, Lameck Beni, Daniel Lamont, Junqi Hu, Macy Yost, Lance A Davidson, Si-Yang Zheng, Guang Li
{"title":"Human iPSC-derived heart valve-like assembloids model valve development and disease pathology.","authors":"Yuanhang He, Abbas Jalili, Carter B Jones, Haoting He, Lameck Beni, Daniel Lamont, Junqi Hu, Macy Yost, Lance A Davidson, Si-Yang Zheng, Guang Li","doi":"10.1016/j.stem.2026.07.011","DOIUrl":"10.1016/j.stem.2026.07.011","url":null,"abstract":"<p><p>Heart valves maintain unidirectional blood flow, yet most understanding of their development and disease comes from animal models that do not fully capture human valve behavior. We present a human induced pluripotent stem cell (iPSC)-derived valve-like assembloid platform that models key aspects of in vivo valve features at the cellular and molecular levels. We found that mechanical forces, endothelial culture conditions, and fluidic shear stress respectively promote valve induction, maintenance, and extracellular matrix stratification. We further used this system to model human valve defects, including genetic mutations, injury, and hyperglycemia-related abnormalities. This assembloid platform enables the in vitro study of human valve development and disease mechanisms.</p>","PeriodicalId":93928,"journal":{"name":"Cell stem cell","volume":" ","pages":"1514-1527.e9"},"PeriodicalIF":20.4,"publicationDate":"2026-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13496497/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148714954","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 : 2026-09-03Epub Date: 2026-08-11DOI: 10.1016/j.stem.2026.07.010
Holly K Voges, Jessica Durrant-Whyte, Michael See, Valerii Iaprintsev, Serene Yeow, Benjamin L Parker, Kaitlyn Bibby, Ellen Keen, Ingrid King, Adam T Piers, Anita C Thomas, Daniel G Donner, Akriti Varshney, Sara Alaei, David Yoannidis, Timothy Semple, Natalie Charitakis, Jerico Revote, Adriano Morandini, Purva Kumbhar, Rebecca Sutton, Francesca Butera, Edouard G Stanley, Janice D Reid, James E Hudson, Amr H Allam, Sara Ellis, Lina H H Le, James P Burgess, Sean J Humphrey, Salvatore Pepe, Hazem Alkazemi, Daniel E Heath, Mirana Ramialison, Fernando J Rossello, Christian P Brizard, David A Elliott, Alejandro Hidalgo, Enzo R Porrello
{"title":"Human heart valve-like tissues from pluripotent stem cells with enhanced maturation recapitulate inflammatory valve disease.","authors":"Holly K Voges, Jessica Durrant-Whyte, Michael See, Valerii Iaprintsev, Serene Yeow, Benjamin L Parker, Kaitlyn Bibby, Ellen Keen, Ingrid King, Adam T Piers, Anita C Thomas, Daniel G Donner, Akriti Varshney, Sara Alaei, David Yoannidis, Timothy Semple, Natalie Charitakis, Jerico Revote, Adriano Morandini, Purva Kumbhar, Rebecca Sutton, Francesca Butera, Edouard G Stanley, Janice D Reid, James E Hudson, Amr H Allam, Sara Ellis, Lina H H Le, James P Burgess, Sean J Humphrey, Salvatore Pepe, Hazem Alkazemi, Daniel E Heath, Mirana Ramialison, Fernando J Rossello, Christian P Brizard, David A Elliott, Alejandro Hidalgo, Enzo R Porrello","doi":"10.1016/j.stem.2026.07.010","DOIUrl":"10.1016/j.stem.2026.07.010","url":null,"abstract":"<p><p>Therapeutic management of heart valve disease is currently hampered by a lack of mechanistic understanding of human valve development and pathobiology. Here, we develop a protocol to generate three-dimensional human heart valve-like tissues from pluripotent stem cells with enhanced maturational properties that partially recapitulate key molecular features of native valves. This includes an abundance of valve interstitial cells, resident macrophage cells, and the transcriptional profile of native heart valves. Importantly, we define a heart valve maturation signature from proteomic analysis and show that maturation of stem cell-derived valve cells is enhanced under 3D culture. We demonstrate that bioengineered valve-like microtissues can be used for modeling valve disease. Namely, treatment with inflammatory cytokines augmented tissue passive tension and induced molecular hallmarks of valve calcification, consistent with the pathological signature of clinical samples from diseased valves. Thus, bioengineered human heart valve-like tissues provide a platform to understand human heart valve development, maturation, and disease pathogenesis.</p>","PeriodicalId":93928,"journal":{"name":"Cell stem cell","volume":" ","pages":"1528-1539.e10"},"PeriodicalIF":20.4,"publicationDate":"2026-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148714884","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 : 2026-09-03Epub Date: 2026-08-10DOI: 10.1016/j.stem.2026.07.008
Zhiquan Liu, Siyu Chen, Wenmin Wang, Fan Zhang, Qing Wang, Grzegorz Walkiewicz, Faruk Hossen, Jinqiong Zhou, Yiting Wang, Yang Sun
{"title":"TIGRa: An ultra-compact programmable activator enabling multiplexed and efficient gene regulation.","authors":"Zhiquan Liu, Siyu Chen, Wenmin Wang, Fan Zhang, Qing Wang, Grzegorz Walkiewicz, Faruk Hossen, Jinqiong Zhou, Yiting Wang, Yang Sun","doi":"10.1016/j.stem.2026.07.008","DOIUrl":"10.1016/j.stem.2026.07.008","url":null,"abstract":"<p><p>Programmable gene activation has broad therapeutic potential but remains constrained by the large effector size, limited multiplexing capacity, and challenges in in vivo delivery. Here, we develop the TIGR-TasR-mediated activator (TIGRa), a compact transcriptional activator derived from the tandem interspaced guide RNA (TIGR)-TIGR-associated protein (TasR) system that is mechanistically distinct from CRISPR-based activators. TIGRa is less than half the size of dSpCas9-based activators while achieving comparable or greater activation efficiency. Its native TIGR array architecture enables efficient multiplexed regulation, supporting simultaneous activation of up to 12 endogenous genes from a single compact construct. TIGRa-mediated multi-gene activation efficiently reprogrammed human fibroblasts into induced pluripotent stem cells. In addition, an all-in-one adeno-associated virus (AAV)-TIGRa vector activated endogenous CaMKII in vivo, promoting retinal ganglion cell survival and preserving visual function in a mouse model of N-methyl-D-aspartic (NMDA)-induced retinal injury. These results establish TIGRa as a compact and multiplexable platform for therapeutic gene regulation and in vivo genetic medicine.</p>","PeriodicalId":93928,"journal":{"name":"Cell stem cell","volume":" ","pages":"1553-1566.e4"},"PeriodicalIF":20.4,"publicationDate":"2026-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13526431/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148708909","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}
求助内容：
应助结果提醒方式：
京公网安备 11010802042870号
