Pub Date : 2026-01-05DOI: 10.1038/s41556-025-01841-4
Sarah May Russell, Mirren Charnley
The discovery that CD8+ T cells divide asymmetrically has generated considerable speculation regarding how such divisions regulate the fate of these cells. Excitingly, a recent study links the inheritance of a fate determinant to divergence in CD8+ T cell fate among the daughters of an asymmetric division.
{"title":"Mitochondrial asymmetry shifts T cell fate","authors":"Sarah May Russell, Mirren Charnley","doi":"10.1038/s41556-025-01841-4","DOIUrl":"10.1038/s41556-025-01841-4","url":null,"abstract":"The discovery that CD8+ T cells divide asymmetrically has generated considerable speculation regarding how such divisions regulate the fate of these cells. Excitingly, a recent study links the inheritance of a fate determinant to divergence in CD8+ T cell fate among the daughters of an asymmetric division.","PeriodicalId":18977,"journal":{"name":"Nature Cell Biology","volume":"28 1","pages":"2-3"},"PeriodicalIF":19.1,"publicationDate":"2026-01-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145902713","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-12-29DOI: 10.1038/s41556-025-01833-4
Laurianne Scourzic, Franco Izzo, Matt Teater, Alexander P. Polyzos, Lucretia Cucereavii, Christopher R. Chin, Antonin Papin, Hugo B. Pinto, Coraline Mlynarczyk, Ioanna Tsialta, Min Xia, Abigail Lidoski, Robert M. Myers, Eva M. Israel, Leandro Venturutti, Simon P. Mackay, Kenneth B. Hoehn, Arthur I. Skoultchi, Wendy Béguelin, Matthias Stadtfeld, Zhengming Chen, Dan A. Landau, Ari M. Melnick, Effie Apostolou
During the germinal centre (GC) reaction, mature B cells undergo rapid and reversible phenotypic shifts that are essential for adaptive immunity. Here we report that GC B cells, unlike other mature B cells, transiently acquire a unique epigenetic plasticity, demonstrated by their enhanced capacity to reprogram to induced pluripotent stem cells. This plasticity depends on T follicular helper (TFH) cells and is not due to increased proliferation or MYC activation. Instead, it involves weakening of B-cell identity and derepression of stem and progenitor programs driven by NF-κB and other TFH-derived signals. Thus, physiological GC plasticity is tightly constrained by the affinity maturation process of positive selection. Loss of histone 1, a chromatin compaction regulator restricting the accessibility of embryonic stem cell programs, further enhances GC plasticity by bypassing this gatekeeping mechanism. Importantly, patients with B-cell lymphoma enriched for GC plasticity signatures had worse outcomes, suggesting that this mechanism may also contribute to lymphomagenesis. Scourzic et al. show that germinal centre B cells display an enhanced ability to reprogram to induced pluripotent stem cells compared to mature B cells. This ability indicates their higher plasticity level and is T follicular helper cell-dependent.
{"title":"T follicular helper cells transiently unlock a plasticity state in germinal centre B cells during the humoral immune response","authors":"Laurianne Scourzic, Franco Izzo, Matt Teater, Alexander P. Polyzos, Lucretia Cucereavii, Christopher R. Chin, Antonin Papin, Hugo B. Pinto, Coraline Mlynarczyk, Ioanna Tsialta, Min Xia, Abigail Lidoski, Robert M. Myers, Eva M. Israel, Leandro Venturutti, Simon P. Mackay, Kenneth B. Hoehn, Arthur I. Skoultchi, Wendy Béguelin, Matthias Stadtfeld, Zhengming Chen, Dan A. Landau, Ari M. Melnick, Effie Apostolou","doi":"10.1038/s41556-025-01833-4","DOIUrl":"10.1038/s41556-025-01833-4","url":null,"abstract":"During the germinal centre (GC) reaction, mature B cells undergo rapid and reversible phenotypic shifts that are essential for adaptive immunity. Here we report that GC B cells, unlike other mature B cells, transiently acquire a unique epigenetic plasticity, demonstrated by their enhanced capacity to reprogram to induced pluripotent stem cells. This plasticity depends on T follicular helper (TFH) cells and is not due to increased proliferation or MYC activation. Instead, it involves weakening of B-cell identity and derepression of stem and progenitor programs driven by NF-κB and other TFH-derived signals. Thus, physiological GC plasticity is tightly constrained by the affinity maturation process of positive selection. Loss of histone 1, a chromatin compaction regulator restricting the accessibility of embryonic stem cell programs, further enhances GC plasticity by bypassing this gatekeeping mechanism. Importantly, patients with B-cell lymphoma enriched for GC plasticity signatures had worse outcomes, suggesting that this mechanism may also contribute to lymphomagenesis. Scourzic et al. show that germinal centre B cells display an enhanced ability to reprogram to induced pluripotent stem cells compared to mature B cells. This ability indicates their higher plasticity level and is T follicular helper cell-dependent.","PeriodicalId":18977,"journal":{"name":"Nature Cell Biology","volume":"28 1","pages":"35-48"},"PeriodicalIF":19.1,"publicationDate":"2025-12-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145857297","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-12-24DOI: 10.1038/s41556-025-01819-2
Isabelle Seufert, Irene Gerosa, Vassiliki Varamogianni-Mamatsi, Anastasiya Vladimirova, Ezgi Sen, Stefanie Mantz, Anne Rademacher, Sabrina Schumacher, Panagiotis Liakopoulos, Petros Kolovos, Simon Anders, Jan-Philipp Mallm, Argyris Papantonis, Karsten Rippe
Gene activation and coregulation have been attributed to different mechanisms, such as enhancer–promoter interactions via chromatin looping or the accumulation of transcription factors into hubs or condensates. However, genome-wide studies exploring mechanistic differences in endogenous gene regulation in primary human cells are scarce. Here we dissect the proinflammatory gene expression programme induced by tumor necrosis factor (TNF) in human endothelial cells using sequencing- and imaging-based methods. Our findings, enabled by the co-accessibility analysis of deep-coverage single-cell chromatin accessibility data with our RWireX software, identified two distinct regulatory chromatin modules: autonomous links of co-accessibility (ACs) between separated sites and domains of contiguous co-accessibility (DCs) with increased local transcription factor binding. The TNF-dependent induction timing and strength as well as changes in transcriptional bursting kinetics differed for genes in the AC and DC modules, pointing to functionally distinct regulatory mechanisms. These findings provide a framework for understanding how cells achieve rapid and precise control of gene expression. Seufert et al. analyse chromatin accessibility to identify sites that open simultaneously in response to TNF. They discover two distinct types of co-accessible regulatory module for controlling the induction of proinflammatory gene expression.
{"title":"Two distinct chromatin modules regulate proinflammatory gene expression","authors":"Isabelle Seufert, Irene Gerosa, Vassiliki Varamogianni-Mamatsi, Anastasiya Vladimirova, Ezgi Sen, Stefanie Mantz, Anne Rademacher, Sabrina Schumacher, Panagiotis Liakopoulos, Petros Kolovos, Simon Anders, Jan-Philipp Mallm, Argyris Papantonis, Karsten Rippe","doi":"10.1038/s41556-025-01819-2","DOIUrl":"10.1038/s41556-025-01819-2","url":null,"abstract":"Gene activation and coregulation have been attributed to different mechanisms, such as enhancer–promoter interactions via chromatin looping or the accumulation of transcription factors into hubs or condensates. However, genome-wide studies exploring mechanistic differences in endogenous gene regulation in primary human cells are scarce. Here we dissect the proinflammatory gene expression programme induced by tumor necrosis factor (TNF) in human endothelial cells using sequencing- and imaging-based methods. Our findings, enabled by the co-accessibility analysis of deep-coverage single-cell chromatin accessibility data with our RWireX software, identified two distinct regulatory chromatin modules: autonomous links of co-accessibility (ACs) between separated sites and domains of contiguous co-accessibility (DCs) with increased local transcription factor binding. The TNF-dependent induction timing and strength as well as changes in transcriptional bursting kinetics differed for genes in the AC and DC modules, pointing to functionally distinct regulatory mechanisms. These findings provide a framework for understanding how cells achieve rapid and precise control of gene expression. Seufert et al. analyse chromatin accessibility to identify sites that open simultaneously in response to TNF. They discover two distinct types of co-accessible regulatory module for controlling the induction of proinflammatory gene expression.","PeriodicalId":18977,"journal":{"name":"Nature Cell Biology","volume":"28 1","pages":"182-196"},"PeriodicalIF":19.1,"publicationDate":"2025-12-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145814050","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-12-22DOI: 10.1038/s41556-025-01828-1
Allana Schooley, Sergey V. Venev, Vasilisa Aksenova, Jesse W. Lehman, Emily Navarrete, Athma A. Pai, Mary Dasso, Job Dekker
Identity-specific chromosome conformation must be re-established at each cell division. To uncover how interphase folding is inherited, we developed an approach that segregates chromosome-intrinsic mechanisms from those propagated through the cytoplasm during G1 nuclear reassembly. Inducible degradation of proteins essential for the establishment of nucleocytoplasmic transport during mitotic exit enabled analysis of folding programmes with distinct modes of inheritance. Here we show that genome compartmentalization is driven entirely by chromosome-intrinsic factors. In addition to conventional compartmental segregation, the chromosome-intrinsic folding programme leads to prominent genome-scale microcompartmentalization of mitotically bookmarked cis-regulatory elements. The microcompartment conformation forms transiently during telophase and is subsequently modulated by a second folding programme inherited through the cytoplasm in early G1. This programme includes cohesin-mediated loop extrusion and factors involved in transcription and RNA processing. The combined and interdependent action of chromosome-intrinsic and cytoplasmic inherited folding programmes determines the interphase chromatin conformation as cells exit mitosis. Schooley et al. find that mitotically bookmarked loci drive a transient chromosome folding state during G1 entry that is subsequently modulated by factors inherited through the cytoplasm.
{"title":"Interphase chromosome conformation is specified by distinct folding programmes inherited through mitotic chromosomes or the cytoplasm","authors":"Allana Schooley, Sergey V. Venev, Vasilisa Aksenova, Jesse W. Lehman, Emily Navarrete, Athma A. Pai, Mary Dasso, Job Dekker","doi":"10.1038/s41556-025-01828-1","DOIUrl":"10.1038/s41556-025-01828-1","url":null,"abstract":"Identity-specific chromosome conformation must be re-established at each cell division. To uncover how interphase folding is inherited, we developed an approach that segregates chromosome-intrinsic mechanisms from those propagated through the cytoplasm during G1 nuclear reassembly. Inducible degradation of proteins essential for the establishment of nucleocytoplasmic transport during mitotic exit enabled analysis of folding programmes with distinct modes of inheritance. Here we show that genome compartmentalization is driven entirely by chromosome-intrinsic factors. In addition to conventional compartmental segregation, the chromosome-intrinsic folding programme leads to prominent genome-scale microcompartmentalization of mitotically bookmarked cis-regulatory elements. The microcompartment conformation forms transiently during telophase and is subsequently modulated by a second folding programme inherited through the cytoplasm in early G1. This programme includes cohesin-mediated loop extrusion and factors involved in transcription and RNA processing. The combined and interdependent action of chromosome-intrinsic and cytoplasmic inherited folding programmes determines the interphase chromatin conformation as cells exit mitosis. Schooley et al. find that mitotically bookmarked loci drive a transient chromosome folding state during G1 entry that is subsequently modulated by factors inherited through the cytoplasm.","PeriodicalId":18977,"journal":{"name":"Nature Cell Biology","volume":"28 1","pages":"82-97"},"PeriodicalIF":19.1,"publicationDate":"2025-12-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41556-025-01828-1.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145801593","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-12-22DOI: 10.1038/s41556-025-01863-y
Jay V Patankar, Tanja M Müller, Srinivas Kantham, Miguel Gonzalez Acera, Fabrizio Mascia, Kristina Scheibe, Mousumi Mahapatro, Christina Heichler, Yuqiang Yu, Wei Li, Barbara Ruder, Claudia Günther, Moritz Leppkes, Mano J Mathew, Stefan Wirtz, Clemens Neufert, Anja A Kühl, Jay Paquette, Kevan Jacobson, Raja Atreya, Sebastian Zundler, Markus F Neurath, Robert N Young, Christoph Becker
{"title":"Author Correction: E-type prostanoid receptor 4 drives resolution of intestinal inflammation by blocking epithelial necroptosis.","authors":"Jay V Patankar, Tanja M Müller, Srinivas Kantham, Miguel Gonzalez Acera, Fabrizio Mascia, Kristina Scheibe, Mousumi Mahapatro, Christina Heichler, Yuqiang Yu, Wei Li, Barbara Ruder, Claudia Günther, Moritz Leppkes, Mano J Mathew, Stefan Wirtz, Clemens Neufert, Anja A Kühl, Jay Paquette, Kevan Jacobson, Raja Atreya, Sebastian Zundler, Markus F Neurath, Robert N Young, Christoph Becker","doi":"10.1038/s41556-025-01863-y","DOIUrl":"https://doi.org/10.1038/s41556-025-01863-y","url":null,"abstract":"","PeriodicalId":18977,"journal":{"name":"Nature Cell Biology","volume":" ","pages":""},"PeriodicalIF":19.1,"publicationDate":"2025-12-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145810642","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-12-22DOI: 10.1038/s41556-025-01851-2
Kyle P. Eagen
Chromosomes unfold and refold each time cells divide. A study by Schooley et al. demonstrates that chromosome-intrinsic and cytoplasmic factors uniquely contribute to interphase chromosome structure, with new possibilities for how gene expression programs are passed from mother cells to daughter cells.
{"title":"Inheriting chromosome conformation","authors":"Kyle P. Eagen","doi":"10.1038/s41556-025-01851-2","DOIUrl":"10.1038/s41556-025-01851-2","url":null,"abstract":"Chromosomes unfold and refold each time cells divide. A study by Schooley et al. demonstrates that chromosome-intrinsic and cytoplasmic factors uniquely contribute to interphase chromosome structure, with new possibilities for how gene expression programs are passed from mother cells to daughter cells.","PeriodicalId":18977,"journal":{"name":"Nature Cell Biology","volume":"28 1","pages":"4-5"},"PeriodicalIF":19.1,"publicationDate":"2025-12-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145810605","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-12-19DOI: 10.1038/s41556-025-01834-3
Jarrett Smith, David P. Bartel
When mammalian cells are exposed to stress, they co-ordinate the condensation of stress granules (SGs) through the action of proteins G3BP1 and G3BP2 (G3BPs) and, simultaneously, undergo a massive reduction in translation. Although SGs and G3BPs have been linked to this translation response, their overall impact has been unclear. Here we investigate the question of how, and indeed whether, G3BPs and SGs shape the stress translation response. We find that SGs are enriched for mRNAs that are resistant to the stress-induced translation shutdown. Although the accurate recruitment of these stress-resistant mRNAs does require the context of stress, a combination of optogenetic tools and spike-normalized ribosome profiling demonstrates that G3BPs and SGs are necessary and sufficient to both help prioritize the translation of their enriched mRNAs and help suppress cytosolic translation. Together, these results support a model in which G3BPs and SGs reinforce the stress translation programme by prioritizing the translation of their resident mRNAs. Smith and Bartel show that mRNA recruitment to stress granules imparts resistance to the integrated stress response translational shutdown.
{"title":"The G3BP stress-granule proteins reinforce the integrated stress response translation programme","authors":"Jarrett Smith, David P. Bartel","doi":"10.1038/s41556-025-01834-3","DOIUrl":"10.1038/s41556-025-01834-3","url":null,"abstract":"When mammalian cells are exposed to stress, they co-ordinate the condensation of stress granules (SGs) through the action of proteins G3BP1 and G3BP2 (G3BPs) and, simultaneously, undergo a massive reduction in translation. Although SGs and G3BPs have been linked to this translation response, their overall impact has been unclear. Here we investigate the question of how, and indeed whether, G3BPs and SGs shape the stress translation response. We find that SGs are enriched for mRNAs that are resistant to the stress-induced translation shutdown. Although the accurate recruitment of these stress-resistant mRNAs does require the context of stress, a combination of optogenetic tools and spike-normalized ribosome profiling demonstrates that G3BPs and SGs are necessary and sufficient to both help prioritize the translation of their enriched mRNAs and help suppress cytosolic translation. Together, these results support a model in which G3BPs and SGs reinforce the stress translation programme by prioritizing the translation of their resident mRNAs. Smith and Bartel show that mRNA recruitment to stress granules imparts resistance to the integrated stress response translational shutdown.","PeriodicalId":18977,"journal":{"name":"Nature Cell Biology","volume":"28 1","pages":"135-148"},"PeriodicalIF":19.1,"publicationDate":"2025-12-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41556-025-01834-3.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145794293","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-12-19DOI: 10.1038/s41556-025-01835-2
Mariana Borsa, Ana Victoria Lechuga-Vieco, Amir H. Kayvanjoo, Edward Jenkins, Yavuz Yazicioglu, Ewoud B. Compeer, Felix C. Richter, Simon Rapp, Robert Mitchell, Tom Youdale, Hien Bui, Emilia Kuuluvainen, Michael L. Dustin, Linda V. Sinclair, Pekka Katajisto, Anna Katharina Simon
T cell immunity deteriorates with age, accompanied by a decline in autophagy and asymmetric cell division. Here we show that autophagy regulates mitochondrial inheritance in CD8+ T cells. Using a mouse model that enables sequential tagging of mitochondria in mother and daughter cells, we demonstrate that autophagy-deficient T cells fail to clear premitotic old mitochondria and inherit them symmetrically. By contrast, autophagy-competent cells that partition mitochondria asymmetrically produce daughter cells with distinct fates: those retaining old mitochondria exhibit reduced memory potential, whereas those that have not inherited old mitochondria and exhibit higher mitochondrial turnover are long-lived and expand upon cognate-antigen challenge. Multiomics analyses suggest that early fate divergence is driven by distinct metabolic programmes, with one-carbon metabolism activated in cells retaining premitotic mitochondria. These findings advance our understanding of how T cell diversity is imprinted early during division and support the development of strategies to modulate T cell function. Borsa et al. show that asymmetric T cell division after activation requires autophagy to promote mitochondrial turnover, with T cells inheriting older mitochondria showing decreased degradation, reduced memory potential and altered metabolism.
{"title":"Autophagy-regulated mitochondrial inheritance controls early CD8+ T cell fate commitment","authors":"Mariana Borsa, Ana Victoria Lechuga-Vieco, Amir H. Kayvanjoo, Edward Jenkins, Yavuz Yazicioglu, Ewoud B. Compeer, Felix C. Richter, Simon Rapp, Robert Mitchell, Tom Youdale, Hien Bui, Emilia Kuuluvainen, Michael L. Dustin, Linda V. Sinclair, Pekka Katajisto, Anna Katharina Simon","doi":"10.1038/s41556-025-01835-2","DOIUrl":"10.1038/s41556-025-01835-2","url":null,"abstract":"T cell immunity deteriorates with age, accompanied by a decline in autophagy and asymmetric cell division. Here we show that autophagy regulates mitochondrial inheritance in CD8+ T cells. Using a mouse model that enables sequential tagging of mitochondria in mother and daughter cells, we demonstrate that autophagy-deficient T cells fail to clear premitotic old mitochondria and inherit them symmetrically. By contrast, autophagy-competent cells that partition mitochondria asymmetrically produce daughter cells with distinct fates: those retaining old mitochondria exhibit reduced memory potential, whereas those that have not inherited old mitochondria and exhibit higher mitochondrial turnover are long-lived and expand upon cognate-antigen challenge. Multiomics analyses suggest that early fate divergence is driven by distinct metabolic programmes, with one-carbon metabolism activated in cells retaining premitotic mitochondria. These findings advance our understanding of how T cell diversity is imprinted early during division and support the development of strategies to modulate T cell function. Borsa et al. show that asymmetric T cell division after activation requires autophagy to promote mitochondrial turnover, with T cells inheriting older mitochondria showing decreased degradation, reduced memory potential and altered metabolism.","PeriodicalId":18977,"journal":{"name":"Nature Cell Biology","volume":"28 1","pages":"66-81"},"PeriodicalIF":19.1,"publicationDate":"2025-12-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41556-025-01835-2.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145786289","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-12-19DOI: 10.1038/s41556-025-01832-5
Byung Ho Lee, Kana Fuji, Heike Petzold, Phil Seymour, Siham Yennek, Coline Schewin, Allison Lewis, Daniel Riveline, Tetsuya Hiraiwa, Masaki Sano, Anne Grapin-Botton
Lumen formation in organ epithelia involves processes such as polarization, secretion, exocytosis and contractility, but what controls lumen shape remains unclear. Here we study how lumina develop spherical or complex structures using pancreatic organoids. Combining computational phase-field modelling and experiments, we found that lumen morphology depends on the balance between cell cycle duration and lumen pressure, low pressure and high proliferation produce complex shapes. Manipulating proliferation and lumen pressure can alter or reverse lumen development both in silico and in vitro. Increasing epithelial permeability reduces lumen pressure, converting from spherical to complex lumina. During pancreas development, the epithelium is initially permeable and becomes sealed, experimentally increasing permeability at late stages impairs ductal morphogenesis. Overall, our work underscores how proliferation, pressure and permeability orchestrate lumen shape, offering insights for tissue engineering and cystic disease treatment. Using pancreatic organoids, Lee et al. show that the balance between epithelial tissue permeability-driven lumenal pressure and cell proliferation affects ductal morphogenesis.
{"title":"Permeability-driven pressure and cell proliferation control lumen morphogenesis in pancreatic organoids","authors":"Byung Ho Lee, Kana Fuji, Heike Petzold, Phil Seymour, Siham Yennek, Coline Schewin, Allison Lewis, Daniel Riveline, Tetsuya Hiraiwa, Masaki Sano, Anne Grapin-Botton","doi":"10.1038/s41556-025-01832-5","DOIUrl":"10.1038/s41556-025-01832-5","url":null,"abstract":"Lumen formation in organ epithelia involves processes such as polarization, secretion, exocytosis and contractility, but what controls lumen shape remains unclear. Here we study how lumina develop spherical or complex structures using pancreatic organoids. Combining computational phase-field modelling and experiments, we found that lumen morphology depends on the balance between cell cycle duration and lumen pressure, low pressure and high proliferation produce complex shapes. Manipulating proliferation and lumen pressure can alter or reverse lumen development both in silico and in vitro. Increasing epithelial permeability reduces lumen pressure, converting from spherical to complex lumina. During pancreas development, the epithelium is initially permeable and becomes sealed, experimentally increasing permeability at late stages impairs ductal morphogenesis. Overall, our work underscores how proliferation, pressure and permeability orchestrate lumen shape, offering insights for tissue engineering and cystic disease treatment. Using pancreatic organoids, Lee et al. show that the balance between epithelial tissue permeability-driven lumenal pressure and cell proliferation affects ductal morphogenesis.","PeriodicalId":18977,"journal":{"name":"Nature Cell Biology","volume":"28 1","pages":"113-124"},"PeriodicalIF":19.1,"publicationDate":"2025-12-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41556-025-01832-5.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145786287","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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