Mardi Fink, Kizito Njah, Shyam J. Patel, David P. Cook, Vanessa Man, Francesco Ruso, Arsheen Rajan, Masahiro Narimatsu, Andreea Obersterescu, Melanie J. Pye, Daniel Trcka, Kin Chan, Arshad Ayyaz, Jeffrey L. Wrana
{"title":"受损肠隐窝中的染色质重塑可协调冗余的 TGFβ 和 Hippo 信号,从而推动肠道再生","authors":"Mardi Fink, Kizito Njah, Shyam J. Patel, David P. Cook, Vanessa Man, Francesco Ruso, Arsheen Rajan, Masahiro Narimatsu, Andreea Obersterescu, Melanie J. Pye, Daniel Trcka, Kin Chan, Arshad Ayyaz, Jeffrey L. Wrana","doi":"10.1038/s41556-024-01550-4","DOIUrl":null,"url":null,"abstract":"Cell state dynamics underlying successful tissue regeneration are undercharacterized. In the intestine, damage prompts epithelial reprogramming into revival stem cells (revSCs) that reconstitute Lgr5+ intestinal stem cells (ISCs). Here single-nuclear multi-omics of mouse crypts regenerating from irradiation shows revSC chromatin accessibility overlaps with ISCs and differentiated lineages. While revSC genes themselves are accessible throughout homeostatic epithelia, damage-induced remodelling of chromatin in the crypt converges on Hippo and the transforming growth factor-beta (TGFβ) signalling pathway, which we show is transiently activated and directly induces functional revSCs. Combinatorial gene expression analysis further suggests multiple sources of revSCs, and we demonstrate TGFβ can reprogramme enterocytes, goblet and paneth cells into revSCs and show individual revSCs form organoids. Despite this, loss of TGFβ signalling yields mild regenerative defects, whereas interference in both Hippo and TGFβ leads to profound defects and death. Intestinal regeneration is thus poised for activation by a compensatory system of crypt-localized, transient morphogen cues that support epithelial reprogramming and robust intestinal repair. Using deep single-nucleus multi-omics profiling, Fink et al. report transition states between crypt epithelial cells and a revival stem cell lineage. They find that the TGFβ and Hippo signalling pathways cooperatively drive intestinal regeneration.","PeriodicalId":18977,"journal":{"name":"Nature Cell Biology","volume":"26 12","pages":"2084-2098"},"PeriodicalIF":17.3000,"publicationDate":"2024-11-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Chromatin remodelling in damaged intestinal crypts orchestrates redundant TGFβ and Hippo signalling to drive regeneration\",\"authors\":\"Mardi Fink, Kizito Njah, Shyam J. Patel, David P. Cook, Vanessa Man, Francesco Ruso, Arsheen Rajan, Masahiro Narimatsu, Andreea Obersterescu, Melanie J. Pye, Daniel Trcka, Kin Chan, Arshad Ayyaz, Jeffrey L. Wrana\",\"doi\":\"10.1038/s41556-024-01550-4\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"Cell state dynamics underlying successful tissue regeneration are undercharacterized. In the intestine, damage prompts epithelial reprogramming into revival stem cells (revSCs) that reconstitute Lgr5+ intestinal stem cells (ISCs). Here single-nuclear multi-omics of mouse crypts regenerating from irradiation shows revSC chromatin accessibility overlaps with ISCs and differentiated lineages. While revSC genes themselves are accessible throughout homeostatic epithelia, damage-induced remodelling of chromatin in the crypt converges on Hippo and the transforming growth factor-beta (TGFβ) signalling pathway, which we show is transiently activated and directly induces functional revSCs. Combinatorial gene expression analysis further suggests multiple sources of revSCs, and we demonstrate TGFβ can reprogramme enterocytes, goblet and paneth cells into revSCs and show individual revSCs form organoids. Despite this, loss of TGFβ signalling yields mild regenerative defects, whereas interference in both Hippo and TGFβ leads to profound defects and death. Intestinal regeneration is thus poised for activation by a compensatory system of crypt-localized, transient morphogen cues that support epithelial reprogramming and robust intestinal repair. Using deep single-nucleus multi-omics profiling, Fink et al. report transition states between crypt epithelial cells and a revival stem cell lineage. 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Chromatin remodelling in damaged intestinal crypts orchestrates redundant TGFβ and Hippo signalling to drive regeneration
Cell state dynamics underlying successful tissue regeneration are undercharacterized. In the intestine, damage prompts epithelial reprogramming into revival stem cells (revSCs) that reconstitute Lgr5+ intestinal stem cells (ISCs). Here single-nuclear multi-omics of mouse crypts regenerating from irradiation shows revSC chromatin accessibility overlaps with ISCs and differentiated lineages. While revSC genes themselves are accessible throughout homeostatic epithelia, damage-induced remodelling of chromatin in the crypt converges on Hippo and the transforming growth factor-beta (TGFβ) signalling pathway, which we show is transiently activated and directly induces functional revSCs. Combinatorial gene expression analysis further suggests multiple sources of revSCs, and we demonstrate TGFβ can reprogramme enterocytes, goblet and paneth cells into revSCs and show individual revSCs form organoids. Despite this, loss of TGFβ signalling yields mild regenerative defects, whereas interference in both Hippo and TGFβ leads to profound defects and death. Intestinal regeneration is thus poised for activation by a compensatory system of crypt-localized, transient morphogen cues that support epithelial reprogramming and robust intestinal repair. Using deep single-nucleus multi-omics profiling, Fink et al. report transition states between crypt epithelial cells and a revival stem cell lineage. They find that the TGFβ and Hippo signalling pathways cooperatively drive intestinal regeneration.
期刊介绍:
Nature Cell Biology, a prestigious journal, upholds a commitment to publishing papers of the highest quality across all areas of cell biology, with a particular focus on elucidating mechanisms underlying fundamental cell biological processes. The journal's broad scope encompasses various areas of interest, including but not limited to:
-Autophagy
-Cancer biology
-Cell adhesion and migration
-Cell cycle and growth
-Cell death
-Chromatin and epigenetics
-Cytoskeletal dynamics
-Developmental biology
-DNA replication and repair
-Mechanisms of human disease
-Mechanobiology
-Membrane traffic and dynamics
-Metabolism
-Nuclear organization and dynamics
-Organelle biology
-Proteolysis and quality control
-RNA biology
-Signal transduction
-Stem cell biology