Cellular and Molecular Gastroenterology and Hepatology最新文献

{"title":"An Epigenetic Basis for Sustained Inflammatory Epithelial Progenitor Cell States in Crohn’s Disease","authors":"Tatiana A. Karakasheva ,&nbsp;Clara Morral Martinez ,&nbsp;Yusen Zhou ,&nbsp;Jingya Qui ,&nbsp;Xinyi E. Chen ,&nbsp;Gloria E. Soto ,&nbsp;Shaneice K. Nettleford ,&nbsp;Olivia T. Hix ,&nbsp;Daana M. Roach ,&nbsp;Alyssa M. Laguerta ,&nbsp;Anusha Thadi ,&nbsp;Rachael M. Edwards ,&nbsp;Daniel Aleynick ,&nbsp;Sarah Weinbrom ,&nbsp;Elizaveta Borodyanskaya ,&nbsp;Oliver H. Pickering ,&nbsp;MaryKate Fulton ,&nbsp;Chia-Hui Chen ,&nbsp;Isabella V. Peterson ,&nbsp;Erik B. Hagen ,&nbsp;Kathryn E. Hamilton","doi":"10.1016/j.jcmgh.2025.101665","DOIUrl":"10.1016/j.jcmgh.2025.101665","url":null,"abstract":"<div><h3>Background &amp; Aims</h3><div>Defining consequential differences in intestinal epithelial stem cells in healthy humans vs those with inflammatory bowel disease (Crohn’s disease and ulcerative colitis) is essential for the development of much needed therapies to restore the epithelial barrier and maintain its fidelity.</div></div><div><h3>Methods</h3><div>We used single-cell transcriptomic and epigenomic approaches in matched patient tissues and organoids to investigate epithelial gene expression and function in children with no pathological diagnosis in the lower gastrointestinal tract and healthy adults compared with those with Crohn’s disease.</div></div><div><h3>Results</h3><div>We identify an inflammatory secretory progenitor (ISP) cell state present almost exclusively in patients with Crohn’s disease compared with healthy subjects. ISPs exhibit gene expression profiles consistent with normal secretory progenitor cells but concomitantly express a suite of distinguishing pro-inflammatory genes. Mechanistically, ISPs exhibit open chromatin at ISP gene loci. Although ISP-specific genes are not expressed in intestinal stem cells, their chromatin is accessible in Crohn’s disease stem cells, suggesting that ISP genes are epigenetically poised in stem cells and subsequently transcriptionally activated in ISPs in the presence of inflammatory stimuli. Consistently, Crohn’s disease colonoids exhibit sustained ISP gene expression that can be elicited further with pro-inflammatory cytokines or via co-culture with pro-inflammatory macrophages.</div></div><div><h3>Conclusions</h3><div>We have defined differences in the epithelial stem and progenitor compartment of patients with Crohn’s disease that suggest aberrant stem cell differentiation and inflammatory gene expression arise and persist during disease.</div></div>","PeriodicalId":55974,"journal":{"name":"Cellular and Molecular Gastroenterology and Hepatology","volume":"20 3","pages":"Article 101665"},"PeriodicalIF":7.1,"publicationDate":"2025-10-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145338343","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":"A Dual-compartment Scaffolding Role for Receptor for Activate C Kinase 1 in Hepatic Glucagon Signaling and Gluconeogenesis","authors":"Cancan Lyu ,&nbsp;Ling Yang ,&nbsp;Songhai Chen","doi":"10.1016/j.jcmgh.2025.101666","DOIUrl":"10.1016/j.jcmgh.2025.101666","url":null,"abstract":"<div><h3>Background &amp; Aims</h3><div>The hepatic glucagon–protein kinase A (PKA)–cAMP response element-binding protein (CREB) signaling axis plays a central role in regulating gluconeogenesis and maintaining glucose homeostasis during fasting. However, the mechanisms that govern the spatial coordination and substrate specificity of this pathway remain incompletely understood. This study determines the role of the scaffolding protein RACK1 (Receptor for Activated C Kinase 1) in orchestrating glucagon signaling to regulate hepatic gluconeogenesis.</div></div><div><h3>Methods</h3><div>RACK1 was acutely deleted in mouse liver and primary hepatocytes. Metabolic phenotypes were assessed by glucose, pyruvate, glucagon and insulin tolerance tests, as well as hepatocyte glucose production assays. Protein interactions were examined by coimmunoprecipitation, glutathione S-transferase (GST) pulldown, and miniTurbo-ID-mediated proximity labeling. Subcellular localization and signaling events were assessed by Western blotting, confocal microscopy, and cellular fractionation. Functional rescue was achieved by hepatic expression of a constitutively active PKA catalytic subunit (PKAcα^W196R).</div></div><div><h3>Results</h3><div>Acute hepatic RACK1 deficiency caused fasting hypoglycemia, impaired gluconeogenesis, and improved glucose, pyruvate, and glucagon tolerance without affecting insulin signaling. RACK1 directly bound glucagon receptor (GCGR) and PKA regulatory (RIIα) and catalytic (PKAcα) subunits, as well as CREB, functioning as a dual-compartment scaffold assembling GCGR–PKA complexes at the plasma membrane and PKAcα–CREB complexes in the nucleus. Loss of RACK1 impaired PKAcα translocation, CREB phosphorylation, and gluconeogenic gene expression. These defects were rescued by PKAcα^W196R expression. Overexpression of RACK1 WD1–2 and WD3–4 domains, which mediate PKA, GCGR, and CREB interactions, similarly disrupted PKA signaling and gluconeogenesis.</div></div><div><h3>Conclusions</h3><div>RACK1 functions as a dual-compartment scaffold, assembling GCGR–PKA at the plasma membrane and PKAcα–CREB in the nucleus, enabling precise glucagon signaling and gluconeogenesis while sparing insulin pathways, thereby ensuring compartmentalized regulation of hepatic glucose homeostasis.</div></div>","PeriodicalId":55974,"journal":{"name":"Cellular and Molecular Gastroenterology and Hepatology","volume":"20 2","pages":"Article 101666"},"PeriodicalIF":7.1,"publicationDate":"2025-10-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145338320","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":"Probiotics Mitigate High-cholesterol Diet-driven Fatty Liver and Pancreatic Cancer by Restoring Macrophage Homeostasis","authors":"Deepti Parida ,&nbsp;Swayambara Mishra ,&nbsp;Amlan Priyadarshee Mohapatra ,&nbsp;Manisha Sethi ,&nbsp;Kirti Ranjan Das ,&nbsp;Salona Kar ,&nbsp;Voddu Suresh ,&nbsp;Shrikrishna Jayaram Bhagat ,&nbsp;Amruta Mohapatra ,&nbsp;Supriya Halder ,&nbsp;Shantibhusan Senapati","doi":"10.1016/j.jcmgh.2025.101644","DOIUrl":"10.1016/j.jcmgh.2025.101644","url":null,"abstract":"<div><h3>Background &amp; Aims</h3><div>High dietary cholesterol is a known risk factor for metabolic dysfunction-associated steatotic liver disease (MASLD) and its associated hepatic carcinogenesis; however, its effect on pancreatic ductal adenocarcinoma (PDAC) is yet to be investigated. The current study explored the mechanistic association between high dietary cholesterol, MASLD, and PDAC. Importantly, we aimed to evaluate the effect of a multi-strain probiotic formulation on hypercholesterolemia-driven MASLD and PDAC.</div></div><div><h3>Methods</h3><div>In this study, wild-type (C57BL/6) and KC (Pdx-1 Cre; Kras^LSL-G12D) mice were fed either with regular diet or high cholesterol and cholic acid diet (HCCD) and received an oral probiotic consortium LR+F15 (<em>Lactobacillus rhamnosus</em> GG and <em>Lactiplantibacillus plantarum</em> ILSF15). Additionally, we also used a syngeneic orthotopic murine PDAC model to evaluate the efficacy of this probiotic consortium. For mechanistic studies, pancreas, liver, intestine, peri-pancreatic fats, peritoneal cells/lavage, and blood were evaluated for metabolic, inflammatory, and malignant changes through histology, enzyme-linked immunosorbent assay, flow cytometry, and quantitative reverse transcription polymerase chain reaction.</div></div><div><h3>Results</h3><div>HCCD induced nonobese MASLD and PDAC progression, which was eased upon probiotics intervention. Importantly, it also increased the survival of the HCCD-fed KC mice. The probiotic intervention protected against HCCD-induced leaky gut, gut microbiota translocation, and inflammatory milieu in different tissues. Interestingly, HCCD significantly increased the population of pro-inflammatory/pro-tumorigenic peritoneal macrophages, which got normalized upon probiotic administration.</div></div><div><h3>Conclusions</h3><div>The probiotic formulation LR+F15 significantly suppressed HCCD-induced MASLD and PDAC progression partly through suppressing leaky gut and normalizing peritoneal macrophages’ inflammatory properties. These findings encourage evaluation of the potential benefits of this probiotic consortium in combination with the existing therapies against PDAC in the future.</div></div>","PeriodicalId":55974,"journal":{"name":"Cellular and Molecular Gastroenterology and Hepatology","volume":"20 3","pages":"Article 101644"},"PeriodicalIF":7.1,"publicationDate":"2025-10-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145330944","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":"Barrington’s Nucleus: A Pontine Defecation Brain Area Exhibiting Prompt and Delayed Defecation Responses","authors":"Kota Bussaka ,&nbsp;Yoshimasa Tanaka ,&nbsp;Kunio Kondoh ,&nbsp;Ken-ichiro Nakajima ,&nbsp;Takatoshi Chinen ,&nbsp;Xiaopeng Bai ,&nbsp;Yosuke Minoda ,&nbsp;Hiroko Ikeda ,&nbsp;Kazuki Inamura ,&nbsp;Tsubasa Takeshima ,&nbsp;Haruei Ogino ,&nbsp;Eikichi Ihara ,&nbsp;Yasuhiko Minokoshi ,&nbsp;Yoshihiro Ogawa","doi":"10.1016/j.jcmgh.2025.101635","DOIUrl":"10.1016/j.jcmgh.2025.101635","url":null,"abstract":"<div><h3>Background &amp; Aims</h3><div>Chronic constipation has attracted considerable attention because of its negative impact on quality of life. Although defecation depends on local anorectal motility coordinated by the central nervous system, how it is regulated by the brain remains unclear.</div></div><div><h3>Methods</h3><div>Brain areas responsible for defecation, known as the defecation brain area (DBA), were identified using a trans-synaptic tracing virus, pseudorabies virus (PRV). Candidate DBAs were assessed using opto- and chemogenetic methods and in vivo monitoring of neural activity.</div></div><div><h3>Results</h3><div>A significant number of PRV-infected cells were observed in the Barrington’s nucleus (Bar), locus coeruleus (LC), ventrolateral periaqueductal gray (vlPAG), and paraventricular hypothalamic nucleus (PVH) following virus infection in the distal colon. Opto- and chemogenetic activation studies revealed that vesicular glutamate transporter 2 (VGluT2) neurons in the Bar and LC, and corticotropin-releasing hormone (CRH) neurons in the Bar exhibit prompt (short-acting) and delayed (long-lasting) contractions in the distal colon, respectively. Their neural activities increased and peaked during spontaneous defecation. In contrast, activation of tyrosine hydroxylase neurons in the LC, which co-express VGluT2, exhibited no response. PRV experiments revealed that PVH^VGluT2 and vlPAG^CRH neurons are upstream neurons that connect to Bar^VGluT2 neurons, and their optogenetic activation resulted in a contraction of the distal colon.</div></div><div><h3>Conclusions</h3><div>The study is the first to show that the Bar works as the pontine DBA, where Bar^VGluT2 and Bar^CRH neurons exert prompt and delayed defecation activity, respectively. PVH^VGluT2 and vlPAG^CRH neurons are candidates for upstream neurons that regulate defecation through Bar^VGluT2 neurons.</div></div>","PeriodicalId":55974,"journal":{"name":"Cellular and Molecular Gastroenterology and Hepatology","volume":"20 1","pages":"Article 101635"},"PeriodicalIF":7.1,"publicationDate":"2025-10-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145281942","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":"Sympathetic Overactivation Drives Colonic Eosinophil Infiltration Linked to Visceral Hypersensitivity in Irritable Bowel Syndrome","authors":"Shaoqi Duan ,&nbsp;Hirosato Kanda ,&nbsp;Feng Zhu ,&nbsp;Masamichi Okubo ,&nbsp;Taro Koike ,&nbsp;Yoshiya Ohno ,&nbsp;Toshiyuki Tanaka ,&nbsp;Yukiko Harima ,&nbsp;Kazunari Miyamichi ,&nbsp;Hirokazu Fukui ,&nbsp;Shinichiro Shinzaki ,&nbsp;Yilong Cui ,&nbsp;Koichi Noguchi ,&nbsp;Yi Dai","doi":"10.1016/j.jcmgh.2025.101658","DOIUrl":"10.1016/j.jcmgh.2025.101658","url":null,"abstract":"<div><h3>Background &amp; Aims</h3><div>Mucosal immune alteration is a characteristic clinical manifestation of irritable bowel syndrome (IBS), and its symptoms are often triggered by psychological stress. The present study aimed to investigate the impact of early life stress-associated dysfunction of the sympathetic nervous system (SNS) on mucosal immune changes in the gastrointestinal tract (GI) and its contribution to visceral hypersensitivity of IBS.</div></div><div><h3>Methods</h3><div>We utilized a traditional animal model of IBS with maternal separation (MS) and evaluated colorectal hypersensitivity, immune alteration, and SNS activity in adult rats with MS. We conducted a series of experiments to manipulate peripheral SNS activity pharmacologically and chemogenetically to explore the interaction between SNS activity and GI events.</div></div><div><h3>Results</h3><div>The MS-induced IBS model exhibited visceral hypersensitivity and eosinophilic infiltration in the colonic mucosa, along with SNS overactivation. Degeneration of the SNS using 6-OHDA neurotoxin decreased eosinophil infiltration and visceral hypersensitivity in the MS model. Notably, specific chemogenetic activation of the peripheral SNS induced eosinophil infiltration in the intestinal mucosa through the noradrenergic signaling-mediated release of eotaxin-1 from mesenchymal cells.</div></div><div><h3>Conclusions</h3><div>This study highlights the critical role of SNS overactivation in eotaxin-1-driven eosinophil infiltration in the colon, leading to the development of visceral hypersensitivity in IBS. The results provide important insights into the mechanistic links among increased sympathetic activity, mucosal immune alteration, and visceral hypersensitivity in individuals with IBS, suggesting potential therapeutic approaches.</div></div>","PeriodicalId":55974,"journal":{"name":"Cellular and Molecular Gastroenterology and Hepatology","volume":"20 3","pages":"Article 101658"},"PeriodicalIF":7.1,"publicationDate":"2025-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145260063","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":"Pathogenic OTUD3 Mutations Predispose to Ulcerative Colitis Due to Barrier Dysfunction","authors":"Rabina Giri ,&nbsp;Minyi Lee ,&nbsp;Graham W. Magor ,&nbsp;Anne-Sophie Bergot ,&nbsp;Yaowu He ,&nbsp;Thomas Kryza ,&nbsp;Tashbib Khan ,&nbsp;Veronika Schreiber ,&nbsp;Robert J. Gordon ,&nbsp;Rachid Zagani ,&nbsp;Sumaira Z. Hasnain ,&nbsp;Rohan Lourie ,&nbsp;Adam Ewing ,&nbsp;John D. Hooper ,&nbsp;Ranjeny Thomas ,&nbsp;Timothy H. Florin ,&nbsp;Andrew Perkins ,&nbsp;Manish Gala ,&nbsp;Jakob Begun","doi":"10.1016/j.jcmgh.2025.101659","DOIUrl":"10.1016/j.jcmgh.2025.101659","url":null,"abstract":"<div><h3>Background &amp; Aims</h3><div>The contribution of common genetic polymorphisms to ulcerative colitis (UC) pathogenesis is modest; however, families with severe colitis may harbor rare variants with large effect sizes that highlight unrecognized pathways.</div></div><div><h3>Methods</h3><div>A multigenerational family with UC necessitating colectomy was identified. Whole exome sequencing of this kindred was performed, implicating a rare variant in <em>OTUD3</em>. Constitutive knock-out and intestinal specific <em>Otud3</em> deficient and heterozygous mice were generated. OTUD3 expression in human colonic biopsies and intestinal organoids was assessed using quantitative reverse transcription polymerase chain reaction and immunofluorescence. Prevalence of rare, damaging variants were compared in distinct patient cohorts. Plasmids containing <em>OTUD3</em> missense variants were introduced into cell lines where <em>OTUD3</em> was disrupted to determine their effects on cellular response to cytokine stimulation.</div></div><div><h3>Results</h3><div>Constitutive disruption or heterozygosity of <em>Otud3</em> in mice, or intestinal-specific deletion, resulted in impaired barrier integrity, tight-junction dysregulation, increased endoplasmic reticulum stress, and penetration of luminal bacteria deep into the colonic crypts that preceded a spontaneous progressive colitis. Analysis of distinct UC cohorts demonstrated enrichment of rare, damaging variants in <em>OTUD3</em>. Introduction of <em>OTUD3</em> variants in intestinal cell lines phenocopied the epithelial immune dysregulation observed in knockout mice. Finally, <em>OTUD3</em> mRNA and epithelial protein expression were decreased in the quiescent colonic epithelial tissue of genotype-unselected individuals with UC compared with matched non-UC controls.</div></div><div><h3>Conclusions</h3><div>Our results demonstrate that OTUD3 is required for colonic epithelial barrier function, and plays a role in the pathogenesis of UC.</div></div>","PeriodicalId":55974,"journal":{"name":"Cellular and Molecular Gastroenterology and Hepatology","volume":"20 2","pages":"Article 101659"},"PeriodicalIF":7.1,"publicationDate":"2025-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145259984","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":"The Placode Lineage Contributes to the Enteric Nervous System: A Caution for Cell Transplantation Therapy for Hirschsprung Disease","authors":"Shigeru Sato,&nbsp;Henry M. Sucov,&nbsp;Takako Makita","doi":"10.1016/j.jcmgh.2025.101657","DOIUrl":"10.1016/j.jcmgh.2025.101657","url":null,"abstract":"","PeriodicalId":55974,"journal":{"name":"Cellular and Molecular Gastroenterology and Hepatology","volume":"20 2","pages":"Article 101657"},"PeriodicalIF":7.1,"publicationDate":"2025-10-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145234038","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":"Reduced Intestinal GLP-1+ Cell Numbers Are Associated With an Inflammation-related Epithelial Metabolic Signature","authors":"Elisabeth Urbauer ,&nbsp;Doriane Aguanno ,&nbsp;Katharina Kuellmer ,&nbsp;Amira Metwaly ,&nbsp;Nadine Waldschmitt ,&nbsp;Mohamed Ahmed ,&nbsp;Sevana Khaloian ,&nbsp;Gabriele Hörmannsperger ,&nbsp;Julien Planchais ,&nbsp;Tobias Fromme ,&nbsp;R. Balfour Sartor ,&nbsp;Harry Sokol ,&nbsp;Dirk Haller ,&nbsp;Eva Rath","doi":"10.1016/j.jcmgh.2025.101656","DOIUrl":"10.1016/j.jcmgh.2025.101656","url":null,"abstract":"<div><h3>Background &amp; Aims</h3><div>Enteroendocrine cells (EECs) are known for their role in digestion and metabolism, yet their role in intestinal inflammation remains unclear. In inflammatory bowel diseases, a contribution of EECs to pathogenesis is indicated by autoantibodies affecting EEC function and general disease symptoms like insulin resistance and altered intestinal motility. Particularly, the L cell-derived hormone glucagon-like peptide 1 (GLP-1), suggested to orchestrate metabolic-inflammatory responses may influence inflammatory pathways in the intestine.</div></div><div><h3>Methods</h3><div>We quantified numbers of GLP-1⁺ cells in 4 different mouse models of intestinal inflammation and performed transcriptional analyses of colonic epithelial cells from inflamed interleukin-10-deficient mice. Using a publicly available single-cell RNA sequencing dataset including mucosal biopsies from patients with Crohn’s disease, we confirmed findings from the murine models. A model of mitochondrial dysfunction (ClpP^ΔIEC mice) as well as murine and human intestinal organoids were used to study molecular mechanisms.</div></div><div><h3>Results</h3><div>Numbers of GLP-1 expressing cells are consistently reduced at the site of active disease in mouse models and patients with Crohn’s disease. Despite this reduction, L cells from inflamed interleukin-10-deficient mice remained functional regarding GLP-1 secretion. Transcriptional analyses of intestinal epithelial cells indicate altered differentiation correlating with an inflammatory metabolic fingerprint. Reduced GLP-1⁺ cells in ClpP^ΔIEC mice and inhibition of respiration in organoid cultures supports a causative role for metabolism in steering differentiation.</div></div><div><h3>Conclusions</h3><div>Reduction of GLP-1⁺ cells represents a general feature of ileal and colonic inflammation in mice and humans. Given the numerous properties of GLP-1, this reduction likely affects inflammatory processes in the mucosa and disease-related symptoms on multiple levels, and therefore, should be considered a therapeutic target in inflammatory bowel diseases.</div></div>","PeriodicalId":55974,"journal":{"name":"Cellular and Molecular Gastroenterology and Hepatology","volume":"20 2","pages":"Article 101656"},"PeriodicalIF":7.1,"publicationDate":"2025-10-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145233609","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":"Human-length Telomeres Limit Regeneration of Liver Epithelial Cells in Mice","authors":"Michael Y. Hu ,&nbsp;Melissa Rowe ,&nbsp;Mark Tigue ,&nbsp;Yitzhak Reizel ,&nbsp;Riham Smoom ,&nbsp;Yehuda Tzfati ,&nbsp;Klaus H. Kaestner","doi":"10.1016/j.jcmgh.2025.101655","DOIUrl":"10.1016/j.jcmgh.2025.101655","url":null,"abstract":"<div><h3>Background &amp; Aims</h3><div>Telomeres, or the ends of linear chromosomes, are critical for maintaining genomic integrity. The commonly used C57BL/6 mouse strain has telomeres about 5 times longer than those present in humans. We recently engineered the C57BL/6 “Telomouse” to enable the study of human length telomeres, which we used here to study the effects of shortened telomeres on liver regeneration.</div></div><div><h3>Methods</h3><div>We performed partial hepatectomy experiments with Telomice using wild type C57BL/6 mice as controls. Staggered injections of the thymidine analogs 5-chloro-2'-deoxyuridine (CldU) and 5-iodo-2'-deoxyuridine (IdU) were used to analyze their incorporation into nuclear DNA during cells’ S-phase to assess proliferation. In a second model, we employed a competitive hepatocyte repopulation assay in fumarylacetoacetate hydrolase (Fah) null mice.</div></div><div><h3>Results</h3><div>We found that human-length telomeres limit the proliferative capacity of cholangiocytes and hepatocytes in short-term liver regeneration. Control mice exhibited significant cholangiocyte proliferation at 36 hours post-partial hepatectomy (PHx), which remained stable at 46 hours post-PHx. In contrast, Telomice exhibited decreased cholangiocyte proliferation at 36 hours post-PHx, which further decreased at 46 hours post-PHx. Both control and Telomice exhibit increased hepatocyte proliferation at 46 hours compared with 36 hours post-PHx. However, Telomice exhibit less proliferation than controls at both time points. Compared with controls, Telomice exhibit an increased DNA damage response in the liver after partial hepatectomy. In a second model, Telomice hepatocytes also exhibited reduced efficacy in a competitive repopulation study using the Fah null mouse model of conditional hepatocyte ablation.</div></div><div><h3>Conclusions</h3><div>Short telomeres induce DNA damage in the regenerating liver, hampering its ability to accelerate cell proliferation and regenerate the liver.</div></div>","PeriodicalId":55974,"journal":{"name":"Cellular and Molecular Gastroenterology and Hepatology","volume":"20 2","pages":"Article 101655"},"PeriodicalIF":7.1,"publicationDate":"2025-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145214081","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":"Activation and Spatial Redistribution of RNA Splicing Factors Trigger Hepatic Regeneration","authors":"Yachun An ,&nbsp;Jiabei Lian ,&nbsp;Wenjing Wei ,&nbsp;Yunuo Mao ,&nbsp;Longxin Qiao ,&nbsp;Tingting Li ,&nbsp;Ruijian Li ,&nbsp;Shumin Li ,&nbsp;Shigang Zhao ,&nbsp;Xuena Chen ,&nbsp;Han Zhao ,&nbsp;Huili Hu","doi":"10.1016/j.jcmgh.2025.101654","DOIUrl":"10.1016/j.jcmgh.2025.101654","url":null,"abstract":"<div><h3>Background &amp; Aims</h3><div>Tissue injury with regenerative obstacle leads to liver failure and inevitable consequent hepatic diseases. Yet, precise spatial and molecular alterations to initiate liver regeneration remain unknown.</div></div><div><h3>Methods</h3><div>We employed spatiotemporal sequencing of regenerating liver combined with high-throughput single-cell RNA sequencing of established hepatocyte organoids (Hep-Orgs) mimicking the regenerative start, elucidate that splicing factors (SFs) were key factors responsible for liver regeneration. Additionally, we verify the function of splicing factors in knockout mice models in vivo.</div></div><div><h3>Results</h3><div>We observed that the upregulation of SFs in regenerative zone of liver and precycling or cycling hepatocytes subpopulation of Hep-Orgs. We demonstrated that the splicing inhibitors suppress liver regeneration by increasing ribosomal proteins. Moreover, we identified HNRNPU as the key SF for liver regeneration benefit to preventing chronic liver diseases like metabolic dysfunction-associated steatotic liver disease.</div></div><div><h3>Conclusions</h3><div>The spatial remodeling of upregulated RNA SFs drives the first regenerative wave from the periportal zone. The reprogrammed subpopulations defined by highly expressed SFs represent original repopulating hepatocytes. Inhibiting RNA splicing leads to cellular upregulation of ribosomal proteins (RPs), less proliferative signals, and abnormal lipid accumulation. Knockout of SFs leads to failure of liver regeneration and zonal disorder. SF reduction marks severe metabolic dysfunction-associated steatotic liver disease in patients and knockout mouse models. Our results lay the molecular foundation for tissue repair initiation and further developing potential therapeutic targets for liver disease.</div></div>","PeriodicalId":55974,"journal":{"name":"Cellular and Molecular Gastroenterology and Hepatology","volume":"20 2","pages":"Article 101654"},"PeriodicalIF":7.1,"publicationDate":"2025-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145208176","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}