Background & aims: Fibrostenosis is a major complication of Crohn's disease (CD) characterized by intestinal remodeling and excessive extracellular matrix (ECM) deposition. A prominent feature is bowel wall muscularization, involving expansion of submucosal myoid cells and muscularis propria smooth muscle cell (SMC) hyperplasia. However, the cellular identity and molecular mechanisms underlying submucosal myoid cell hyperplasia remain poorly characterized.
Methods: Preoperative intestinal ultrasound from 117 patients with CD was retrospectively reviewed, and ileal tissues from 25 normal, 35 nonstenotic CD, and 44 stenotic CD cases were analyzed histologically. High-resolution spatial transcriptomics was applied to 1 nonfibrotic and 1 fibrostenotic ileal specimen with marked submucosal myoid cell expansion. Findings were validated using public single-cell RNA sequencing datasets (n = 158), immunofluorescence, primary pericyte cultures, and quantitative polymerase chain reaction.
Results: Submucosal myoid cells were predominantly identified as high ECM-producing myofibroblasts, possibly representing the dominant stromal population expanded in fibrotic submucosa. Spatial and pseudotemporal analyses demonstrated their origin from muscularis mucosae and submucosal vascular SMCs. Additionally, pericytes underwent significant expansion and transcriptional reprogramming toward a myofibroblast-like phenotype. Fibroblast sub-clustering revealed spatial heterogeneity, with FAP+ fibroblasts enriched specifically in fibrotic regions. Inflammatory monocytes colocalized with stromal cells, exhibiting robust predicted ligand-receptor interactions indicative of immune-stromal crosstalk.
Conclusions: This case-level, high-resolution spatial analysis delineates a spatially organized fibrotic niche within a CD stricture, composed of distinct stromal and immune populations. We define the identity and origins of profibrotic myofibroblasts and characterize pericyte-to-myofibroblast reprogramming, thereby highlighting specific cell subtypes as prime therapeutic targets for antifibrotic strategies.
{"title":"Elucidating a Myofibroblast-dominated Fibrotic Niche in Crohn's Disease-associated Fibrostenosis Through High-resolution Spatial Transcriptomics.","authors":"Da Zhang, Xinru Zou, Mengjia He, Shibo Sun, Anqi Yu, Jintao Shi, Ting Ouyang, Xiaoxia Lin, Hui Yang, Lan Bai, Kai Sun, Jiaolong Shi, Fangting Wu, Wenting Xie, Jingyan Li, Fang Xie","doi":"10.1016/j.jcmgh.2025.101701","DOIUrl":"10.1016/j.jcmgh.2025.101701","url":null,"abstract":"<p><strong>Background & aims: </strong>Fibrostenosis is a major complication of Crohn's disease (CD) characterized by intestinal remodeling and excessive extracellular matrix (ECM) deposition. A prominent feature is bowel wall muscularization, involving expansion of submucosal myoid cells and muscularis propria smooth muscle cell (SMC) hyperplasia. However, the cellular identity and molecular mechanisms underlying submucosal myoid cell hyperplasia remain poorly characterized.</p><p><strong>Methods: </strong>Preoperative intestinal ultrasound from 117 patients with CD was retrospectively reviewed, and ileal tissues from 25 normal, 35 nonstenotic CD, and 44 stenotic CD cases were analyzed histologically. High-resolution spatial transcriptomics was applied to 1 nonfibrotic and 1 fibrostenotic ileal specimen with marked submucosal myoid cell expansion. Findings were validated using public single-cell RNA sequencing datasets (n = 158), immunofluorescence, primary pericyte cultures, and quantitative polymerase chain reaction.</p><p><strong>Results: </strong>Submucosal myoid cells were predominantly identified as high ECM-producing myofibroblasts, possibly representing the dominant stromal population expanded in fibrotic submucosa. Spatial and pseudotemporal analyses demonstrated their origin from muscularis mucosae and submucosal vascular SMCs. Additionally, pericytes underwent significant expansion and transcriptional reprogramming toward a myofibroblast-like phenotype. Fibroblast sub-clustering revealed spatial heterogeneity, with FAP<sup>+</sup> fibroblasts enriched specifically in fibrotic regions. Inflammatory monocytes colocalized with stromal cells, exhibiting robust predicted ligand-receptor interactions indicative of immune-stromal crosstalk.</p><p><strong>Conclusions: </strong>This case-level, high-resolution spatial analysis delineates a spatially organized fibrotic niche within a CD stricture, composed of distinct stromal and immune populations. We define the identity and origins of profibrotic myofibroblasts and characterize pericyte-to-myofibroblast reprogramming, thereby highlighting specific cell subtypes as prime therapeutic targets for antifibrotic strategies.</p>","PeriodicalId":55974,"journal":{"name":"Cellular and Molecular Gastroenterology and Hepatology","volume":" ","pages":"101701"},"PeriodicalIF":7.1,"publicationDate":"2025-12-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145679503","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}
Pub Date : 2025-12-01DOI: 10.1016/j.jcmgh.2025.101700
Abigail E Russi, Brian J DeBosch
{"title":"Storage Wars: Adipose-liver Crosstalk as a Determinant of Liver Injury.","authors":"Abigail E Russi, Brian J DeBosch","doi":"10.1016/j.jcmgh.2025.101700","DOIUrl":"10.1016/j.jcmgh.2025.101700","url":null,"abstract":"","PeriodicalId":55974,"journal":{"name":"Cellular and Molecular Gastroenterology and Hepatology","volume":" ","pages":"101700"},"PeriodicalIF":7.1,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145671135","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}
Pub Date : 2025-12-01DOI: 10.1016/j.jcmgh.2025.101693
Klaas Van Mechelen, Jing Zhao, Madeleine R Di Natale, Linxuan Jiang, David K Lai, Hui Yu, Matilde Oviedo Querejazu, John B Furness, Pieter Vanden Berghe, Marlene M Hao, Lincon A Stamp
{"title":"Unlocking the Neurogenic Potential of Enteric Glial Cells for Hirschsprung Disease Therapy.","authors":"Klaas Van Mechelen, Jing Zhao, Madeleine R Di Natale, Linxuan Jiang, David K Lai, Hui Yu, Matilde Oviedo Querejazu, John B Furness, Pieter Vanden Berghe, Marlene M Hao, Lincon A Stamp","doi":"10.1016/j.jcmgh.2025.101693","DOIUrl":"10.1016/j.jcmgh.2025.101693","url":null,"abstract":"","PeriodicalId":55974,"journal":{"name":"Cellular and Molecular Gastroenterology and Hepatology","volume":" ","pages":"101693"},"PeriodicalIF":7.1,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145671193","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}
Pub Date : 2025-12-01DOI: 10.1016/j.jcmgh.2025.101696
Noah R Martin, Gregory D Fairn
{"title":"K<sup>+</sup> Flux Capacitor: NKCC1-mediated Potassium Flow Prevents an Inflammatory Overload.","authors":"Noah R Martin, Gregory D Fairn","doi":"10.1016/j.jcmgh.2025.101696","DOIUrl":"10.1016/j.jcmgh.2025.101696","url":null,"abstract":"","PeriodicalId":55974,"journal":{"name":"Cellular and Molecular Gastroenterology and Hepatology","volume":" ","pages":"101696"},"PeriodicalIF":7.1,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145671102","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}
Pub Date : 2025-11-19DOI: 10.1016/j.jcmgh.2025.101685
Lincoln N Strickland, Kelsey A Klute, Jennifer M Bailey-Lundberg
{"title":"Mechanistic Insights Driving Translational Progress in Pancreatic Cancer.","authors":"Lincoln N Strickland, Kelsey A Klute, Jennifer M Bailey-Lundberg","doi":"10.1016/j.jcmgh.2025.101685","DOIUrl":"10.1016/j.jcmgh.2025.101685","url":null,"abstract":"","PeriodicalId":55974,"journal":{"name":"Cellular and Molecular Gastroenterology and Hepatology","volume":" ","pages":"101685"},"PeriodicalIF":7.1,"publicationDate":"2025-11-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145575051","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}
Pub Date : 2025-11-17DOI: 10.1016/j.jcmgh.2025.101682
Shreya Deb , Yongguo Zhang , Yueqing An , Yinglin Xia , Jun Sun
Backgrounds & Aims
SNX27, member of the sorting nexin (SNX) family, carries a unique PDZ domain and mediates recycling of endocytosed transmembrane proteins. SNX27 is critical for neurodevelopmental processes; however, its role in intestine remains unexplored. We aim to determine the previously unknown roles of SNX27 in regulating intestinal homeostasis, epithelial barrier integrity, and inflammatory responses.
Methods
We used available National Center for Biotechnology Information Gene Expression Omnibus and single-cell RNA sequencing datasets to analyze SNX27 expression in human inflammatory bowel disease (IBD). We generated a novel mouse model of SNX27 conditional deletion from intestinal epithelial cells (SNX27ΔIEC) and challenged these mice with dextran sulfate sodium (DSS).
Results
SNX27 expression was significantly lower in human IBD, including ulcerative colitis (UC) and Crohn’s disease (CD). SNX27ΔIEC mice had significantly lower bodyweight and exhibited increased proliferation and poor differentiation of secretory Paneth and goblet cells. We found reduced mucin layer and downregulation of crucial epithelial barrier proteins β-catenin, E-cadherin, ZO-1, ZO-2, and Claudin10 in SNX27ΔIEC mice. SNX27ΔIEC mice showed high intestinal permeability and spontaneously developed intestinal inflammation. Moreover, SNX27ΔIEC mice were more susceptible towards DSS-induced colitis, compared with the SNX27Loxp mice.
Conclusions
Overall, deletion of intestinal epithelial SNX27 weakens barrier functions and promotes inflammation. Our results indicate a novel role of SNX27 in regulating intestinal physiology and protecting against intestinal disorders. Thus, understanding the mechanisms of SNX27 downregulation in IBD will provide insights into new prevention and targets against chronic inflammation.
{"title":"Loss of Intestinal Endosome-associated Protein Sorting Nexin 27 Disrupts Epithelial Barrier and Promotes Inflammation","authors":"Shreya Deb , Yongguo Zhang , Yueqing An , Yinglin Xia , Jun Sun","doi":"10.1016/j.jcmgh.2025.101682","DOIUrl":"10.1016/j.jcmgh.2025.101682","url":null,"abstract":"<div><h3>Backgrounds & Aims</h3><div>SNX27, member of the sorting nexin (SNX) family, carries a unique PDZ domain and mediates recycling of endocytosed transmembrane proteins. SNX27 is critical for neurodevelopmental processes; however, its role in intestine remains unexplored. We aim to determine the previously unknown roles of SNX27 in regulating intestinal homeostasis, epithelial barrier integrity, and inflammatory responses.</div></div><div><h3>Methods</h3><div>We used available National Center for Biotechnology Information Gene Expression Omnibus and single-cell RNA sequencing datasets to analyze SNX27 expression in human inflammatory bowel disease (IBD). We generated a novel mouse model of SNX27 conditional deletion from intestinal epithelial cells (SNX27<sup>ΔIEC</sup>) and challenged these mice with dextran sulfate sodium (DSS).</div></div><div><h3>Results</h3><div>SNX27 expression was significantly lower in human IBD, including ulcerative colitis (UC) and Crohn’s disease (CD). SNX27<sup>ΔIEC</sup> mice had significantly lower bodyweight and exhibited increased proliferation and poor differentiation of secretory Paneth and goblet cells. We found reduced mucin layer and downregulation of crucial epithelial barrier proteins <em>β</em>-catenin, E-cadherin, ZO-1, ZO-2, and Claudin10 in SNX27<sup>ΔIEC</sup> mice. SNX27<sup>ΔIEC</sup> mice showed high intestinal permeability and spontaneously developed intestinal inflammation. Moreover, SNX27<sup>ΔIEC</sup> mice were more susceptible towards DSS-induced colitis, compared with the SNX27<sup>Loxp</sup> mice.</div></div><div><h3>Conclusions</h3><div>Overall, deletion of intestinal epithelial SNX27 weakens barrier functions and promotes inflammation. Our results indicate a novel role of SNX27 in regulating intestinal physiology and protecting against intestinal disorders. Thus, understanding the mechanisms of SNX27 downregulation in IBD will provide insights into new prevention and targets against chronic inflammation.</div></div>","PeriodicalId":55974,"journal":{"name":"Cellular and Molecular Gastroenterology and Hepatology","volume":"20 3","pages":"Article 101682"},"PeriodicalIF":7.1,"publicationDate":"2025-11-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145558293","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}
Pub Date : 2025-11-13DOI: 10.1016/j.jcmgh.2025.101677
Michelle M Cooley, Guy E Groblewski
{"title":"Distinct chronic Pancreatitis Genetic Variants CPA1 N256K and PNLIP T221M Share Common Pathological Grounds.","authors":"Michelle M Cooley, Guy E Groblewski","doi":"10.1016/j.jcmgh.2025.101677","DOIUrl":"10.1016/j.jcmgh.2025.101677","url":null,"abstract":"","PeriodicalId":55974,"journal":{"name":"Cellular and Molecular Gastroenterology and Hepatology","volume":" ","pages":"101677"},"PeriodicalIF":7.1,"publicationDate":"2025-11-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145531049","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}
Pub Date : 2025-11-04DOI: 10.1016/j.jcmgh.2025.101674
Xun Wang , Xinyu Zhan , Yiyun Gao , Hao Wang , Zheng Liu , Mu Liu , Ling Lu , Haoming Zhou
Background & Aims
Acute drug-induced liver injury (DILI) is a major cause of acute liver dysfunction and even liver failure. Peritoneal macrophages have been reported to invade into the injured liver for tissue repair. Herein, we aimed to investigate the role of autophagy-related 16 like 1 gene (ATG16L1) in regulating the reparative function of peritoneal macrophages during DILI caused by acetaminophen (APAP).
Methods
Myeloid ATG16L1 knockout (KO), overexpression (KI) or wild-type (WT) mice were challenged with a single dose of intraperitoneal APAP (300 mg/kg) injection. Intraperitoneal injection or depletion of peritoneal macrophages was conducted for the in vivo analysis. Co-culture of primary hepatocytes and peritoneal macrophages were applied for in vitro analysis.
Results
Peritoneal macrophages were able to rapidly invade into the liver in response to DILI. Peritoneal macrophage injection promoted, and peritoneal macrophage depletion impaired the resolution of inflammation and liver repair post DILI. DILI triggered ATG16L1 expression in intrahepatic accumulated peritoneal macrophages. Interestingly, compared with WT or KI peritoneal macrophages, KO peritoneal macrophages showed enhanced intrahepatic migration ability via Schlafen family member 5 (SLFN5)-CD44 signaling pathway, leading to less injury at early time of 24 hours post DILI in mice with KO peritoneal macrophage infusion. In addition, ATG16L1-mediated autophagy promoted phagocytosis and reparative phenotype of peritoneal macrophages by regulating reactive oxygen species (ROS)-Mer tyrosine kinase (MerTK) signaling. Moreover, peritoneal macrophage ATG16L1 promoted hepatocyte proliferation dependent on the interleukin (IL)-10–C-X-C motif chemokine receptor 2 (CXCR2) axis.
Conclusions
ATG16L1 activation enhanced peritoneal macrophage phagocytosis and reparative phenotype via autophagy-ROS-MerTK signaling and promoted IL-10-CXCR2-dependent hepatocyte proliferation during DILI. Peritoneal macrophage ATG16L1 might be a novel therapeutic target for DILI.
{"title":"ATG16L1 Regulates Reparative Function of Peritoneal Macrophages During Acute Drug-induced Liver Injury","authors":"Xun Wang , Xinyu Zhan , Yiyun Gao , Hao Wang , Zheng Liu , Mu Liu , Ling Lu , Haoming Zhou","doi":"10.1016/j.jcmgh.2025.101674","DOIUrl":"10.1016/j.jcmgh.2025.101674","url":null,"abstract":"<div><h3>Background & Aims</h3><div>Acute drug-induced liver injury (DILI) is a major cause of acute liver dysfunction and even liver failure. Peritoneal macrophages have been reported to invade into the injured liver for tissue repair. Herein, we aimed to investigate the role of autophagy-related 16 like 1 gene (ATG16L1) in regulating the reparative function of peritoneal macrophages during DILI caused by acetaminophen (APAP).</div></div><div><h3>Methods</h3><div>Myeloid ATG16L1 knockout (KO), overexpression (KI) or wild-type (WT) mice were challenged with a single dose of intraperitoneal APAP (300 mg/kg) injection. Intraperitoneal injection or depletion of peritoneal macrophages was conducted for the in vivo analysis. Co-culture of primary hepatocytes and peritoneal macrophages were applied for in vitro analysis.</div></div><div><h3>Results</h3><div>Peritoneal macrophages were able to rapidly invade into the liver in response to DILI. Peritoneal macrophage injection promoted, and peritoneal macrophage depletion impaired the resolution of inflammation and liver repair post DILI. DILI triggered ATG16L1 expression in intrahepatic accumulated peritoneal macrophages. Interestingly, compared with WT or KI peritoneal macrophages, KO peritoneal macrophages showed enhanced intrahepatic migration ability via Schlafen family member 5 (SLFN5)-CD44 signaling pathway, leading to less injury at early time of 24 hours post DILI in mice with KO peritoneal macrophage infusion. In addition, ATG16L1-mediated autophagy promoted phagocytosis and reparative phenotype of peritoneal macrophages by regulating reactive oxygen species (ROS)-Mer tyrosine kinase (MerTK) signaling. Moreover, peritoneal macrophage ATG16L1 promoted hepatocyte proliferation dependent on the interleukin (IL)-10–C-X-C motif chemokine receptor 2 (CXCR2) axis.</div></div><div><h3>Conclusions</h3><div>ATG16L1 activation enhanced peritoneal macrophage phagocytosis and reparative phenotype via autophagy-ROS-MerTK signaling and promoted IL-10-CXCR2-dependent hepatocyte proliferation during DILI. Peritoneal macrophage ATG16L1 might be a novel therapeutic target for DILI.</div></div>","PeriodicalId":55974,"journal":{"name":"Cellular and Molecular Gastroenterology and Hepatology","volume":"20 2","pages":"Article 101674"},"PeriodicalIF":7.1,"publicationDate":"2025-11-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145460720","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}
Pub Date : 2025-11-04DOI: 10.1016/j.jcmgh.2025.101675
Beatriz Thomasi
{"title":"Gut Feelings Get Intense Due to Early Life Stress and Immune Imbalance.","authors":"Beatriz Thomasi","doi":"10.1016/j.jcmgh.2025.101675","DOIUrl":"10.1016/j.jcmgh.2025.101675","url":null,"abstract":"","PeriodicalId":55974,"journal":{"name":"Cellular and Molecular Gastroenterology and Hepatology","volume":" ","pages":"101675"},"PeriodicalIF":7.1,"publicationDate":"2025-11-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145460694","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}
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