Cellular and Molecular Gastroenterology and Hepatology最新文献

{"title":"Irritable Bowel Syndrome With Diarrhea in Pediatric Patients Is Associated With Type 2 and Type 9 T Cells in the Intestinal Mucosa","authors":"Xin Chen, Brener Cunha Carvalho, Anika Sinha, Nanci Pittman, Keith Benkov, Joanne Lai, Maria Curotto de Lafaille, David Dunkin","doi":"10.1016/j.jcmgh.2025.101488","DOIUrl":"10.1016/j.jcmgh.2025.101488","url":null,"abstract":"","PeriodicalId":55974,"journal":{"name":"Cellular and Molecular Gastroenterology and Hepatology","volume":"19 6","pages":"Article 101488"},"PeriodicalIF":7.1,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143538138","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":"Myosin Light Chain 9 Mediates Graft Fibrosis After Pediatric Liver Transplantation Through TLR4/MYD88/NF-κB Signaling","authors":"Zhixin Zhang ,&nbsp;Chong Dong ,&nbsp;Shengqiao Zhao ,&nbsp;Zhuyuan Si ,&nbsp;Weiping Zheng ,&nbsp;Kai Wang ,&nbsp;Chao Sun ,&nbsp;Zhuolun Song ,&nbsp;Wei Gao","doi":"10.1016/j.jcmgh.2024.101453","DOIUrl":"10.1016/j.jcmgh.2024.101453","url":null,"abstract":"<div><h3>Background &amp; Aims</h3><div>The incidence of graft fibrosis is elevated after pediatric liver transplantation (pLT) and is influenced by cold ischemic time (CIT). Myosin light chain 9 (MYL9), a member of the myosin family, could act on hepatic stellate cells (HSCs) and induce a transition to active phase. We hypothesized that cold ischemic injury could stimulate MYL9 expression and lead to graft fibrosis.</div></div><div><h3>Methods</h3><div>We tested the hypothesis by analyzing multi-omics data from human protocol liver biopsy samples 2 years after LT, performing rat LT with different CIT and conducting in vitro studies in HSC cell lines with MYL9 knockdown and overexpression.</div></div><div><h3>Results</h3><div>Clinically, CIT is an independent risk factor for graft fibrosis after pLT. Omics analysis identified MYL9 as a prominent contributor in graft fibrosis. MYL9 is strongly correlated with liver fibrosis grade and the progression of fibrosis. The study of rat LT model demonstrated MYL9 expression increases with the prolongation of CIT, and its role is specific to transplant setting. Mechanistically, in vitro experiments with HSCs exposed to hypoxia/reoxygenation revealed a substantial decrease in HSCs activation after MYL9 knockdown. Conversely, overexpression of MYL9 significantly enhanced the activation of HSCs. Subsequent transcriptome sequencing of HSCs with MYL9 knockdown unveiled that MYL9 primarily functions through the TLR4/MYD88/NF-κB signaling pathway. Liver graft fibrosis was ameliorated when toll like receptor 4 signaling was inhibited in rats.</div></div><div><h3>Conclusions</h3><div>Our findings demonstrate that prolonged CIT up-regulates the expression of MYL9 in liver graft after LT. MYL9 activates HSCs and promotes fibrosis through a TLR4/MYD88/NF-κB signaling dependent manner.</div></div>","PeriodicalId":55974,"journal":{"name":"Cellular and Molecular Gastroenterology and Hepatology","volume":"19 5","pages":"Article 101453"},"PeriodicalIF":7.1,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142959422","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Tofacitinib Mitigates the Increased SARS-CoV-2 Infection Susceptibility Caused by an IBD Risk Variant in the PTPN2 Gene","authors":"Marianne R. Spalinger ,&nbsp;Golshid Sanati ,&nbsp;Pritha Chatterjee ,&nbsp;Rong Hai ,&nbsp;Jiang Li ,&nbsp;Alina N. Santos ,&nbsp;Tara M. Nordgren ,&nbsp;Michel L. Tremblay ,&nbsp;Lars Eckmann ,&nbsp;Elaine Hanson ,&nbsp;Michael Scharl ,&nbsp;Xiwei Wu ,&nbsp;Brigid S. Boland ,&nbsp;Declan F. McCole","doi":"10.1016/j.jcmgh.2024.101447","DOIUrl":"10.1016/j.jcmgh.2024.101447","url":null,"abstract":"<div><h3>Background &amp; Aims</h3><div>Coronavirus disease (COVID-19), caused by severe acquired respiratory syndrome-Coronavirus-2 (SARS-CoV-2), triggered a global pandemic with severe medical and socioeconomic consequences. Although fatality rates are higher among the elderly and those with underlying comorbidities, host factors that promote susceptibility to SARS-CoV-2 infection and severe disease are poorly understood. Although individuals with certain autoimmune/inflammatory disorders show increased susceptibility to viral infections, there is incomplete knowledge of SARS-CoV-2 susceptibility in these diseases. The aim of our study was to investigate whether the autoimmunity risk gene, <em>PTPN2,</em> which also confers elevated risk to develop inflammatory bowel disease, affects susceptibility to SARS-CoV-2 viral uptake.</div></div><div><h3>Methods</h3><div>Using samples from <em>PTPN2</em> genotyped patients with inflammatory bowel disease, <em>PTPN2-</em>deficient mice, and human intestinal and lung epithelial cell lines, we investigated how <em>PTPN2</em> affects expression of the SARS-CoV-2 receptor angiotensin converting enzyme 2 (ACE2), and uptake of virus-like particles expressing the SARS-CoV2 spike protein and live SARS-CoV-2 virus.</div></div><div><h3>Results</h3><div>We report that the autoimmune <em>PTPN2</em> loss-of-function risk variant rs1893217 promotes expression of the SARS-CoV-2 receptor, ACE2, and increases cellular entry of SARS-CoV-2 spike protein and live virus. Elevated ACE2 expression and viral entry were mediated by increased Janus kinase-signal transducers and activators of transcription signaling and were reversed by the Janus kinase inhibitor, tofacitinib.</div></div><div><h3>Conclusion</h3><div>Collectively, our findings uncover a novel risk biomarker for increased expression of the SARS-CoV-2 receptor and viral entry, and identify a clinically approved therapeutic agent to mitigate this risk.</div></div>","PeriodicalId":55974,"journal":{"name":"Cellular and Molecular Gastroenterology and Hepatology","volume":"19 5","pages":"Article 101447"},"PeriodicalIF":7.1,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142932534","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cover","authors":"","doi":"10.1016/S2352-345X(24)00187-5","DOIUrl":"10.1016/S2352-345X(24)00187-5","url":null,"abstract":"","PeriodicalId":55974,"journal":{"name":"Cellular and Molecular Gastroenterology and Hepatology","volume":"19 1","pages":"Article 101432"},"PeriodicalIF":7.1,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143135559","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Activation of AMP-activated Protein Kinase by Metformin Inhibits Dedifferentiation of Platelet-derived Growth Factor-BB-induced Vascular Smooth Muscle Cells to Improve Arterial Remodeling in Cirrhotic Portal Hypertension","authors":"Guangbo Wu ,&nbsp;Qiang Fan ,&nbsp;Min Chen ,&nbsp;Guqing Luo,&nbsp;Zhenghao Wu,&nbsp;Jinbo Zhao,&nbsp;Jiayun Lin,&nbsp;Chihao Zhang,&nbsp;Hongjie Li,&nbsp;Xiaoliang Qi,&nbsp;Haizhong Huo,&nbsp;Lei Zheng,&nbsp;Meng Luo","doi":"10.1016/j.jcmgh.2025.101487","DOIUrl":"10.1016/j.jcmgh.2025.101487","url":null,"abstract":"&lt;div&gt;&lt;h3&gt;Background &amp; Aims&lt;/h3&gt;&lt;div&gt;Portal hypertension (PHT) is the potentially deadly complication of liver cirrhosis. Intrahepatic vascular resistance and the splanchnic hyperdynamic circulation are 2 principal driving factors contributing to the maintenance and exacerbation of PHT. However, in the advanced stages of cirrhosis, the fibrotic process in the liver becomes irreversible, leading to persistent and intractable increases in intrahepatic vascular resistance. Arterial remodeling emerges as a crucial mechanism driving the hyperdynamic splanchnic circulation. Therefore, ameliorating the hyperdynamic splanchnic circulation has become an indispensable component of PHT therapeutic strategies.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Methods&lt;/h3&gt;&lt;div&gt;Liver cirrhosis with PHT was induced in the rats by common bile duct ligation (BDL). Based on the transcriptomic sequencing of the mesenteric arteries, we investigated the effects and mechanisms of metformin on the arterial remodeling at different stages of cirrhosis. We further validated potential molecular mechanisms through &lt;em&gt;in vitro&lt;/em&gt; experiments using the A7r5 smooth muscle cell line and primary vascular smooth muscle cells (VSMCs).&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Results&lt;/h3&gt;&lt;div&gt;Our findings revealed the beneficial effects of metformin on liver cirrhosis and PHT in rats following BDL for 4 and 6 weeks. Metformin was observed to ameliorate PHT and splanchnic hyperdynamic circulation in BDL rats, even in the advanced stages of liver cirrhosis. This effect was evidenced by reduced portal pressure and cardiac output, decreased superior mesenteric artery (SMA) flow, accompanied by improvements in systemic vascular resistance and SMA resistance. Moreover, chronic inflammation in BDL rats was alleviated by metformin, which might inhibit the driving factors of angiogenesis and arterial remodeling. Notably, SMA dilation and arterial remodeling in BDL rats were potent alleviated following metformin treatment. Metformin ameliorated arterial remodeling in BDL rats by inhibiting the dedifferentiation of contractile VSMCs, resulting in the upregulation of contractile protein expressions such as alpha-smooth muscle actin (α-SMA) and smooth muscle 22α (SM22α). Platelet-derived growth factor-BB (PDGF-BB)/platelet-derived growth factor receptor beta (PDGFR-β) signaling exerted crucial roles in regulating the VSMCs cell phenotype. Activation of AMP-activated protein kinase (AMPK) by metformin blocked the downstream pathway of PDGF-BB/PDGFRβ. Furthermore, &lt;em&gt;in vitro&lt;/em&gt; cell experiments, VSMCs were respectively treated with AMPK activator metformin or AMPK inhibitor Compound C. We revealed the molecular mechanism that metformin inhibited the phenotypic switching of A7r5 cells induced by PDGF-BB and primary VSMCs from BDL rats, which was mediated by activating AMPK to enhance the expression of contractile protein α-SMA. These findings suggest that AMPK can ameliorate the progression of arterial remodeling during PHT via suppressi","PeriodicalId":55974,"journal":{"name":"Cellular and Molecular Gastroenterology and Hepatology","volume":"19 6","pages":"Article 101487"},"PeriodicalIF":7.1,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143538136","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":"Studies of Slc30a10 Deficiency in Mice Reveal That Intestinal Iron Transporters Dmt1 and Ferroportin Transport Manganese","authors":"Milankumar Prajapati ,&nbsp;Jared Z. Zhang ,&nbsp;Grace S. Chong ,&nbsp;Lauren Chiu ,&nbsp;Courtney J. Mercadante ,&nbsp;Heather L. Kowalski ,&nbsp;Olga Antipova ,&nbsp;Barry Lai ,&nbsp;Martina Ralle ,&nbsp;Brian P. Jackson ,&nbsp;Tracy Punshon ,&nbsp;Shuling Guo ,&nbsp;Mariam Aghajan ,&nbsp;Thomas B. Bartnikas","doi":"10.1016/j.jcmgh.2025.101489","DOIUrl":"10.1016/j.jcmgh.2025.101489","url":null,"abstract":"<div><h3>Background &amp; Aims</h3><div>SLC11A2 (DMT1) and SLC40A1 (ferroportin) are essential for dietary iron absorption, but their role in manganese transport is debated. SLC30A10 deficiency causes severe manganese excess due to loss of gastrointestinal manganese excretion. Patients are treated with chelators but also respond to oral iron, suggesting that iron can outcompete manganese for absorption in this disease. Here, we determine if divalent metal transport 1 (Dmt1) and ferroportin can transport manganese using Slc30a10-deficient mice as a model.</div></div><div><h3>Methods</h3><div>Manganese absorption and levels and other disease parameters were assessed in <em>Slc30a10</em>^<em>-/-</em> mice with and without intestinal Dmt1 and ferroportin deficiency using gastric gavage, surgical bile collections, multiple metal assays, and other techniques. The contribution of intestinal Slc30a10 deficiency to ferroportin-dependent manganese absorption was explored by determining if intestinal Slc30a10 deficiency increases manganese absorption in a mouse model of hereditary hemochromatosis, a disease of iron excess due to ferroportin upregulation.</div></div><div><h3>Results</h3><div>Manganese absorption was increased in Slc30a10-deficient mice despite manganese excess. Intestinal Dmt1 and ferroportin deficiency attenuated manganese absorption and excess in Slc30a10-deficient mice. Intestinal Slc30a10 deficiency increased manganese absorption and levels in the hemochromatosis mouse model.</div></div><div><h3>Conclusions</h3><div>Aberrant absorption contributes prominently to SLC30A10 deficiency, a disease previously attributed to impaired excretion, and is dependent upon intestinal Dmt1 and ferroportin and exacerbated by loss of intestinal Slc30a10. This work expands our understanding of overlaps between manganese and iron transport and the mechanisms by which the body regulates absorption of 2 nutrients that can share transport pathways. We propose that a reconsideration of the role of Dmt1 and ferroportin in manganese homeostasis is warranted.</div></div>","PeriodicalId":55974,"journal":{"name":"Cellular and Molecular Gastroenterology and Hepatology","volume":"19 7","pages":"Article 101489"},"PeriodicalIF":7.1,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143538200","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 Protective Role of DDIT4 in Helicobacter pylori-induced Gastric Metaplasia Through Metabolic Regulation of Ferroptosis","authors":"Huan Wang ,&nbsp;Xinbo Xu ,&nbsp;Yaobin Ouyang ,&nbsp;Xiao Fei ,&nbsp;Cong He ,&nbsp;Xianhe Yang ,&nbsp;Yuping Ren ,&nbsp;Yanan Zhou ,&nbsp;Sihai Chen ,&nbsp;Yi Hu ,&nbsp;Jianping Liu ,&nbsp;Zhongming Ge ,&nbsp;William Ka Kei Wu ,&nbsp;Nonghua Lu ,&nbsp;Chuan Xie ,&nbsp;Xidong Wu ,&nbsp;Yin Zhu ,&nbsp;Nianshuang Li","doi":"10.1016/j.jcmgh.2024.101448","DOIUrl":"10.1016/j.jcmgh.2024.101448","url":null,"abstract":"<div><h3>Background &amp; Aims</h3><div><em>Helicobacter pylori</em> (<em>H pylori</em>) infection is a significant factor leading to gastric atrophy, metaplasia and cancer development. Here, we investigated the role of the stress response gene DDIT4 in the pathogenesis of <em>H pylori</em> infection.</div></div><div><h3>Methods</h3><div>Cell lines, transgenic mice, and human tissue samples were implemented. Proteomics were performed on <em>Ddit4</em>^<em>+/+</em> and <em>Ddit4</em>^<em>-/-</em> mice infected with <em>H pylori</em> strain PMSS1. C57BL/6 mice were administered with tamoxifen to induce gastric metaplasia. Stomach tissues were analyzed for histopathologic features, reactive oxygen species, Fe²⁺, lipid peroxidation, expression of DDIT4, and ferroptosis-related proteins.</div></div><div><h3>Results</h3><div>DDIT4 expression was upregulated at 6 hours but significantly decreased at 24 hours in response to <em>H pylori</em> infection in gastric epithelial cells. Gastric DDIT4 were downregulated in INS-GAS mice at 4 months post <em>H pylori</em> infection. Notably, <em>H pylori</em> infection led to more severe gastric metaplasia lesion in <em>Ddit4</em>-knockout mice. The proteomic profiling revealed an increase in ferroptosis in the gastric tissues of infected <em>Ddit4</em>-deficient mice, compared with infected wild-type mice. Mechanistically, knockout of DDIT4 promoted <em>H pylori</em>-induced ferroptosis through the accumulation of lipid peroxides and ROS levels, and alterations in proteins such as GPX4, ALOX15, and HMOX1. Overexpression of DDIT4 counteracted <em>H pylori</em>-induced stem cell marker CD44V9 through modulation of ferroptosis. Similarly, in another mouse model of gastric metaplasia treated with tamoxifen, as well as in human GIM tissues, we observed the loss of DDIT4 and induction of ferroptosis.</div></div><div><h3>Conclusions</h3><div>Our results indicate that DDIT4 serves as a protective factor against <em>H pylori</em>-induced gastric metaplasia by metabolic resistance to ferroptosis.</div></div>","PeriodicalId":55974,"journal":{"name":"Cellular and Molecular Gastroenterology and Hepatology","volume":"19 5","pages":"Article 101448"},"PeriodicalIF":7.1,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143411715","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Periplakin Attenuates Liver Fibrosis via Reprogramming CD44Low Cells into CD44High Liver Progenitor Cells","authors":"Lichao Zhang ,&nbsp;Zhiyong Xiong ,&nbsp;Zebin Chen ,&nbsp;Meiyining Xu ,&nbsp;Siyu Zhao ,&nbsp;Xianzhi Liu ,&nbsp;Kefeng Jiang ,&nbsp;Yunyi Hu ,&nbsp;Shurui Liu ,&nbsp;Xi Sun ,&nbsp;Zhongdao Wu ,&nbsp;Jia Shen ,&nbsp;Lifu F. Wang","doi":"10.1016/j.jcmgh.2025.101498","DOIUrl":"10.1016/j.jcmgh.2025.101498","url":null,"abstract":"<div><h3>Background &amp; Aims</h3><div>Liver progenitor cells (LPCs) contribute significantly to the restoration of injured liver parenchyma and promote liver regeneration, thereby ameliorating liver fibrosis. However, the mechanism of the derivation of LPCs remains poorly understood.</div></div><div><h3>Methods</h3><div>We first examined the expression of periplakin (PPL) in patients and mouse models with liver fibrosis. Adenovirus overexpressing PPL was injected into the tail vein of mouse models to detect the regulatory effect of PPL on liver fibrosis. Single-cell sequencing explored how PPL influences liver fibrosis progression. Additionally, PPL⁺CD44^Low cells and PPL⁺CD44^High LPCs were transplanted into 3,5-diethoxycarbonyl-1,4-dihydrocollidine–induced mouse models to assess their therapeutic efficacy in treating liver fibrosis.</div></div><div><h3>Results</h3><div>The expression of PPL is upregulated in fibrotic livers in human and mouse models of liver fibrosis. Functionally, we found that PPL overexpression significantly attenuated liver fibrosis. Mechanistically, PPL was specifically expressed in LPCs and promoted LPC expansion. Moreover, we observed that PPL⁺ cells could be categorized into PPL⁺CD44^Low and PPL⁺CD44^High subsets, and PPL⁺CD44^Low cells were found to redifferentiate into PPL⁺CD44^High LPCs during liver fibrosis. Furthermore, transplantation of PPL⁺CD44^High LPCs notably suppressed liver fibrosis.</div></div><div><h3>Conclusions</h3><div>These findings demonstrate that PPL⁺CD44^Low cells can be reprogrammed into PPL⁺CD44^High LPCs, which ameliorate liver fibrosis, suggesting a potential application of PPL for the treatment of liver fibrosis.</div></div>","PeriodicalId":55974,"journal":{"name":"Cellular and Molecular Gastroenterology and Hepatology","volume":"19 7","pages":"Article 101498"},"PeriodicalIF":7.1,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143665522","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":"Cellular Crosstalk Promotes Hepatic Progenitor Cell Proliferation and Stellate Cell Activation in 3D Co-culture","authors":"Maya W. Haaker ,&nbsp;Jung-Chin Chang ,&nbsp;Brian K. Chung ,&nbsp;Tobias S. Pieper ,&nbsp;Falko Noé ,&nbsp;Tongtong Wang ,&nbsp;Niels Geijsen ,&nbsp;Martin Houweling ,&nbsp;Christian Wolfrum ,&nbsp;Arie B. Vaandrager ,&nbsp;Espen Melum ,&nbsp;Bart Spee ,&nbsp;J. Bernd Helms","doi":"10.1016/j.jcmgh.2025.101472","DOIUrl":"10.1016/j.jcmgh.2025.101472","url":null,"abstract":"<div><h3>Background &amp; Aims</h3><div>Following liver damage, ductular reaction often coincides with liver fibrosis. Proliferation of hepatic progenitor cells is observed in ductular reaction, whereas activated hepatic stellate cells (HSCs) are the main drivers of liver fibrosis. These observations may suggest a functional interaction between these 2 cell types. Here, we report on an <em>in vitro</em> co-culture system to examine these interactions and validate their co-expression in human liver explants.</div></div><div><h3>Methods</h3><div>In a 3D organoid co-culture system, we combined freshly isolated quiescent mouse HSCs and fluorescently labeled progenitor cells (undifferentiated intrahepatic cholangiocyte organoids), permitting real-time observation of cell morphology and behavior. After 7 days, cells were sorted based on the fluorescent label and analyzed for changes in gene expression.</div></div><div><h3>Results</h3><div>In the 3D co-culture system, the proliferation of progenitor cells is enhanced, and HSCs are activated, recapitulating the cellular events observed in the patient liver. Both effects in 3D co-culture require close contact between the 2 different cell types. HSC activation during 3D co-culture differs from quiescent (3D mono-cultured) HSCs and activated HSCs on plastic (2D mono-culture). Upregulation of a cluster of genes containing <em>Aldh1a2</em>, <em>Cthrc1</em>, and several genes related to frizzled binding/Wnt signaling were exclusively observed in 3D co-cultured HSCs. The localized co-expression of specific genes was confirmed by spatial transcriptomics in human liver explants.</div></div><div><h3>Conclusion</h3><div>An <em>in vitro</em> 3D co-culture system provides evidence for direct interactions between HSCs and progenitor cells, which are sufficient to drive responses that are similar to those seen during ductular reaction and fibrosis. This model paves the way for further research into the cellular basis of liver pathology.</div></div>","PeriodicalId":55974,"journal":{"name":"Cellular and Molecular Gastroenterology and Hepatology","volume":"19 5","pages":"Article 101472"},"PeriodicalIF":7.1,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143076594","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The Human Milk-derived Peptide Drives Rapid Regulation of Macrophage Inflammation Responses in the Neonatal Intestine","authors":"Fuqiang Yuan ,&nbsp;Xu Han ,&nbsp;Masha Huang ,&nbsp;Yinglin Su ,&nbsp;Yiting Zhang ,&nbsp;Mengyuan Hu ,&nbsp;Xiang Yu ,&nbsp;Weilai Jin ,&nbsp;Yun Li ,&nbsp;Le Zhang","doi":"10.1016/j.jcmgh.2024.101420","DOIUrl":"10.1016/j.jcmgh.2024.101420","url":null,"abstract":"<div><h3>Background &amp; Aims</h3><div>The interactions between human milk and the regulation of innate immune homeostasis in newborns, and their impact on intestinal health, are not fully understood. This study aimed to explore the role of peptides in human milk extracellular vesicles (EVs) in this process.</div></div><div><h3>Methods</h3><div>A comprehensive screening of peptides within human milk EVs was performed, leading to the identification of a beta-casein-derived peptide (CASB_135-150). The effects of CASB_135-150 on intestinal injury were evaluated in a rat necrotizing enterocolitis (NEC) model. Immunofluorescence analysis was used to determine its distribution, and its impact on NF-κB signaling and inflammation was studied in bone marrow-derived macrophages (BMDMs) and intestinal macrophages. Protein-protein interaction (PPI) analysis, single-cell RNA-seq (scRNA-seq), and co-immunoprecipitation (co-IP) experiments were conducted to explore the mechanism underlying CASB_135-150 function.</div></div><div><h3>Results</h3><div>CASB_135-150 significantly mitigated intestinal injury in the rat NEC model. Immunofluorescence analysis revealed that CASB_135-150 could target intestinal macrophages and rapidly inhibited NF-κB signaling and reduced inflammation. ScRNA-seq analyses indicated a strong association between FHL2 and NEC development, and co-IP confirmed the interaction between CASB_135-150 and FHL2. CASB_135-150 disrupted the FHL2/TRAF6 complex, reducing TRAF6 protein levels. Mutation of key amino acids in CASB_135-150 disrupted its interaction with FHL2 and abolished its ability to inhibit NF-κB signaling, which also prevented its protective effect in vivo. RNA-seq of intestinal tissue further highlighted the impact of CASB_135-150 on the NF-κB signaling pathway.</div></div><div><h3>Conclusions</h3><div>Our study identifies CASB_135-150, a novel peptide in human milk EVs, that rapidly regulates macrophage inflammatory responses and protects against NEC-induced intestinal injury. These findings provide new insights into the role of human milk in modulating the infant immune system and intestinal health.</div></div>","PeriodicalId":55974,"journal":{"name":"Cellular and Molecular Gastroenterology and Hepatology","volume":"19 2","pages":"Article 101420"},"PeriodicalIF":7.1,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11652890/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142481784","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}