Cellular and Molecular Gastroenterology and Hepatology最新文献

{"title":"A Helpful Bug in the System: Gut Microbes and Their Positive Impact on Portal Pressure Modulation","authors":"Moira B. Hilscher","doi":"10.1016/j.jcmgh.2024.101399","DOIUrl":"10.1016/j.jcmgh.2024.101399","url":null,"abstract":"","PeriodicalId":55974,"journal":{"name":"Cellular and Molecular Gastroenterology and Hepatology","volume":"18 6","pages":"Article 101399"},"PeriodicalIF":7.1,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142333070","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":"IGF2BP1/IMP1 Deletion Enhances a Facultative Stem Cell State via Regulation of MAP1LC3B","authors":"Louis R. Parham ,&nbsp;Patrick A. Williams ,&nbsp;Kay Katada ,&nbsp;Shaneice K. Nettleford ,&nbsp;Priya Chatterji ,&nbsp;Kofi K. Acheampong ,&nbsp;Charles H. Danan ,&nbsp;Xianghui Ma ,&nbsp;Lauren A. Simon ,&nbsp;Kaitlyn E. Naughton ,&nbsp;Rei Mizuno ,&nbsp;Tatiana Karakasheva ,&nbsp;Emily A. McMillan ,&nbsp;Kelly A. Whelan ,&nbsp;Donita C. Brady ,&nbsp;Sydney M. Shaffer ,&nbsp;Kathryn E. Hamilton","doi":"10.1016/j.jcmgh.2023.12.001","DOIUrl":"10.1016/j.jcmgh.2023.12.001","url":null,"abstract":"<div><h3>Background &amp; Aims</h3><p>The intestinal epithelium interfaces with a diverse milieu of luminal contents while maintaining robust digestive and barrier functions. Facultative intestinal stem cells are cells that survive tissue injury and divide to re-establish the epithelium. Prior studies have shown autophagic state as functional marker of facultative intestinal stem cells, but regulatory mechanisms are not known. The current study evaluated a post-transcriptional regulation of autophagy as an important factor for facultative stem cell state and tissue regeneration.</p></div><div><h3>Methods</h3><p>We evaluated stem cell composition, autophagic vesicle content, organoid formation, and in vivo regeneration in mice with intestinal epithelial deletion of the RNA binding protein <em>IGF2</em> messenger RNA binding protein 1 (IMP1). The contribution of autophagy to resulting in vitro and in vivo phenotypes was evaluated via genetic inactivation of <em>Atg7</em>. Molecular analyses of IMP1 modulation of autophagy at the protein and transcript localization levels were performed using IMP1 mutant studies and single-molecule fluorescent in situ hybridization.</p></div><div><h3>Results</h3><p>Epithelial <em>Imp1</em> deletion reduced leucine rich repeat containing G protein coupled receptor 5 cell frequency but enhanced both organoid formation efficiency and in vivo regeneration after irradiation. We confirmed prior studies showing increased autophagy with IMP1 deletion. Deletion of <em>Atg7</em> reversed the enhanced regeneration observed with <em>Imp1</em> deletion. IMP1 deletion or mutation of IMP1 phosphorylation sites enhanced expression of essential autophagy protein microtubule-associated protein 1 light chain 3β. Furthermore, immunofluorescence imaging coupled with single-molecule fluorescent in situ hybridization showed IMP1 colocalization with <em>MAP1LC3B</em> transcripts at homeostasis. Stress induction led to decreased colocalization.</p></div><div><h3>Conclusions</h3><p>Depletion of IMP1 enhances autophagy, which promotes intestinal regeneration via expansion of facultative intestinal stem cells.</p></div>","PeriodicalId":55974,"journal":{"name":"Cellular and Molecular Gastroenterology and Hepatology","volume":"17 3","pages":"Pages 439-451"},"PeriodicalIF":7.2,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2352345X2300214X/pdfft?md5=a5294ecfdf885b7c2780c0ea378dd133&pid=1-s2.0-S2352345X2300214X-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138562828","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 Recurrent Liver MAN2A1-FER Oncoprotein Lacks Kinase Activity: Implications for the Use of Tyrosine Kinase Inhibitors","authors":"Mathieu Desaunay,&nbsp;Edwige Voisset,&nbsp;Sebastien Letard,&nbsp;Philippe Roche,&nbsp;Paulo De Sepulveda","doi":"10.1016/j.jcmgh.2023.12.007","DOIUrl":"10.1016/j.jcmgh.2023.12.007","url":null,"abstract":"","PeriodicalId":55974,"journal":{"name":"Cellular and Molecular Gastroenterology and Hepatology","volume":"17 4","pages":"Pages 667-669"},"PeriodicalIF":7.2,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2352345X23002205/pdfft?md5=a38de6963a10ccc7458cbedd3fc6acf1&pid=1-s2.0-S2352345X23002205-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139028038","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":"Genetic Variation Between Small Bowel and Colon-Predominant Crohn's Disease","authors":"Halee Patel,&nbsp;R. Alan Harris,&nbsp;Justin H. Qian,&nbsp;Numan Oezguen,&nbsp;Ashleigh Watson,&nbsp;Reka G. Szigeti,&nbsp;Stanley Cho,&nbsp;Wenly Ruan,&nbsp;Savini Britto,&nbsp;Antone Opekun,&nbsp;Geoffrey Preidis,&nbsp;Richard Kellermayer","doi":"10.1016/j.jcmgh.2024.02.010","DOIUrl":"10.1016/j.jcmgh.2024.02.010","url":null,"abstract":"","PeriodicalId":55974,"journal":{"name":"Cellular and Molecular Gastroenterology and Hepatology","volume":"17 6","pages":"Pages 1069-1071"},"PeriodicalIF":7.2,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2352345X24000389/pdfft?md5=47811aecfd1ff6d9066f4683f258cc80&pid=1-s2.0-S2352345X24000389-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139900930","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":"Actinomyces odontolyticus: From Carries to Colorectal Cancer","authors":"Keith A. Breau","doi":"10.1016/j.jcmgh.2024.02.009","DOIUrl":"10.1016/j.jcmgh.2024.02.009","url":null,"abstract":"","PeriodicalId":55974,"journal":{"name":"Cellular and Molecular Gastroenterology and Hepatology","volume":"17 5","pages":"Pages 879-880"},"PeriodicalIF":7.2,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2352345X24000377/pdfft?md5=e9b59bca61ebfdcf587c6bec689dab66&pid=1-s2.0-S2352345X24000377-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139948825","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":"Trailblazing TRAIL Therapy: Illuminating Pathways for Cholangiocarcinoma Treatment","authors":"Sungjin Ko","doi":"10.1016/j.jcmgh.2024.02.008","DOIUrl":"10.1016/j.jcmgh.2024.02.008","url":null,"abstract":"","PeriodicalId":55974,"journal":{"name":"Cellular and Molecular Gastroenterology and Hepatology","volume":"17 5","pages":"Pages 885-886"},"PeriodicalIF":7.2,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2352345X24000365/pdfft?md5=d443e504f6049522c33c4cb83c703f7c&pid=1-s2.0-S2352345X24000365-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140023451","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":"Interindividual Variation in Gut Nitrergic Neuron Density Is Regulated By GDNF Levels and ETV1","authors":"Heikki T. Virtanen ,&nbsp;Peyman Choopanian ,&nbsp;L. Lauriina Porokuokka ,&nbsp;Richard Forsgård ,&nbsp;Daniel R. Garton ,&nbsp;Soophie Olfat ,&nbsp;Riitta Korpela ,&nbsp;Mehdi Mirzaie ,&nbsp;Jaan-Olle Andressoo","doi":"10.1016/j.jcmgh.2024.101405","DOIUrl":"10.1016/j.jcmgh.2024.101405","url":null,"abstract":"<div><h3>Background &amp; Aims</h3><div>The size and function of the enteric nervous system (ENS) can vary substantially between individuals. Because ENS function is involved in the etiology of a growing number of common human diseases, understanding mechanisms that regulate ENS variation is important.</div></div><div><h3>Methods</h3><div>We analyzed RNAseq data from 41 normal adult human colon biopsies and single-cell RNA-seq data from human and mouse developing gut. To establish cause-consequence relationship we used alleles in mice that allow levels change of the candidate effector molecule in the comparable range to human samples. We used siRNA and primary neuronal cultures to define downstream molecular events and characterized gut functional changes in mice where molecular phenotypes paralleled findings in humans.</div></div><div><h3>Results</h3><div>We found that glial cell line–derived neurotrophic factor (GDNF) levels in the human colon vary about 5-fold and correlate strongly with nitrergic marker expression. In mice, we defined that GDNF levels are regulated via its 3’ untranslated region (3’ UTR) in the gastrointestinal tract and observed similar correlation between GDNF levels and nitrergic lineage development. We identified miR-9 and miR-133 as evolutionarily conserved candidates for negative regulation of GDNF expression in the gastrointestinal tract. Functionally, an increase in inhibitory nitrergic innervation results in an increase in gastrointestinal tract transit time, stool size, and water content accompanied with modestly reduced epithelial barrier function. Mechanistically, we found that GDNF levels regulate nitrergic lineage development via induction of transcription factor ETV1, corroborated by single-cell gene expression data in human and mouse developing enteric neurons.</div></div><div><h3>Conclusions</h3><div>Our results reveal how normal variation in GDNF levels influence ENS size, composition, and gut function, suggesting a mechanism for well-known interindividual variation among those parameters.</div></div>","PeriodicalId":55974,"journal":{"name":"Cellular and Molecular Gastroenterology and Hepatology","volume":"18 6","pages":"Article 101405"},"PeriodicalIF":7.1,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142301805","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 Good, the Bad, and the Ugly” – About Diverse Phenotypes of Hepatic Stellate Cells in the Liver","authors":"Alexandra Bogomolova ,&nbsp;Asha Balakrishnan ,&nbsp;Michael Ott ,&nbsp;Amar Deep Sharma","doi":"10.1016/j.jcmgh.2024.01.002","DOIUrl":"10.1016/j.jcmgh.2024.01.002","url":null,"abstract":"<div><p>Hepatic stellate cells (HSCs) and their activated derivatives, often referred to as myofibroblasts (MFs), play a key role in progression of chronic liver injuries leading to fibrosis, cirrhosis, and hepatocellular carcinoma. Until recently, MFs were considered a homogenous cell type majorly due to lack of techniques that allow complex molecular studies at a single-cell resolution. Recent technical advancements in genetic lineage-tracing models as well as the exponential growth of studies with single-cell transcriptome and proteome analyses have uncovered hidden heterogeneities among the HSC and MF populations in healthy states as well as chronic liver injuries at the various stages of tissue deformation. The identification of different phenotypes along the HSC/MF axis, which either maintain essential liver functions (“good” HSCs), emerge during fibrosis (“bad” HSCs), or even promote hepatocellular carcinoma (“ugly” HSCs), may lay the foundation for targeting a particular MF phenotype as potential treatment for chronic liver injuries.</p></div>","PeriodicalId":55974,"journal":{"name":"Cellular and Molecular Gastroenterology and Hepatology","volume":"17 4","pages":"Pages 607-622"},"PeriodicalIF":7.2,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2352345X2400002X/pdfft?md5=5125ee8e287bd3ecb24133294c27807e&pid=1-s2.0-S2352345X2400002X-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139433154","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":"Noncanonical TRAIL Signaling Promotes Myeloid-Derived Suppressor Cell Abundance and Tumor Growth in Cholangiocarcinoma","authors":"Emilien J. Loeuillard ,&nbsp;Binbin Li ,&nbsp;Hannah E. Stumpf ,&nbsp;Jingchun Yang ,&nbsp;Jessica R. Willhite ,&nbsp;Jennifer L. Tomlinson ,&nbsp;Fred Rakhshan Rohakhtar ,&nbsp;Vernadette A. Simon ,&nbsp;Rondell P. Graham ,&nbsp;Rory L. Smoot ,&nbsp;Haidong Dong ,&nbsp;Sumera I. Ilyas","doi":"10.1016/j.jcmgh.2024.01.006","DOIUrl":"10.1016/j.jcmgh.2024.01.006","url":null,"abstract":"<div><h3>Background &amp; Aims</h3><p>Proapoptotic tumor necrosis factor–related apoptosis-inducing ligand (TRAIL) signaling as a cause of cancer cell death is a well-established mechanism. However, TRAIL-receptor (TRAIL-R) agonists have had very limited anticancer activity in human beings, challenging the concept of TRAIL as a potent anticancer agent. Herein, we aimed to define mechanisms by which TRAIL⁺ cancer cells can leverage noncanonical TRAIL signaling in myeloid-derived suppressor cells (MDSCs) promoting their abundance in murine cholangiocarcinoma (CCA).</p></div><div><h3>Methods</h3><p>Multiple immunocompetent syngeneic, orthotopic models of CCA were used. Single-cell RNA sequencing and cellular indexing of transcriptomes and epitopes by sequencing of CD45⁺ cells in murine tumors from the different CCA models was conducted.</p></div><div><h3>Results</h3><p>In multiple immunocompetent murine models of CCA, implantation of TRAIL⁺ murine cancer cells into <em>Trail-r</em>^<em>-/-</em> mice resulted in a significant reduction in tumor volumes compared with wild-type mice. Tumor-bearing <em>Trail-r</em>^<em>-/-</em> mice had a significant decrease in the abundance of MDSCs owing to attenuation of MDSC proliferation. Noncanonical TRAIL signaling with consequent nuclear factor-κB activation in MDSCs facilitated enhanced MDSC proliferation. Single-cell RNA sequencing and cellular indexing of transcriptomes and epitopes by sequencing of immune cells from murine tumors showed enrichment of a nuclear factor-κB activation signature in MDSCs. Moreover, MDSCs were resistant to TRAIL-mediated apoptosis owing to enhanced expression of cellular FLICE inhibitory protein, an inhibitor of proapoptotic TRAIL signaling. Accordingly, cellular FLICE inhibitory protein knockdown sensitized murine MDSCs to TRAIL-mediated apoptosis. Finally, cancer cell–restricted deletion of <em>Trail</em> significantly reduced MDSC abundance and murine tumor burden.</p></div><div><h3>Conclusions</h3><p>Our findings highlight the therapeutic potential of targeting TRAIL⁺ cancer cells for treatment of a poorly immunogenic cancer.</p></div>","PeriodicalId":55974,"journal":{"name":"Cellular and Molecular Gastroenterology and Hepatology","volume":"17 5","pages":"Pages 853-876"},"PeriodicalIF":7.2,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2352345X24000055/pdfft?md5=b89f7c56e45a1fe15f09ae8c7aa77e65&pid=1-s2.0-S2352345X24000055-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139466199","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":"CDKN2A-p16 Deletion and Activated KRASG12D Drive Barrett’s-Like Gland Hyperplasia-Metaplasia and Synergize in the Development of Dysplasia Precancer Lesions","authors":"Jing Sun ,&nbsp;Jorge L. Sepulveda ,&nbsp;Elena V. Komissarova ,&nbsp;Caitlin Hills ,&nbsp;Tyler D. Seckar ,&nbsp;Narine M. LeFevre ,&nbsp;Hayk Simonyan ,&nbsp;Colin Young ,&nbsp;Gloria Su ,&nbsp;Armando Del Portillo ,&nbsp;Timothy C. Wang ,&nbsp;Antonia R. Sepulveda","doi":"10.1016/j.jcmgh.2024.01.014","DOIUrl":"10.1016/j.jcmgh.2024.01.014","url":null,"abstract":"<div><h3>Background &amp; Aims</h3><p>Barrett’s esophagus is the precursor of esophageal dysplasia and esophageal adenocarcinoma. CDKN2A-p16 deletions were reported in 34%–74% of patients with Barrett’s esophagus who progressed to dysplasia and esophageal adenocarcinoma, suggesting that p16 loss may drive neoplastic progression. KRAS activation frequently occurs in esophageal adenocarcinoma and precancer lesions. LGR5⁺ stem cells in the squamocolumnar-junction (SCJ) of mouse stomach contribute as Barrett’s esophagus progenitors. We aimed to determine the functional effects of p16 loss and KRAS activation in Barrett’s-like metaplasia and dysplasia development.</p></div><div><h3>Methods</h3><p>We established mouse models with conditional knockout of CDKN2A-p16 (p16KO) and/or activated KRAS^G12D expression targeting SCJ LGR5⁺ cells in interleukin 1b transgenic mice and characterized histologic alterations (mucous-gland hyperplasia/metaplasia, inflammation, and dysplasia) in mouse SCJ. Gene expression was determined by microarray, RNA sequencing, and immunohistochemistry of SCJ tissues and cultured 3-dimensional organoids.</p></div><div><h3>Results</h3><p>p16KO mice exhibited increased mucous-gland hyperplasia/metaplasia versus control mice (<em>P</em> = .0051). Combined p16KO+KRAS^G12D resulted in more frequent dysplasia and higher dysplasia scores (<em>P</em> = .0036), with 82% of p16KO+KRAS^G12D mice developing high-grade dysplasia. SCJ transcriptome analysis showed several activated pathways in p16KO versus control mice (apoptosis, tumor necrosis factor-α/nuclear factor-kB, proteasome degradation, p53 signaling, MAPK, KRAS, and G1-to-S transition).</p></div><div><h3>Conclusions</h3><p>p16 deletion in LGR5⁺ cell precursors triggers increased SCJ mucous-gland hyperplasia/metaplasia. KRAS^G12D synergizes with p16 deletion resulting in higher grades of SCJ glandular dysplasia, mimicking Barrett’s high-grade dysplasia. These genetically modified mouse models establish a functional role of p16 and activated KRAS in the progression of Barrett’s-like lesions to dysplasia in mice, representing an <em>in vivo</em> model of esophageal adenocarcinoma precancer. Derived 3-dimensional organoid models further provide <em>in vitro</em> modeling opportunities of esophageal precancer stages.</p></div>","PeriodicalId":55974,"journal":{"name":"Cellular and Molecular Gastroenterology and Hepatology","volume":"17 5","pages":"Pages 769-784"},"PeriodicalIF":7.2,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2352345X24000146/pdfft?md5=0aa29fe556e0ec453bca72e8f31695cb&pid=1-s2.0-S2352345X24000146-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139587531","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}