Cellular and Molecular Gastroenterology and Hepatology最新文献

{"title":"Mesencephalic Astrocyte-derived Neurotrophic Factor Supports Hepatitis B Virus-induced Immunotolerance","authors":"Huiyuan Xie ,&nbsp;Haiyan Deng ,&nbsp;Xiaoping Yang ,&nbsp;Xianxian Gao ,&nbsp;Shanru Yang ,&nbsp;Weiyi Chen ,&nbsp;Yixuan Wang ,&nbsp;Naibin Yang ,&nbsp;Liang Yong ,&nbsp;Xin Hou","doi":"10.1016/j.jcmgh.2024.05.008","DOIUrl":"10.1016/j.jcmgh.2024.05.008","url":null,"abstract":"<div><h3>Background &amp; Aims</h3><p>The immune tolerance induced by hepatitis B virus (HBV) is a major challenge for achieving effective viral clearance, and the mechanisms involved are not well-understood. One potential factor involved in modulating immune responses is mesencephalic astrocyte-derived neurotrophic factor (MANF), which has been reported to be increased in patients with chronic hepatitis B. In this study, our objective is to examine the role of MANF in regulating immune responses to HBV.</p></div><div><h3>Methods</h3><p>We utilized a commonly used HBV-harboring mouse model, where mice were hydrodynamically injected with the pAAV/HBV1.2 plasmid. We assessed the HBV load by measuring the levels of various markers including hepatitis B surface antigen, hepatitis B envelope antigen, hepatitis B core antigen, HBV DNA, and HBV RNA.</p></div><div><h3>Results</h3><p>Our study revealed that following HBV infection, both myeloid cells and hepatocytes exhibited increased expression of MANF. Moreover, we observed that mice with myeloid-specific MANF knockout (Manf^Mye-/-) displayed reduced HBV load and improved HBV-specific T cell responses. The decreased HBV-induced tolerance in Manf^Mye-/- mice was associated with reduced accumulation of myeloid-derived suppressor cells (MDSCs) in the liver. Restoring MDSC levels in Manf^Mye-/- mice through MDSC adoptive transfer reinstated HBV-induced tolerance. Mechanistically, we found that MANF promoted MDSC expansion by activating the IL-6/STAT3 pathway. Importantly, our study demonstrated the effectiveness of a combination therapy involving an hepatitis B surface antigen vaccine and nanoparticle-encapsulated MANF siRNA in effectively clearing HBV in HBV-carrier mice.</p></div><div><h3>Conclusion</h3><p>The current study reveals that MANF plays a previously unrecognized regulatory role in liver tolerance by expanding MDSCs in the liver through IL-6/STAT3 signaling, leading to MDSC-mediated CD8⁺ T cell exhaustion.</p></div>","PeriodicalId":55974,"journal":{"name":"Cellular and Molecular Gastroenterology and Hepatology","volume":null,"pages":null},"PeriodicalIF":7.1,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2352345X24001140/pdfft?md5=43d4376f89a1060ffb852ae42d8ee968&pid=1-s2.0-S2352345X24001140-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140961077","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":"Th2 Cell Activation in Chronic Liver Disease Is Driven by Local IL33 and Contributes to IL13-Dependent Fibrogenesis","authors":"Johanna Reißing ,&nbsp;Marie Berres ,&nbsp;Pavel Strnad ,&nbsp;Alexander Wree ,&nbsp;Maria Eugenia Inzaugarat ,&nbsp;Christian Trautwein ,&nbsp;Tony Bruns ,&nbsp;Henning Wolfgang Zimmermann","doi":"10.1016/j.jcmgh.2023.12.011","DOIUrl":"10.1016/j.jcmgh.2023.12.011","url":null,"abstract":"<div><h3>Background &amp; Aims</h3><p>Type 2 immune responses contribute to liver fibrosis in parasite infections, but their role in other liver diseases is less well understood. Here, we aimed at unravelling mechanisms involved in T helper 2 (Th2) T-cell polarization, activation, and recruitment in human liver fibrosis and cirrhosis.</p></div><div><h3>Methods</h3><p>Tissues, cells, and serum from human livers were analyzed using quantitative reverse-transcription polymerase chain reaction, enzyme-linked immunosorbent assay, fluorescence in situ hybridization, immunostaining, flow cytometry, and various functional in vitro assays. Cellular interactions and soluble mediators involved in T-cell polarization and recruitment were studied, as well as their effect on hepatic stellate cell (HSC) activation, proliferation, and extracellular matrix synthesis.</p></div><div><h3>Results</h3><p>In human liver fibrosis, a stage-dependent increase in Th2-related transcription factors, Th2 cytokines, and trans-acting T-cell–specific transcription factor–expressing T cells was observed, and was highest in cirrhotic livers. The alarmin interleukin (IL)33 was found to be increased in livers and sera from patients with cirrhosis, to act as a chemotactic agent for Th2 cells, and to induce type 2 polarization of CD4+ T cells. Oval cells, liver sinusoidal endothelial cells, intrahepatic macrophages, and migrating monocytes were identified as sources of IL33. IL33-activated T cells, but not IL33 alone, induced HSC activation, as shown by Ki67 and α-smooth muscle actin staining, increased collagen type I alpha 1 chain messenger RNA expression, and wound healing assays. The profibrotic effect of IL33-activated T cells was contact-independent and could be antagonized using monoclonal antibodies against IL13.</p></div><div><h3>Conclusion</h3><p>In patients with chronic liver disease, the alarmin IL33 promotes the recruitment and activation of CD4+ T cells with Th2-like properties, which activate paracrine HSC in an IL13-dependent manner and promotes fibrogenesis.</p></div>","PeriodicalId":55974,"journal":{"name":"Cellular and Molecular Gastroenterology and Hepatology","volume":null,"pages":null},"PeriodicalIF":7.2,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2352345X23002278/pdfft?md5=2e5b8335236214bf8d30b1dc63316401&pid=1-s2.0-S2352345X23002278-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139054066","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":"Gut Bacteria-derived Membrane Vesicles Induce Colonic Dysplasia by Inducing DNA Damage in Colon Epithelial Cells","authors":"Yu Miyakawa ,&nbsp;Motoyuki Otsuka ,&nbsp;Chikako Shibata ,&nbsp;Takahiro Seimiya ,&nbsp;Keisuke Yamamoto ,&nbsp;Rei Ishibashi ,&nbsp;Takahiro Kishikawa ,&nbsp;Eri Tanaka ,&nbsp;Takayuki Isagawa ,&nbsp;Norihiko Takeda ,&nbsp;Noriaki Kamio ,&nbsp;Kenichi Imai ,&nbsp;Mitsuhiro Fujishiro","doi":"10.1016/j.jcmgh.2024.01.010","DOIUrl":"10.1016/j.jcmgh.2024.01.010","url":null,"abstract":"<div><h3>Background &amp; Aims</h3><p>Colorectal cancer (CRC) is the third most common cancer in the world. Gut microbiota has recently been implicated in the development of CRC. <em>Actinomyces odontolyticus</em> is one of the most abundant bacteria in the gut of patients with very early stages of CRC. <em>A odontolyticus</em> is an anaerobic bacterium existing principally in the oral cavity, similar to <em>Fusobacterium nucleatum,</em> which is known as a colon carcinogenic bacterium. Here we newly determined the biological functions of <em>A odontolyticus</em> on colonic oncogenesis.</p></div><div><h3>Methods</h3><p>We examined the induction of intracellular signaling by <em>A odontolyticus</em> in human colonic epithelial cells (CECs). DNA damage levels in CECs were confirmed using the human induced pluripotent stem cell-derived gut organoid model and mouse colon tissues in vivo.</p></div><div><h3>Results</h3><p><em>A odontolyticus</em> secretes membrane vesicles (MVs), which induce nuclear factor kappa B signaling and also produce excessive reactive oxygen species (ROS) in colon epithelial cells. We found that <em>A odontolyticus</em> secretes lipoteichoic acid-rich MVs, promoting inflammatory signaling via TLR2. Simultaneously, those MVs are internalized into the colon epithelial cells, co-localize with the mitochondria, and cause mitochondrial dysfunction, resulting in excessive ROS production and DNA damage. Induction of excessive DNA damage in colonic cells by <em>A odontolyticus</em>-derived MVs was confirmed in the gut organoid model and also in mouse colon tissues.</p></div><div><h3>Conclusions</h3><p><em>A odontolyticus</em> secretes MVs, which cause chronic inflammation and ROS production in colonic epithelial cells, leading to the initiation of CRC.</p></div>","PeriodicalId":55974,"journal":{"name":"Cellular and Molecular Gastroenterology and Hepatology","volume":null,"pages":null},"PeriodicalIF":7.2,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2352345X24000109/pdfft?md5=e23ca47bd954111738ee31e9c0a144d5&pid=1-s2.0-S2352345X24000109-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139668490","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":"Therapeutic Effect of Proteinase-Activated Receptor-1 Antagonist on Colitis-Associated Carcinogenesis","authors":"Xiaodong Li ,&nbsp;Lin-Hai Kurahara ,&nbsp;Zhixin Zhao ,&nbsp;Feiyan Zhao ,&nbsp;Ryo Ishikawa ,&nbsp;Kiyomi Ohmichi ,&nbsp;Gaopeng Li ,&nbsp;Tetsuo Yamashita ,&nbsp;Takeshi Hashimoto ,&nbsp;Mayumi Hirano ,&nbsp;Zhihong Sun ,&nbsp;Katsuya Hirano","doi":"10.1016/j.jcmgh.2024.04.001","DOIUrl":"10.1016/j.jcmgh.2024.04.001","url":null,"abstract":"<div><h3>Background &amp; Aims</h3><p>Inflammatory bowel disease is associated with carcinogenesis, which limits the prognosis of the patients. The local expression of proteinases and proteinase-activated receptor 1 (PAR₁) increases in inflammatory bowel disease. The present study investigated the therapeutic effects of PAR₁ antagonism on colitis-associated carcinogenesis.</p></div><div><h3>Methods</h3><p>A colitis-associated carcinogenesis model was prepared in mice by treatment with azoxymethane (AOM) and dextran sulfate sodium (DSS). PAR₁ antagonist E5555 was administered in long- and short-term protocol, starting on the day of AOM injection and 1 week after completing AOM/DSS treatment, respectively. The fecal samples were collected for metagenome analysis of gut microbiota. The intestinal myofibroblasts of the Crohn’s disease patients were used to elucidate underlying cellular mechanisms. Caco-2 cells were used to investigate a possible source of PAR₁ agonist proteinases.</p></div><div><h3>Results</h3><p>AOM/DSS model showed weight loss, diarrhea, tumor development, inflammation, fibrosis, and increased production of inflammatory cytokines. The β-diversity, but not α-diversity, of microbiota significantly differed between AOM/DSS and control mice. E5555 alleviated these pathological changes and altered the microbiota β-diversity in AOM/DSS mice. The thrombin expression was up-regulated in tumor and non-tumor areas, whereas PAR₁ mRNA expression was higher in tumor areas compared with non-tumor areas. E5555 inhibited thrombin-triggered elevation of cytosolic Ca²⁺ concentration and ERK1/2 phosphorylation, as well as IL6-induced signal transducer and activator of transcription 3 (STAT3) phosphorylation in intestinal myofibroblasts. Caco-2 cell-conditioned medium contained immunoreactive thrombin, which cleaved the recombinant protein containing the extracellular domain of PAR₁ at the thrombin cleavage site.</p></div><div><h3>Conclusions</h3><p>PAR₁ antagonism is proposed to be a novel therapeutic strategy for treatment of inflammatory bowel disease and its associated carcinogenesis.</p></div>","PeriodicalId":55974,"journal":{"name":"Cellular and Molecular Gastroenterology and Hepatology","volume":null,"pages":null},"PeriodicalIF":7.2,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2352345X24000717/pdfft?md5=8b994d1d5ae16166b21f33644cff1753&pid=1-s2.0-S2352345X24000717-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140790423","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":"Role of ICAM-1 in the Adhesion of T Cells to Enteric Glia: Perspectives in the Formation of Plexitis in Crohn’s Disease","authors":"Julie Pabois ,&nbsp;Tony Durand ,&nbsp;Catherine Le Berre ,&nbsp;Rhiannon T. Filippone ,&nbsp;Théo Noël ,&nbsp;Emilie Durieu ,&nbsp;Céline Bossard ,&nbsp;Sarah Bruneau ,&nbsp;Malvyne Rolli-Derkinderen ,&nbsp;Kulmira Nurgali ,&nbsp;Michel Neunlist ,&nbsp;Arnaud Bourreille ,&nbsp;Isabelle Neveu ,&nbsp;Philippe Naveilhan","doi":"10.1016/j.jcmgh.2024.02.016","DOIUrl":"10.1016/j.jcmgh.2024.02.016","url":null,"abstract":"<div><h3>Background &amp; Aims</h3><p>The presence of myenteric plexitis in the proximal resection margins is a predictive factor of early postoperative recurrence in Crohn’s disease. To decipher the mechanisms leading to their formation, T-cell interactions with enteric neural cells were studied in vitro and in vivo.</p></div><div><h3>Methods</h3><p>T cells close to myenteric neural cells were retrospectively quantified in ileocolonic resections from 9 control subjects with cancer and 20 patients with Crohn’s disease. The mechanisms involved in T-cell adhesion were then investigated in co-cultures of T lymphocytes with enteric glial cells (glia). Finally, the implication of adhesion molecules in the development of plexitis and colitis was studied in vitro but also in vivo in Winnie mice.</p></div><div><h3>Results</h3><p>The mean number of T cells close to glia, but not neurons, was significantly higher in the myenteric ganglia of relapsing patients with Crohn’s disease (2.42 ± 0.5) as compared with controls (0.36 ± 0.08, <em>P</em> = .0007). Co-culture experiments showed that exposure to proinflammatory cytokines enhanced T-cell adhesion to glia and increased intercellular adhesion molecule-1 (ICAM-1) expression in glia. We next demonstrated that T-cell adhesion to glia was inhibited by an anti–ICAM-1 antibody. Finally, using the Winnie mouse model of colitis, we showed that the blockage of ICAM-1/lymphocyte function-associated antigen-1 (LFA-1) with lifitegrast reduced colitis severity and decreased T-cell infiltration in the myenteric plexus.</p></div><div><h3>Conclusions</h3><p>Our present work argues for a role of glia–T-cell interaction in the development of myenteric plexitis through the adhesion molecules ICAM-1/LFA-1 and suggests that deciphering the functional consequences of glia–T-cell interaction is important to understand the mechanisms implicated in the development and recurrence of Crohn’s disease.</p></div>","PeriodicalId":55974,"journal":{"name":"Cellular and Molecular Gastroenterology and Hepatology","volume":null,"pages":null},"PeriodicalIF":7.2,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2352345X2400050X/pdfft?md5=da24d11348be30a3d1f546e383c7dccf&pid=1-s2.0-S2352345X2400050X-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140013771","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":"Fatty Acid Esterification as a NASH Therapeutic Target","authors":"Ikki Sakuma,&nbsp;Daniel F. Vatner","doi":"10.1016/j.jcmgh.2023.10.011","DOIUrl":"10.1016/j.jcmgh.2023.10.011","url":null,"abstract":"","PeriodicalId":55974,"journal":{"name":"Cellular and Molecular Gastroenterology and Hepatology","volume":null,"pages":null},"PeriodicalIF":7.2,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2352345X2300190X/pdfft?md5=2a16e99e77d59699d75db91baafb36f5&pid=1-s2.0-S2352345X2300190X-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138178095","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":"Heterozygous Spink1 Deficiency Promotes Trypsin-dependent Chronic Pancreatitis in Mice","authors":"Alexandra Demcsák,&nbsp;Miklós Sahin-Tóth","doi":"10.1016/j.jcmgh.2024.05.009","DOIUrl":"10.1016/j.jcmgh.2024.05.009","url":null,"abstract":"<div><h3>Background &amp; Aims</h3><p>Heterozygous <em>SPINK1</em> mutations are strong risk factors for chronic pancreatitis in humans, yet heterozygous disruption of mouse <em>Spink1</em> yielded no pancreatic phenotype. To resolve this contradiction, we used CRISPR/Cas9-mediated genome editing to generate heterozygous <em>Spink1</em>-deleted mice (<em>Spink1-KO</em>^het) in the C57BL/6N strain and studied the effect of this allele in trypsin-independent and trypsin-dependent pancreatitis models.</p></div><div><h3>Methods</h3><p>We investigated severity of acute pancreatitis and progression to chronic pancreatitis in <em>Spink1-KO</em>^het mice after transient (10 injections) and prolonged (2 × 8 injections) cerulein hyperstimulation. We crossed <em>Spink1-KO</em>^het mice with <em>T7D23A</em> and <em>T7D22N,K24R</em> mice that carry strongly autoactivating trypsinogen mutants and exhibit spontaneous chronic pancreatitis.</p></div><div><h3>Results</h3><p>Prolonged but not transient cerulein stimulation resulted in increased intrapancreatic trypsin activity and more severe acute pancreatitis in <em>Spink1-KO</em>^het mice relative to the C57BL/6N control strain. After the acute episode, <em>Spink1-KO</em>^het mice developed progressive disease with chronic pancreatitis-like features, whereas C57BL/6N mice recovered rapidly. Trypsinogen mutant mice carrying the <em>Spink1-KO</em>^het allele exhibited strikingly more severe chronic pancreatitis than the respective parent strains.</p></div><div><h3>Conclusions</h3><p>Heterozygous <em>Spink1</em> deficiency caused more severe acute pancreatitis after prolonged cerulein stimulation and promoted chronic pancreatitis after the cerulein-induced acute episode, and in two strains of trypsinogen mutant mice with spontaneous disease. In contrast, acute pancreatitis induced with limited cerulein hyperstimulation was unaffected by heterozygous <em>Spink1</em> deletion, in agreement with recent observations that trypsin activity does not mediate pathologic responses in this model. Taken together, the findings strongly support the notion that loss-of-function <em>SPINK1</em> mutations in humans increase chronic pancreatitis risk in a trypsin-dependent manner.</p></div>","PeriodicalId":55974,"journal":{"name":"Cellular and Molecular Gastroenterology and Hepatology","volume":null,"pages":null},"PeriodicalIF":7.1,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2352345X24001152/pdfft?md5=fcd6a6d57f664b7a4d6aa24940431b9c&pid=1-s2.0-S2352345X24001152-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141072312","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 Ties That Bind: Enteric Glia Link T Cells to Plexitis in Crohn’s","authors":"Brian D. Gulbransen","doi":"10.1016/j.jcmgh.2024.03.011","DOIUrl":"10.1016/j.jcmgh.2024.03.011","url":null,"abstract":"","PeriodicalId":55974,"journal":{"name":"Cellular and Molecular Gastroenterology and Hepatology","volume":null,"pages":null},"PeriodicalIF":7.2,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2352345X24000663/pdfft?md5=bc37fdfdc8cfce1639d80afc44f7ab54&pid=1-s2.0-S2352345X24000663-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140855773","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":"Scaffolding Supports the Hippo","authors":"","doi":"10.1016/j.jcmgh.2024.05.011","DOIUrl":"10.1016/j.jcmgh.2024.05.011","url":null,"abstract":"","PeriodicalId":55974,"journal":{"name":"Cellular and Molecular Gastroenterology and Hepatology","volume":null,"pages":null},"PeriodicalIF":7.1,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2352345X24001176/pdfft?md5=61597794f1bd71f3236b26e48d5ddba2&pid=1-s2.0-S2352345X24001176-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141288927","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":"Acvr1b Loss Increases Formation of Pancreatic Precancerous Lesions From Acinar and Ductal Cells of Origin","authors":"","doi":"10.1016/j.jcmgh.2024.101387","DOIUrl":"10.1016/j.jcmgh.2024.101387","url":null,"abstract":"<div><h3>Background &amp; Aims</h3><p>Pancreatic ductal adenocarcinoma can develop from precursor lesions, including pancreatic intraepithelial neoplasia and intraductal papillary mucinous neoplasm (IPMN). Previous studies indicated that loss of <em>Acvr1b</em> accelerates the Kras-mediated development of papillary IPMN in the mouse pancreas; however, the cell type predominantly affected by these genetic changes remains unclear.</p></div><div><h3>Methods</h3><p>We investigated the contribution of cellular origin by inducing IPMN associated mutations (KRAS^G12D expression and <em>Acvr1b</em> loss) specifically in acinar (<em>Ptf1a</em>^{<em>CreER</em>}<em>;Kras</em>^{<em>LSL-G12D</em>}<em>;Acvr1b</em>^{<em>fl/fl</em>} mice) or ductal (<em>Sox9CreER;Kras</em>^{<em>LSL-G12D</em>}<em>;Acvr1b</em>^{<em>fl/fl</em>} mice) cells in mice. We then performed magnetic resonance imaging and a thorough histopathologic analysis of their pancreatic tissues.</p></div><div><h3>Results</h3><p>The loss of <em>Acvr1b</em> increased the development of pancreatic intraepithelial neoplasia and IPMN-like lesions when either acinar or ductal cells expressed a Kras mutation. Magnetic resonance imaging, immunohistochemistry, and histology revealed large IPMN-like lesions in these mice that exhibited features of flat, gastric epithelium. In addition, cyst formation in both mouse models was accompanied by chronic pancreatitis. Experimental acute pancreatitis accelerated the development of large mucinous cysts and pancreatic intraepithelial neoplasia when acinar, but not ductal, cells expressed mutant Kras and lost <em>Acvr1b</em>.</p></div><div><h3>Conclusions</h3><p>These findings indicate that loss of <em>Acvr1b</em> in the presence of the Kras oncogene promotes the development of large and small precancerous lesions from both ductal and acinar cells. However, the IPMN-like phenotype was not equivalent to that observed when these mutations were made in all pancreatic cells during development. Our study underscores the significance of the cellular context in the initiation and progression of precursor lesions from exocrine cells.</p></div>","PeriodicalId":55974,"journal":{"name":"Cellular and Molecular Gastroenterology and Hepatology","volume":null,"pages":null},"PeriodicalIF":7.1,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2352345X24001425/pdfft?md5=ff59ce20a13fca8c0be9687f86fc11bd&pid=1-s2.0-S2352345X24001425-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141903656","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}