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首页> 外文期刊>EBioMedicine >Knockdown of vimentin reduces mesenchymal phenotype of cholangiocytes in the Mdr2?/? mouse model of primary sclerosing cholangitis (PSC)
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Knockdown of vimentin reduces mesenchymal phenotype of cholangiocytes in the Mdr2?/? mouse model of primary sclerosing cholangitis (PSC)

机译：波形蛋白的敲低降低了Mdr2β/β中胆管细胞的间质表型。原发性硬化性胆管炎（PSC）的小鼠模型

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Background Cholangiocytes are the target cells of cholangiopathies including primary sclerosing cholangitis (PSC). Vimentin is an intermediate filament protein that has been found in various types of mesenchymal cells. The aim of this study is to evaluate the role of vimentin in the progression of biliary damage/liver fibrosis and whether there is a mesenchymal phenotype of cholangiocytes in the Mdr2sup?/?/sup model of PSC. Methods In vivo studies were performed in 12 wk. Mdr2sup?/?/sup male mice with or without vimentin Vivo-Morpholino treatment and their corresponding control groups. Liver specimens from human PSC patients, human intrahepatic biliary epithelial cells (HIBEpiC) and human hepatic stellate cell lines (HHSteCs) were used to measure changes in epithelial-to-mesenchymal transition (EMT). Findings There was increased mesenchymal phenotype of cholangiocytes in Mdr2sup?/?/sup mice, which was reduced by treatment of vimentin Vivo-Morpholino. Concomitant with reduced vimentin expression, there was decreased liver damage, ductular reaction, biliary senescence, liver fibrosis and TGF-β1 secretion in Mdr2sup?/?/sup mice treated with vimentin Vivo-Morpholino. Human PSC patients and derived cell lines had increased expression of vimentin and other mesenchymal markers compared to healthy controls and HIBEpiC, respectively. In vitro silencing of vimentin in HIBEpiC suppressed TGF-β1-induced EMT and fibrotic reaction. HHSteCs had decreased fibrotic reaction and increased cellular senescence after stimulation with cholangiocyte supernatant with reduced vimentin levels. Interpretation Our study demonstrated that knockdown of vimentin reduces mesenchymal phenotype of cholangiocytes, which leads to decreased biliary senescence and liver fibrosis. Inhibition of vimentin may be a key therapeutic target in the treatment of cholangiopathies including PSC. Fund National Institutes of Health (NIH) awards, VA Merit awards.
机译：背景胆管细胞是胆管疾病的靶细胞，包括原发性硬化性胆管炎（PSC）。波形蛋白是一种中间丝蛋白，已在各种类型的间充质细胞中发现。这项研究的目的是评估波形蛋白在胆囊损害/肝纤维化进展中的作用，以及在PSC的Mdr2 ？/？模型中是否存在胆管细胞的间充质表型。方法体内研究在12周内进行。带有或不带有波形蛋白的Mdr2 ？/？雄性小鼠Vivo-Morpholino处理及其相应的对照组。使用来自人类PSC患者，人类肝内胆汁上皮细胞（HIBEpiC）和人类肝星状细胞系（HHSteCs）的肝脏标本来测量上皮向间质转化（EMT）的变化。结果Mdr2 ？/？小鼠胆管细胞的间充质表型增加，而波形蛋白Vivo-Morpholino处理可减少这种情况。伴波形蛋白表达降低的是，用波形蛋白Vivo-Morpholino处理的Mdr2 ？/？小鼠肝损伤，导管反应，胆管衰老，肝纤维化和TGF-β1分泌减少。与健康对照组和HIBEpiC相比，人类PSC患者和衍生细胞系的波形蛋白和其他间充质标记物的表达分别增加。 HIBEpiC中波形蛋白的体外沉默抑制了TGF-β1诱导的EMT和纤维化反应。用波形蛋白水平降低的胆管细胞上清液刺激后，HHSteCs减少了纤维化反应，并增加了细胞衰老。解释我们的研究表明，波形蛋白的敲除可减少胆管细胞的间质表型，从而降低胆汁衰老和肝纤维化。波形蛋白的抑制可能是包括PSC在内的胆管病的关键治疗靶标。资助美国国立卫生研究院（NIH）奖，VA优异奖。

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