دورية أكاديمية

Knockdown of vimentin reduces mesenchymal phenotype of cholangiocytes in the Mdr2−/− mouse model of primary sclerosing cholangitis (PSC)Research in context

التفاصيل البيبلوغرافية
العنوان: Knockdown of vimentin reduces mesenchymal phenotype of cholangiocytes in the Mdr2−/− mouse model of primary sclerosing cholangitis (PSC)Research in context
المؤلفون: Tianhao Zhou, Konstantina Kyritsi, Nan Wu, Heather Francis, Zhihong Yang, Lixian Chen, April O'Brien, Lindsey Kennedy, Ludovica Ceci, Vik Meadows, Praveen Kusumanchi, Chaodong Wu, Leonardo Baiocchi, Nicholas J. Skill, Romil Saxena, Amelia Sybenga, Linglin Xie, Suthat Liangpunsakul, Fanyin Meng, Gianfranco Alpini, Shannon Glaser
المصدر: EBioMedicine, Vol 48, Iss , Pp 130-142 (2019)
بيانات النشر: Elsevier, 2019.
سنة النشر: 2019
المجموعة: LCC:Medicine
LCC:Medicine (General)
مصطلحات موضوعية: Medicine, Medicine (General), R5-920
الوصف: 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 Mdr2−/− model of PSC. Methods: In vivo studies were performed in 12 wk. Mdr2−/− 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 Mdr2−/− 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 Mdr2−/− 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. Keywords: Ductular reaction, Fibroblast, Fibrosis, Senescence, Transforming growth factor beta 1
نوع الوثيقة: article
وصف الملف: electronic resource
اللغة: English
تدمد: 2352-3964
Relation: http://www.sciencedirect.com/science/article/pii/S2352396419306115; https://doaj.org/toc/2352-3964
DOI: 10.1016/j.ebiom.2019.09.013
URL الوصول: https://doaj.org/article/606ab22e62a04d15a60b567e6cc3dc44
رقم الأكسشن: edsdoj.606ab22e62a04d15a60b567e6cc3dc44
قاعدة البيانات: Directory of Open Access Journals
الوصف
تدمد:23523964
DOI:10.1016/j.ebiom.2019.09.013