Knockdown of vimentin reduces mesenchymal phenotype of cholangiocytes in the Mdr2−/− mouse model of primary sclerosing cholangitis (PSC)Research in context
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
Affiliations
Tianhao Zhou
Department of Medical Physiology, College of Medicine, Texas A&M University, Bryan, TX, United States of America
Konstantina Kyritsi
Gastroenterology, Medicine, Indiana University, Indianapolis, IN, United States of America
Nan Wu
Gastroenterology, Medicine, Indiana University, Indianapolis, IN, United States of America
Heather Francis
Richard L. Roudebush VA Medical Center, Indianapolis, IN, United States of America; Gastroenterology, Medicine, Indiana University, Indianapolis, IN, United States of America
Zhihong Yang
Richard L. Roudebush VA Medical Center, Indianapolis, IN, United States of America; Gastroenterology, Medicine, Indiana University, Indianapolis, IN, United States of America
Lixian Chen
Department of Medical Physiology, College of Medicine, Texas A&M University, Bryan, TX, United States of America
April O'Brien
Department of Medical Physiology, College of Medicine, Texas A&M University, Bryan, TX, United States of America
Lindsey Kennedy
Gastroenterology, Medicine, Indiana University, Indianapolis, IN, United States of America
Ludovica Ceci
Gastroenterology, Medicine, Indiana University, Indianapolis, IN, United States of America
Vik Meadows
Gastroenterology, Medicine, Indiana University, Indianapolis, IN, United States of America
Praveen Kusumanchi
Richard L. Roudebush VA Medical Center, Indianapolis, IN, United States of America; Gastroenterology, Medicine, Indiana University, Indianapolis, IN, United States of America
Chaodong Wu
Department of Nutrition and Food Science, College of Medicine, Texas A&M University, United States of America
Leonardo Baiocchi
University of Tor Vergata, Rome, Italy
Nicholas J. Skill
Department of Surgery, Indiana University, Indianapolis, IN, United States of America
Romil Saxena
Department of Pathology, Indiana University, Indianapolis, IN, United States of America
Amelia Sybenga
Department of Pathology, Microbiology and Immunology, Vanderbilt University School of Medicine, Nashville, TN, United States of America
Linglin Xie
Department of Nutrition and Food Science, College of Medicine, Texas A&M University, United States of America
Suthat Liangpunsakul
Richard L. Roudebush VA Medical Center, Indianapolis, IN, United States of America; Gastroenterology, Medicine, Indiana University, Indianapolis, IN, United States of America
Fanyin Meng
Richard L. Roudebush VA Medical Center, Indianapolis, IN, United States of America; Gastroenterology, Medicine, Indiana University, Indianapolis, IN, United States of America
Gianfranco Alpini
Richard L. Roudebush VA Medical Center, Indianapolis, IN, United States of America; Gastroenterology, Medicine, Indiana University, Indianapolis, IN, United States of America; Correspondence to: G. Alpini, Indiana Center for Liver Research, Richard L. Roudebush VA Medical Center and Indiana University, Gastroenterology, Medicine, 1481 W 10th street, Dedication Wing – Room D-2004, Indianapolis, IN 46202, United States of America.
Shannon Glaser
Department of Medical Physiology, College of Medicine, Texas A&M University, Bryan, TX, United States of America; Correspondence to: S. Glaser, Texas A&M University College of Medicine, Department of Medical Physiology, 8447 Riverside Parkway, MREB II Office 2342, Bryan, TX 77807, United States of America.
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
