Dataset Information

Knockdown of vimentin reduces mesenchymal phenotype of cholangiocytes in the Mdr2^-/- mouse model of primary sclerosing cholangitis (PSC).

ABSTRACT:

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-?1 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-?1-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.

SUBMITTER: Zhou T

PROVIDER: S-EPMC6838376 | biostudies-literature | 2019 Oct

REPOSITORIES: biostudies-literature

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Publications

Knockdown of vimentin reduces mesenchymal phenotype of cholangiocytes in the Mdr2<sup>-/-</sup> mouse model of primary sclerosing cholangitis (PSC).

Zhou Tianhao T Kyritsi Konstantina K Wu Nan N Francis Heather H Yang Zhihong Z Chen Lixian L O'Brien April A Kennedy Lindsey L Ceci Ludovica L Meadows Vik V Kusumanchi Praveen P Wu Chaodong C Baiocchi Leonardo L Skill Nicholas J NJ Saxena Romil R Sybenga Amelia A Xie Linglin L Liangpunsakul Suthat S Meng Fanyin F Alpini Gianfranco G Glaser Shannon S

EBioMedicine 20190912

<h4>Background</h4>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<sup>-/-</sup> model of PSC.<h4>Methods</h4>In vivo studies were performed in 12 wk. Mdr2 ...[more]

PMID: 31522982

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Dataset Information

Knockdown of vimentin reduces mesenchymal phenotype of cholangiocytes in the Mdr2^-/- mouse model of primary sclerosing cholangitis (PSC).

Background

Methods

Findings

Interpretation

Publications

Knockdown of vimentin reduces mesenchymal phenotype of cholangiocytes in the Mdr2<sup>-/-</sup> mouse model of primary sclerosing cholangitis (PSC).

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

Dataset Information

Knockdown of vimentin reduces mesenchymal phenotype of cholangiocytes in the Mdr2-/- mouse model of primary sclerosing cholangitis (PSC).

Background

Methods

Findings

Interpretation

Publications

Knockdown of vimentin reduces mesenchymal phenotype of cholangiocytes in the Mdr2<sup>-/-</sup> mouse model of primary sclerosing cholangitis (PSC).

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

Knockdown of vimentin reduces mesenchymal phenotype of cholangiocytes in the Mdr2^-/- mouse model of primary sclerosing cholangitis (PSC).