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

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 AlpiniShannon Glaser

Research output: Contribution to journalArticle

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-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.

Original languageEnglish (US)
JournalEBioMedicine
DOIs
StateAccepted/In press - Jan 1 2019

Fingerprint

Sclerosing Cholangitis
Vimentin
Phenotype
Liver
Morpholinos
Liver Cirrhosis
Hepatic Stellate Cells
Epithelial-Mesenchymal Transition
Epithelial Cells
Cell Line
Intermediate Filament Proteins
Cell Aging
National Institutes of Health (U.S.)
Therapeutics
Cells
Health

Keywords

  • Ductular reaction
  • Fibroblast
  • Fibrosis
  • Senescence
  • Transforming growth factor beta 1

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

Knockdown of vimentin reduces mesenchymal phenotype of cholangiocytes in the Mdr2−/− mouse model of primary sclerosing cholangitis (PSC). / Zhou, Tianhao; Kyritsi, Konstantina; Wu, Nan; Francis, Heather; Yang, Zhihong; Chen, Lixian; O'Brien, April; Kennedy, Lindsey; Ceci, Ludovica; Meadows, Vik; Kusumanchi, Praveen; Wu, Chaodong; Baiocchi, Leonardo; Skill, Nicholas J.; Saxena, Romil; Sybenga, Amelia; Xie, Linglin; Liangpunsakul, Suthat; Meng, Fanyin; Alpini, Gianfranco; Glaser, Shannon.

In: EBioMedicine, 01.01.2019.

Research output: Contribution to journalArticle

Zhou, T, Kyritsi, K, Wu, N, Francis, H, Yang, Z, Chen, L, O'Brien, A, Kennedy, L, Ceci, L, Meadows, V, Kusumanchi, P, Wu, C, Baiocchi, L, Skill, NJ, Saxena, R, Sybenga, A, Xie, L, Liangpunsakul, S, Meng, F, Alpini, G & Glaser, S 2019, 'Knockdown of vimentin reduces mesenchymal phenotype of cholangiocytes in the Mdr2−/− mouse model of primary sclerosing cholangitis (PSC)', EBioMedicine. https://doi.org/10.1016/j.ebiom.2019.09.013
Zhou, Tianhao ; Kyritsi, Konstantina ; Wu, Nan ; Francis, Heather ; Yang, Zhihong ; Chen, Lixian ; O'Brien, April ; Kennedy, Lindsey ; Ceci, Ludovica ; Meadows, Vik ; Kusumanchi, Praveen ; Wu, Chaodong ; Baiocchi, Leonardo ; Skill, Nicholas J. ; Saxena, Romil ; Sybenga, Amelia ; Xie, Linglin ; Liangpunsakul, Suthat ; Meng, Fanyin ; Alpini, Gianfranco ; Glaser, Shannon. / Knockdown of vimentin reduces mesenchymal phenotype of cholangiocytes in the Mdr2−/− mouse model of primary sclerosing cholangitis (PSC). In: EBioMedicine. 2019.
@article{ad85dd3fc9064b88b08b0d4709b193e0,
title = "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-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",
author = "Tianhao Zhou and Konstantina Kyritsi and Nan Wu and Heather Francis and Zhihong Yang and Lixian Chen and April O'Brien and Lindsey Kennedy and Ludovica Ceci and Vik Meadows and Praveen Kusumanchi and Chaodong Wu and Leonardo Baiocchi and Skill, {Nicholas J.} and Romil Saxena and Amelia Sybenga and Linglin Xie and Suthat Liangpunsakul and Fanyin Meng and Gianfranco Alpini and Shannon Glaser",
year = "2019",
month = "1",
day = "1",
doi = "10.1016/j.ebiom.2019.09.013",
language = "English (US)",
journal = "EBioMedicine",
issn = "2352-3964",
publisher = "Elsevier BV",

}

TY - JOUR

T1 - Knockdown of vimentin reduces mesenchymal phenotype of cholangiocytes in the Mdr2−/− mouse model of primary sclerosing cholangitis (PSC)

AU - Zhou, Tianhao

AU - Kyritsi, Konstantina

AU - Wu, Nan

AU - Francis, Heather

AU - Yang, Zhihong

AU - Chen, Lixian

AU - O'Brien, April

AU - Kennedy, Lindsey

AU - Ceci, Ludovica

AU - Meadows, Vik

AU - Kusumanchi, Praveen

AU - Wu, Chaodong

AU - Baiocchi, Leonardo

AU - Skill, Nicholas J.

AU - Saxena, Romil

AU - Sybenga, Amelia

AU - Xie, Linglin

AU - Liangpunsakul, Suthat

AU - Meng, Fanyin

AU - Alpini, Gianfranco

AU - Glaser, Shannon

PY - 2019/1/1

Y1 - 2019/1/1

N2 - 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.

AB - 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.

KW - Ductular reaction

KW - Fibroblast

KW - Fibrosis

KW - Senescence

KW - Transforming growth factor beta 1

UR - http://www.scopus.com/inward/record.url?scp=85072011543&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85072011543&partnerID=8YFLogxK

U2 - 10.1016/j.ebiom.2019.09.013

DO - 10.1016/j.ebiom.2019.09.013

M3 - Article

C2 - 31522982

AN - SCOPUS:85072011543

JO - EBioMedicine

JF - EBioMedicine

SN - 2352-3964

ER -