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Epithelial-mesenchymal transition contributes to portal tract fibrogenesis during human chronic liver disease

Lookup NU author(s): Dr Karolina Rygiel, Dr Helen Robertson, Dr Helen Marshall, Marcin Pekalski, Liena Zhao, Dr Trevor Booth, Professor David Jones, Professor Alastair Burt, Professor John Kirby

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Abstract

The relationship between bile duct damage and portal fibrosis in chronic liver diseases remains unclear. This study was designed to show whether human intrahepatic biliary epithelial cells can undergo epithelial-mesenchymal cell transition, thereby directly contributing to fibrogenesis. Primary human cholangiocytes were stimulated with transforming growth factor-β (TGFβ) or TGFβ-presenting T cells and examined for evidence of transition to a mesenchymal phenotype. Liver sections were labelled to detect antigens associated with biliary epithelial cells (cytokeratin 7 and 19 and E-cadherin), T cells (CD8), epithelial-mesenchymal transition (S100A4, vimentin and matrix metalloproteinase-2 (MMP-2)), myofibroblasts (α-smooth muscle actin) and intracellular signal-transduction mediated by phosphorylated (p)Smad 2/3; in situ hybridisation was performed to detect mRNA encoding TGFβ and S100A4. Stimulation of cultured cells with TGFβ induced the expression of pSmad2/3, S100A4 and α-smooth muscle actin; these cells became highly motile. Although normal bile ducts expressed ALK5 (TGFβ RI), low levels of TGFβ mRNA and nuclear pSmad2/3, they did not express S100A4, vimentin or MMP-2. However, TGFβ mRNA and nuclear pSmad2/3 were strongly expressed in damaged ducts, which also expressed S100A4, vimentin and MMP-2. Fibroblast-like cells which expressed S100A4 were present around many damaged bile ducts. Cells in the 'ductular reaction' expressed both epithelial and mesenchymal markers together with high levels of TGFβ mRNA and pSmad2/3. In conclusion, the cells forming small- and medium-sized bile ducts and the ductular reaction undergo EMT during chronic liver diseases, resulting in the formation of invasive fibroblasts; this process may be driven by a response to local TGFβ, possibly presented by infiltrating T cells. © 2008 USCAP, Inc All rights reserved.


Publication metadata

Author(s): Rygiel KA, Robertson H, Marshall HL, Pekalski M, Zhao L, Booth TA, Jones DEJ, Burt AD, Kirby JA

Publication type: Article

Publication status: Published

Journal: Laboratory Investigation

Year: 2008

Volume: 88

Issue: 2

Pages: 112-123

ISSN (print): 0023-6837

ISSN (electronic): 1530-0307

Publisher: Nature Publishing Group

URL: http://dx.doi.org/10.1038/labinvest.3700704

DOI: 10.1038/labinvest.3700704

PubMed id: 18059363


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