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T Cell-Mediated Biliary Epithelial-to-Mesenchymal Transition in Liver Allograft Rejection

Lookup NU author(s): Dr Karolina Rygiel, Dr Helen Robertson, Dr Joe Willet, Dr John Brain, Professor Alastair Burt, Professor David Jones, Professor John Kirby

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Abstract

Loss of bile duct epithelium is characteristic of early chronic rejection following liver transplantation. Recent studies have suggested that intrahepatic biliary epithelial cells can transform into myofibroblasts. This study examines the induction and molecular regulation of this transition during allograft rejection. Immortalized human cholangiocytes were stimulated with either transforming growth factor beta 1 (TGF beta 1) or a T cell line, and they were examined for morphological, proteomic, and functional features. Posttransplant liver biopsy sections were also examined. Treatment of cholangiocytes with TGF beta 1 or TGF beta-presenting T cells induced a bipolar morphology, reduced expression of E-cadherin and zona occludens 1 (ZO-1), and increased vimentin, fibronectin, matrix metalloproteinase 2 (MMP-2), MMP-9, and S100 calcium binding protein A4 (S100A4); treated cells invaded a model basement membrane. Chemokines induced T cell penetration of 3-dimensional, cultured bile duct-like structures and bile ducts in liver biopsy sections. A spatial association was observed between duct-infiltrating T cells and cholangiocyte expression of mesenchymal markers, including S100A4. Inhibition of S100A4 expression in vitro blocked TGF beta 1-mediated loss of E-cadherin and ZO-1 but did not reduce induction of fibronectin, MMP-2, or MMP-9. This study demonstrates the potential for T cells to induce an intrahepatic biliary epithelial-to-mesenchymal cell transition during chronic rejection. Furthermore, S100A4 expression by cholangiocytes was identified as a crucial regulator of this transition. Liver Transpl 16:567-576, 2010. (C) 2010 AASLD.


Publication metadata

Author(s): Rygiel KA, Robertson H, Willet JDP, Brain JG, Burt AD, Jones DEJ, Kirby JA

Publication type: Article

Publication status: Published

Journal: Liver Transplantation

Year: 2010

Volume: 16

Issue: 5

Pages: 567-576

Print publication date: 01/05/2010

ISSN (print): 1527-6465

ISSN (electronic): 1527-6473

Publisher: Wiley-Blackwell

URL: http://dx.doi.org/10.1002/lt.22029

DOI: 10.1002/lt.22029


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