T cell-mediated biliary epithelial-to-mesenchymal transition in liver allograft rejection.
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 beta1 (TGFbeta1) 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 TGFbeta1 or TGFbeta-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 TGFbeta1-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.
Rygiel
Karolina A
KA
Applied Immunobiology and Transplantation Research Group, Institute of Cellular Medicine, Medical School, Newcastle University, Newcastle upon Tyne, United Kingdom.
Robertson
Helen
H
Willet
Joseph D P
JD
Brain
John G
JG
Burt
Alastair D
AD
Jones
David E J
DE
Kirby
John A
JA
D001652:Bile Ducts / Q000276:immunology / Q000473:pathology*; D001706:Biopsy; D015820:Cadherins / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects / Q000502:physiology; D002461:Cell Line, Transformed; D002908:Chronic Disease; D003094:Collagen; D004338:Drug Combinations; D004847:Epithelial Cells / Q000276:immunology / Q000378:metabolism / Q000473:pathology*; D005347:Fibroblasts / Q000276:immunology / Q000473:pathology*; D055785:Gene Knockdown Techniques; D006084:Graft Rejection / Q000276:immunology / Q000473:pathology*; D006801:Humans; D007150:Immunohistochemistry; D016130:Immunophenotyping; D007797:Laminin; D016031:Liver Transplantation; D011509:Proteoglycans; D000071999:S100 Calcium-Binding Protein A4; D009418:S100 Proteins / Q000235:genetics; D013601:T-Lymphocytes / Q000276:immunology / Q000473:pathology*; D053773:Transforming Growth Factor beta1 / Q000494:pharmacology; D014184:Transplantation, Homologous
D015820:Cadherins; D004338:Drug Combinations; D007797:Laminin; D011509:Proteoglycans; D000071999:S100 Calcium-Binding Protein A4; D009418:S100 Proteins; D053773:Transforming Growth Factor beta1; C059485:matrigel; C077591:S100A4 protein, human; D003094:Collagen