Z Gastroenterol 2006; 44 - P260
DOI: 10.1055/s-2006-950857

Epithelial-mesenchymal transdifferentiation of bile duct cells during fibrogenesis due to cholestasis

F Schulze 1, O Ostrowski 1, K Schardt 1, O Dirsch 1, U Töx 2, HP Dienes 1, M Odenthal 1
  • 1Institute of Pathology, Cologne, Germany
  • 2Clinic of Internal Medicine, Cologne, Germany

Epithelial-mesenchymal transition (EMT) was previously shown in kidney during tubulo-interstitial fibrosis. It is a process in which epithelial cell layers lose polarity plus cell-cell contacts and undergo cytoskeleton reorganization. In order to study whether bile-duct epithelial cells are able to undergo EMT during fibrogenesis we analysed liver tissues with cholestasis.

Methods: Cryo-conserved and formalin-fixed, paraffin embedded liver tissue of sham operated and bile-duct ligated rats was investigated by immunohistochemistry. Antibodies against epithelial and mesenchymal marker proteins were used for immunhistochemical detection: antibodies against vimentin, alpha-smooth-muscle-actin (α-SMA) and desmin were taken to detect mesenchymal cells and antibodies against E-cadherin, N-cadherin, cytokeratin-7 and beta-catenin to detect epithelial cells. In addition 60 human liver biopsies with cholestatic periportal fibrosis were analysed.

Results: In rats, periportal fibrogenesis accompanied by prominent biliary epithelial proliferation was induced by bile duct ligation. Immunohistochemistry with antibodies against mesenchymal marker proteins revealed α-SMA and desmin staining of sinusoidal and periportal myofibroblasts in addition to smooth muscle cells. However, immunochemistry using vimentin antibodies showed pronounced staining of bile duct cells in addition to sinusoidal and vessel-associated mesenchymal cells. In order to proof epithelial origin we performed double-staining with mesenchymal and epithelial-specific antibodies. Beta-catenin, known as an epithelial-specific factor involved in EMT activation, was observed to be located in vimentin-positve bile duct cells. In human, vimentin positive bile duct derivatives could also be detected in liver tissues with cholestasis.

Conclusion: In summary, bile duct cells transform into mesenchymal cells during fibrogenic processes due to cholestasis. The relevance of EMT in hepatic fibrogenesis will be the focus of further investigations.