Published online before print November 30, 2007

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Copyright © 2007 American Society for Investigative Pathology
American Journal of Pathology, doi:10.2353/ajpath.2007.070337

Accepted for publication August 28, 2007.

Article

Cholangiocytes with Mesenchymal Features Contribute to Progressive Hepatic Fibrosis of the Polycystic Kidney Rat

Yasunori Sato^*, Kenichi Harada^*, Satoru Ozaki^*, Shinichi Furubo, Kazuo Kizawa, Takahiro Sanzen, Mitsue Yasoshima^*, Hiroko Ikeda^*, Motoko Sasaki^*, and Yasuni Nakanuma^*@

From the Department of Human Pathology,* Kanazawa University Graduate School of Medicine, Kanazawa; and the Drug Safety Research Laboratory, Toyama Chemical Company Limited, Toyama, Japan

^@ To whom correspondence should be addressed. E-mail: pbcpsc{at}kenroku.kanazawa-u.ac.jp.

	Abstract

The polycystic kidney (PCK) rat is an animal model of Caroli's disease with congenital hepatic fibrosis, in which the mechanism of progressive hepatic fibrosis remains unknown. This study aimed to clarify the mechanism of hepatic fibrosis of the PCK rat from the viewpoint of the contribution of pathological cholangiocytes. In liver sections of the PCK rats, intrahepatic bile ducts were constituted by two different phenotypes: bile ducts lined by cuboidal-shaped and flat-shaped cholangiocytes. The flat-shaped cholangiocytes showed reduced immunohistochemical expression of the biliary epithelial marker cytokeratin 19 and positive immunoreactivity for vimentin and fibronectin. When cultured cholangiocytes of the PCK rat were treated with transforming growth factor (TGF)-1, a potent inducer of epithelial-mesenchymal transition, induction of vimentin, fibronectin, and collagen expression occurred in the PCK cholangiocytes. Although the TGF-1 treatment reduced cytokeratin 19 expression, the epithelial cell features characterized by the expression of E-cadherin and zonula occludens-1 was maintained, and -smooth muscle actin expression was not induced in the cholangiocytes. Cholangiocytes of the PCK rat may acquire mesenchymal features in response to TGF-1 and participate in progressive hepatic fibrosis by producing extracellular matrix molecules, which seems to be a different event from epithelial-mesenchymal transition.