Cholangiocytes with mesenchymal features contribute to progressive hepatic fibrosis of the polycystic kidney rat.
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)-beta1, a potent inducer of epithelial-mesenchymal transition, induction of vimentin, fibronectin, and collagen expression occurred in the PCK cholangiocytes. Although the TGF-beta1 treatment reduced cytokeratin 19 expression, the epithelial cell features characterized by the expression of E-cadherin and zonula occludens-1 was maintained, and alpha-smooth muscle actin expression was not induced in the cholangiocytes. Cholangiocytes of the PCK rat may acquire mesenchymal features in response to TGF-beta1 and participate in progressive hepatic fibrosis by producing extracellular matrix molecules, which seems to be a different event from epithelial-mesenchymal transition.
Sato
Yasunori
Y
Department of Human Pathology, Kanazawa University, Graduate School of Medicine, Kanazawa 920-8640, Japan.
Harada
Kenichi
K
Ozaki
Satoru
S
Furubo
Shinichi
S
Kizawa
Kazuo
K
Sanzen
Takahiro
T
Yasoshima
Mitsue
M
Ikeda
Hiroko
H
Sasaki
Motoko
M
Nakanuma
Yasuni
Y
D000375:Aging; D000818:Animals; D001652:Bile Ducts / Q000276:immunology / Q000473:pathology*; D015415:Biomarkers / Q000378:metabolism; D016767:Caroli Disease / Q000150:complications*; D004195:Disease Models, Animal; D008103:Liver Cirrhosis / Q000209:etiology* / Q000473:pathology*; D008297:Male; D008648:Mesoderm / Q000473:pathology*; D007690:Polycystic Kidney Diseases / Q000150:complications*; D051381:Rats; D011919:Rats, Inbred Strains; D018125:Receptors, Transforming Growth Factor beta / Q000378:metabolism; D053773:Transforming Growth Factor beta1 / Q000378:metabolism
D015415:Biomarkers; D018125:Receptors, Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1