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.

[1]  K. Tsuneyama,et al.  Cell-kinetic study of proliferating bile ductules in various hepatobiliary diseases. , 2008, Liver.

[2]  T. Terada,et al.  Caroli's disease in congenital hepatic fibrosis and infantile polycystic disease. , 2008, Liver.

[3]  K. Isse,et al.  Inhibition of intrahepatic bile duct dilation of the polycystic kidney rat with a novel tyrosine kinase inhibitor gefitinib. , 2006, The American journal of pathology.

[4]  Yasunori Sato,et al.  Decreased expression of Bmi1 is closely associated with cellular senescence in small bile ducts in primary biliary cirrhosis. , 2006, The American journal of pathology.

[5]  N. LaRusso,et al.  Development and characterization of a cholangiocyte cell line from the PCK rat, an animal model of Autosomal Recessive Polycystic Kidney Disease , 2006, Laboratory Investigation.

[6]  E. Avner,et al.  Molecular and cellular pathophysiology of autosomal recessive polycystic kidney disease (ARPKD) , 2006, Cell and Tissue Research.

[7]  F. Anglani,et al.  TGFβ1 induces epithelial–mesenchymal transition, but not myofibroblast transdifferentiation of human kidney tubular epithelial cells in primary culture , 2006 .

[8]  Youhua Liu,et al.  Hepatocyte growth factor attenuates liver fibrosis induced by bile duct ligation. , 2006, The American journal of pathology.

[9]  T. Roskams,et al.  Effects of angiogenic factor overexpression by human and rodent cholangiocytes in polycystic liver diseases , 2006, Hepatology.

[10]  J. Thiery,et al.  Complex networks orchestrate epithelial–mesenchymal transitions , 2006, Nature Reviews Molecular Cell Biology.

[11]  J. Barnes,et al.  Origin of interstitial fibroblasts in an accelerated model of angiotensin II-induced renal fibrosis. , 2005, The American journal of pathology.

[12]  Yasunori Sato,et al.  Diffuse expression of heparan sulfate proteoglycan and connective tissue growth factor in fibrous septa with many mast cells relate to unresolving hepatic fibrosis of congenital hepatic fibrosis , 2005, Liver international : official journal of the International Association for the Study of the Liver.

[13]  K. Zerres,et al.  A mouse model for cystic biliary dysgenesis in autosomal recessive polycystic kidney disease (ARPKD) , 2005, Hepatology.

[14]  A. Nicholson,et al.  Induction of epithelial-mesenchymal transition in alveolar epithelial cells by transforming growth factor-beta1: potential role in idiopathic pulmonary fibrosis. , 2005, The American journal of pathology.

[15]  T. Yoshioka,et al.  Transdifferentiation of mature rat hepatocytes into bile duct-like cells in vitro. , 2005, The American journal of pathology.

[16]  T. Manabe,et al.  Frequent cellular senescence in small bile ducts in primary biliary cirrhosis: a possible role in bile duct loss , 2005, The Journal of pathology.

[17]  E. Ritman,et al.  Molecular Pathogenesis of Genetic and Inherited Diseases Biliary Dysgenesis in the PCK Rat , an Orthologous Model of Autosomal Recessive Polycystic Kidney Disease , 2004 .

[18]  J. Massagué,et al.  Epithelial-Mesenchymal Transitions Twist in Development and Metastasis , 2004, Cell.

[19]  H. Moses,et al.  Induction by transforming growth factor-β1 of epithelial to mesenchymal transition is a rare event in vitro , 2004, Breast Cancer Research.

[20]  N. LaRusso,et al.  Defects in cholangiocyte fibrocystin expression and ciliary structure in the PCK rat. , 2003, Gastroenterology.

[21]  N. LaRusso,et al.  Cellular and subcellular localization of the ARPKD protein; fibrocystin is expressed on primary cilia. , 2003, Human molecular genetics.

[22]  A. Anjo,et al.  Fetal liver stroma consists of cells in epithelial-to-mesenchymal transition. , 2003, Blood.

[23]  E. Avner,et al.  PKHD1, the polycystic kidney and hepatic disease 1 gene, encodes a novel large protein containing multiple immunoglobulin-like plexin-transcription-factor domains and parallel beta-helix 1 repeats. , 2002, American journal of human genetics.

[24]  Vicente E. Torres,et al.  The gene mutated in autosomal recessive polycystic kidney disease encodes a large, receptor-like protein , 2002, Nature Genetics.

[25]  R. Kalluri,et al.  Renal fibrosis: collagen composition and assembly regulates epithelial-mesenchymal transdifferentiation. , 2001, The American journal of pathology.

[26]  Y. Nakanuma,et al.  Polycystic kidney rat is a novel animal model of Caroli's disease associated with congenital hepatic fibrosis. , 2001, The American journal of pathology.

[27]  T. Starzl,et al.  Replicative senescence of biliary epithelial cells precedes bile duct loss in chronic liver allograft rejection: increased expression of p21(WAF1/Cip1) as a disease marker and the influence of immunosuppressive drugs. , 2001, The American journal of pathology.

[28]  D. Schuppan,et al.  Proliferating bile duct epithelial cells are a major source of connective tissue growth factor in rat biliary fibrosis. , 2001, The American journal of pathology.

[29]  T. Terada,et al.  Expression of tenascin, type IV collagen and laminin during human intrahepatic bile duct development and in intrahepatic cholangiocarcinoma , 1994, Histopathology.

[30]  V. Desmet.  Congenital diseases of intrahepatic bile ducts: Variations on the theme “ductal plate malformation” , 1992, Hepatology.

[31]  Y. Nakanuma,et al.  Expression of vimentin in proliferating and damaged bile ductules and interlobular bile ducts in nonneoplastic hepatobiliary diseases. , 1992, Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc.

[32]  R. Timpl,et al.  A network model for the organization of type IV collagen molecules in basement membranes. , 1981, European journal of biochemistry.

[33]  V. Torres,et al.  Mechanisms of Disease: autosomal dominant and recessive polycystic kidney diseases , 2006, Nature Clinical Practice Nephrology.

[34]  F. Anglani,et al.  TGFbeta1 induces epithelial-mesenchymal transition, but not myofibroblast transdifferentiation of human kidney tubular epithelial cells in primary culture. , 2006, International journal of experimental pathology.

[35]  J. Zavadil,et al.  TGF-beta and epithelial-to-mesenchymal transitions. , 2005, Oncogene.

[36]  Yasunori Sato,et al.  Activation of the MEK5/ERK5 cascade is responsible for biliary dysgenesis in a rat model of Caroli's disease. , 2005, The American journal of pathology.

[37]  Youhua Liu.  Epithelial to mesenchymal transition in renal fibrogenesis: pathologic significance, molecular mechanism, and therapeutic intervention. , 2004, Journal of the American Society of Nephrology : JASN.

[38]  K. Miyazaki,et al.  Critical role of type IV collagens in the growth of bile duct carcinoma. In vivo and in vitro studies. , 2001, Pathology, research and practice.