Role of defective fibrocystin in the induction of epithelial-mesenchymal transition and development of portal fibrosis

Hepatic fibrosis is a major histopathological lesion that is generated in response to liver injury and is characterized by an excessive formation of extracellular matrix (ECM). The main clinical consequences of hepatic fibrosis is portal hypertension. The histogenesis of liver fibrosis requires the activation of portal myofibroblasts, but the mechanisms responsible for this activation are still unknown. Recently, it has been shown that the epithelial-mesenchymal transition (EMT) may have a key role in fibrogenesis sclerosing diseases affecting various organs such as kidney and lung.
As for hepatic fibrosis there is no evidence, however, about a possible role of EMT. Among the various mechanisms that induce EMT, alterations of the ECM are an important trigger. The interactions of epithelial cell with ECM are mediated by membrane proteins that act as meccanoceptors. Among these, inactivation of Fibrocystin (FPC), encoded by the PKHD1 gene, involves alteration of the cytoskeleton and reduces intercellular adhesions, which are consistent with EMT. The FPC is expressed by colangiocytes, and is involved in maintaining the tubular structure of the bile ducts. In mice, inactivation of the Pkhd1 gene determines biliary dysgenesis, periportale fibrosis and portal hypertension. This phenotype is the liver of some hortologous of malformating colangiopaties of genetic origin (such as autosomal-recessive form of polycystic kidney, congenital hepatic fibrosis and Caroli’s disease), which significantly affect children and young adults. We therefore hypothesized that a defect in the FPC could induce an abnormal recognition of ECM by the cholangiocyte, which induces EMT in the biliary epithelium and then gradual development of portal fibrosis. Our preliminary data confirm this hypothesis, based on the expression of EMT markers bhy cholangiocytes in sections of liver obtained from both mouse model of Pkhd1 deficiency and from human pathology. These studies will improve our knowledge on the mechanisms responsible for portal fibrosis in genetic colangiopaties.