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Hepatic fibrosis is characterized by abnormal accumulation of extracellular matrix (ECM) that can lead to ductopenia, cirrhosis, and even malignant transformation. In this review, we examine cholestatic liver diseases characterized by extensive biliary fibrosis such as primary sclerosing cholangitis (PSC), primary biliary cholangitis (PBC), polycystic liver disease (PLD), and MDR2 -/- and BDL mouse models. Following biliary injury, cholangiocytes, the epithelial cells that line the bile ducts, become reactive and adopt a neuroendocrine phenotype in which they secrete and respond to neurohormones and neuropeptides in an autocrine and paracrine fashion. Emerging evidence indicates that cholangiocytes influence and respond to changes in the ECM and stromal cells in the microenvironment. For example, activated myofibroblasts and hepatic stellate cells are major drivers of collagen deposition and biliary fibrosis. Additionally, the liver is richly innervated with adrenergic, cholinergic, and peptidergic fibers that release neurohormones and peptides to maintain homeostasis and can be deranged in disease states. This review summarizes how cholangiocytes interact with their surrounding environment, with particular focus on how autonomic and sensory regulation affects fibrotic pathophysiology., (Published by Elsevier Masson SAS.)

Notch signalling is an evolutionarily conserved intercellular pathway involved in many aspects of development and tissue renewal in several organs. The importance of Notch signalling in liver development and morphogenesis is well established. However, the post-natal role of Notch in liver repair/regeneration is only now beginning to be unveiled. Despite the simplicity of the pathway activation, a fine spatial-temporal regulation of Notch signalling is required to avoid pathologic effects. This review highlights recent advances in the field indicating that Notch signalling is involved in the reparative morphogenesis of the biliary tree and in liver carcinogenesis. Defective Notch signalling leads to impaired ability of the liver to repair liver damage, while excessive activation may be involved in liver cancer. Even though much remains to be understood about these mechanisms, including the cross-talk between Notch signalling and other liver morphogens, current evidence suggests that the modulation of the Notch pathway may represent a therapeutic target in chronic liver disease., (Copyright © 2013 Elsevier Masson SAS. All rights reserved.)

Aim: Ezrin and radixin are actin-binding proteins that contribute to the integrity of epithelia. Abnormalities of bile secretion occur primarily in cholestatic liver diseases and are associated with changes in cell cytoskeleton. Expression of these proteins during liver development and in cholestatic liver diseases remains poorly investigated., Methods: Ezrin and radixin expression was analyzed in fetal, adult and pediatric cholestatic human liver (i.e. biliary atresia, sclerosing cholangitis) by immunohistochemistry., Results: In adult and fetal livers, ezrin was expressed exclusively in the cells of the biliary lineage (i.e. biliary epithelial cells and ductal cells) whereas radixin was located not only in hepatocytes but also in cells of the biliary lineage. In the lobule of mature livers, radixin displayed a zonal distribution with predominant expression in the periportal region. In cholestatic diseases, both proteins were expressed in cells of the ductular reaction. An aberrant expression of ezrin was detected in hepatocytes of cirrhotic nodules with a CK7-positive pattern and in malignant hepatocytes in a course of cholestatic disease toward cancer., Conclusions: Among the components of the liver epithelial cells, ezrin was exclusively expressed in biliary phenotype cells, while radixin was found in biliary and hepatocytic lineages, with a periportal zonal expression. In cholestatic diseases, ezrin was expressed in hepatocytes supporting the appearance of a biliary phenotype., (Copyright © 2013. Published by Elsevier Masson SAS.)