Revisiting Epithelial-to-Mesenchymal Transition in Liver Fibrosis: Clues for a Better Understanding of the "Reactive" Biliary Epithelial Phenotype

Abstract

Whether liver epithelial cells contribute to the development of hepatic scarring by undergoing epithelial-to-mesenchymal transition (EMT) is a controversial issue. Herein, we revisit the concept of EMT in cholangiopathies, a group of severe hepatic disorders primarily targeting the bile duct epithelial cell (cholangiocyte), leading to progressive portal fibrosis, the main determinant of liver disease progression. Unfortunately, therapies able to halt this process are currently lacking. In cholangiopathies, fibrogenesis is part of ductular reaction, a reparative complex involving epithelial, mesenchymal, and inflammatory cells. Ductular reactive cells (DRC) are cholangiocytes derived from the activation of the hepatic progenitor cell compartment. These cells are arranged into irregular strings and express a "reactive" phenotype, which enables them to extensively crosstalk with the other components of ductular reaction. We will first discuss EMT in liver morphogenesis and then highlight how some of these developmental programs are partly reactivated in DRC. Evidence for "bona fide" EMT changes in cholangiocytes is lacking, but expression of some mesenchymal markers represents a fundamental repair mechanism in response to chronic biliary damage with potential harmful fibrogenetic effects. Understanding microenvironmental cues and signaling perturbations promoting these changes in DRC may help to identify potential targets for new antifibrotic therapies in cholangiopathies.

Figure 1

Partial expression of some mesenchymal features by ductular reactive cells. By dual immunofluorescence of a liver tissue section from a patient with ischemic cholangiopathy, with the cholangiocyte marker K7 (green), some mesenchymal features (red) are expressed by ductular reactive cells (coincident staining in yellow). They include downregulation of E-cadherin at the cell junctions of the epithelial layer (a) and upregulation in the cytoplasm of vimentin (c) and S100A4 (e) and in the basal side of fibronectin (f). In contrast, ductular reactive cells do not express typical markers of EMT, such as nuclear expression of β-catenin (b) and α-SMA (d) (M = 200x).

Figure 2

Epithelial-mesenchymal cell interactions promote ductular reaction. Crosstalk mechanisms with portal myofibroblasts and macrophages mediated by Hedgehog (Hh) and TGF-β1, respectively, are critical in generating ductular reactive cells (DRC) from activation of the hepatic progenitor cell (HPC) compartment, residing in the niche nearby the canals of Hering. Hh and TGF-β1 stimulate DRC to gain a range of mesenchymal changes typical of a “reactive” phenotype.