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Stem Cells Int. 2016;2016:2953727. doi: 10.1155/2016/2953727. Epub 2016 Jan 6.

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

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1
Department of Molecular Medicine, University of Padua School of Medicine, Viale G. Colombo 3, 35131 Padua, Italy; Liver Center, Section of Digestive Diseases, Yale University, TAC Building, 333 Cedar Street, New Haven, CT 06520, USA.
2
School of Medicine and Surgery, University of Milan-Bicocca, Via Cadore 48, 20900 Monza, Italy.
3
Department of Molecular Medicine, University of Padua School of Medicine, Viale G. Colombo 3, 35131 Padua, Italy; School of Medicine and Surgery, University of Milan-Bicocca, Via Cadore 48, 20900 Monza, Italy.
4
Liver Center, Section of Digestive Diseases, Yale University, TAC Building, 333 Cedar Street, New Haven, CT 06520, USA; School of Medicine and Surgery, University of Milan-Bicocca, Via Cadore 48, 20900 Monza, Italy.

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.

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