Expert Reviews in Molecular Medicine

Review Article

Cholangiocyte proliferation and liver fibrosis

Shannon S. Glasera1 c1, Eugenio Gaudioa2, Tim Millera1, Domenico Alvaroa3 and Gianfranco Alpinia1

a1 Department of Medicine, Scott and White and Texas A&M Health Science Center, Temple, TX 76504, USA.

a2 Department of Anatomy, Sapienza University of Rome, Via Alfonso Borelli 50, 00161 Rome, Italy.

a3 Division of Gastroenterology, Sapienza University of Rome, Polo Pontino, Via R. Rossellini 51, 00137 Rome, Italy.

Abstract

Cholangiocyte proliferation is triggered during extrahepatic bile duct obstruction induced by bile duct ligation, which is a common in vivo model used for the study of cholangiocyte proliferation and liver fibrosis. The proliferative response of cholangiocytes during cholestasis is regulated by the complex interaction of several factors, including gastrointestinal hormones, neuroendocrine hormones and autocrine or paracrine signalling mechanisms. Activation of biliary proliferation (ductular reaction) is thought to have a key role in the initiation and progression of liver fibrosis. The first part of this review provides an overview of the primary functions of cholangiocytes in terms of secretin-stimulated bicarbonate secretion – a functional index of cholangiocyte growth. In the second section, we explore the important regulators, both inhibitory and stimulatory, that regulate the cholangiocyte proliferative response during cholestasis. We discuss the role of proliferating cholangiocytes in the induction of fibrosis either directly via epithelial mesenchymal transition or indirectly via the activation of other liver cell types. The possibility of targeting cholangiocyte proliferation as potential therapy for reducing and/or preventing liver fibrosis, and future avenues for research into how cholangiocytes participate in the process of liver fibrogenesis are described.

Correspondence

c1 Corresponding author: Medical Research Building Room 316B, Scott and White and Texas A&M Health Science Center, 702 SW HK Dodgen Loop, Temple, TX 76504, USA. Tel: +1 254 742 7058; Fax: +1 254 724 5944; E-mail: sglaser@tamu.edu