Members of the Cyr61/CTGF/NOV Protein Family: Emerging Players in Hepatic Progenitor Cell Activation and Intrahepatic Cholangiocarcinoma.

Qunfeng Wu,Liya Pi,Joanna Song,Junmei Zhou,Chen Liu,Marda Jorgensen

doi:10.1155/2016/2313850

Abstract

Hepatic stem/progenitor cells (HPC) reside quiescently in normal biliary trees and are activated in the form of ductular reactions during severe liver damage when the replicative ability of hepatocytes is inhibited. HPC niches are full of profibrotic stimuli favoring scarring and hepatocarcinogenesis. The Cyr61/CTGF/NOV (CCN) protein family consists of six members, CCN1/CYR61, CCN2/CTGF, CCN3/NOV, CCN4/WISP1, CCN5/WISP2, and CCN6/WISP3, which function as extracellular signaling modulators to mediate cell-matrix interaction during angiogenesis, wound healing, fibrosis, and tumorigenesis. This study investigated expression patterns of CCN proteins in HPC and cholangiocarcinoma (CCA). Mouse HPC were induced by the biliary toxin 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC). Differential expression patterns of CCN proteins were found in HPC from DDC damaged mice and in human CCA tumors. In addition, we utilized reporter mice that carried Ccn2/Ctgf promoter driven GFP and detected strong Ccn2/Ctgf expression in epithelial cell adhesion molecule (EpCAM)+ HPC under normal conditions and in DDC-induced liver damage. Abundant CCN2/CTGF protein was also found in cytokeratin 19 (CK19)+ human HPC that were surrounded by α-smooth muscle actin (α-SMA)+ myofibroblast cells in intrahepatic CCA tumors. These results suggest that CCN proteins, particularly CCN2/CTGF, function in HPC activation and CCA development.

Highlights

The normal liver fosters a small subset of adult stem cells that reside quiescently in the Canals of Hering, which is a transitional zone located between the bile canaliculi and interlobular ductal systems [1]
DDC feeding is associated with increased biliary porphyrin secretion and segmental bile duct obstruction leading to pronounced pericholangitis, ductular reaction, activation of periductal myofibroblasts, and extensive collagen deposition in periportal areas within treated livers [26]
Ccn3/Nov and Ccn6/Wisp3 did not show significant induction. These differential expression patterns suggested the involvement of Ccn1/Cyr61, Ccn2/Ctgf, Ccn4/Wisp1v, and Ccn5/Wisp2 in DDC-induced liver injury

Summary

Introduction

The normal liver fosters a small subset of adult stem cells that reside quiescently in the Canals of Hering, which is a transitional zone located between the bile canaliculi and interlobular ductal systems [1]. In response to massive parenchymal damage or severe impairment, if hepatocyte proliferation is arrested, the stem cells become activated in the form of ductular reactions and produce atypical ductular cells, termed hepatic progenitor cells (HPC) in humans or oval cells in rodents [2, 3]. These cells are capable of aiding in both hepatocytic regeneration and biliary regeneration. HPC within the biliary tree have been gaining relevance in relation to liver cancer, intrahepatic cholangiocarcinoma (CCA) and hepatocellular carcinoma (HCC). It has been proposed that CHC directly derives from HPC activation and differentiation [20]

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