β-PDGF receptor expressed by hepatic stellate cells regulates fibrosis in murine liver injury, but not carcinogenesis.

Abstract

BACKGROUND & AIMS:

Rapid induction of β-PDGF receptor (β-PDGFR) is a core feature of hepatic stellate cell activation, but its cellular impact in vivo is not well characterized. We explored the contribution of β-PDGFR-mediated pathway activation to hepatic stellate cell responses in liver injury, fibrogenesis, and carcinogenesis in vivo using genetic models with divergent β-PDGFR activity, and assessed its prognostic implications in human cirrhosis.

METHODS:

The impact of either loss or constitutive activation of β-PDGFR in stellate cells on fibrosis was assessed following carbon tetrachloride (CCl4) or bile duct ligation. Hepatocarcinogenesis in fibrotic liver was tracked after a single dose of diethylnitrosamine (DEN) followed by repeated injections of CCl4. Genome-wide expression profiling was performed from isolated stellate cells that expressed or lacked β-PDGFR to determine deregulated pathways and evaluate their association with prognostic gene signatures in human cirrhosis.

RESULTS:

Depletion of β-PDGFR in hepatic stellate cells decreased injury and fibrosis in vivo, while its auto-activation accelerated fibrosis. However, there was no difference in development of DEN-induced pre-neoplastic foci. Genomic profiling revealed ERK, AKT, and NF-κB pathways and a subset of a previously identified 186-gene prognostic signature in hepatitis C virus (HCV)-related cirrhosis as downstream of β-PDGFR in stellate cells. In the human cohort, the β-PDGFR signature was not associated with HCC development, but was significantly associated with a poorer outcome in HCV cirrhosis.

CONCLUSIONS:

β-PDGFR is a key mediator of hepatic injury and fibrogenesis in vivo and contributes to the poor prognosis of human cirrhosis, but not by increasing HCC development.

• Authors: Peri Kocabayoglu, Abigale Lade, Youngmin A Lee, Ana-Cristina Dragomir, Xiaochen Sun, Maria Isabel Fiel, Swan Thung, Costica Aloman, Philippe Soriano, Yujin Hoshida, Scott L Friedman
• Journal: Journal of hepatology (J Hepatol) Vol. 63 Issue 1 Pg. 141-7 (Jul 2015) ISSN: 1600-0641 [Electronic] Netherlands
• PMID: 25678385 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2015 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

Chemical References

• Receptor, Platelet-Derived Growth Factor beta

Topics

• Animals
• Cell Proliferation
• Cells, Cultured
• Chemical and Drug Induced Liver Injury (complications)
• Disease Models, Animal
• Hepatic Stellate Cells (metabolism, pathology)
• Liver (metabolism, pathology)
• Liver Cirrhosis (etiology, metabolism, pathology)
• Mice
• Mice, Transgenic
• Receptor, Platelet-Derived Growth Factor beta (biosynthesis)
• Signal Transduction