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

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

Research output: Contribution to journalArticle

54 Scopus citations

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.

Original languageEnglish (US)
Article number5540
Pages (from-to)141-147
Number of pages7
JournalJournal of Hepatology
Volume63
Issue number1
DOIs
StatePublished - Jul 1 2015
Externally publishedYes

Keywords

  • Cirrhosis
  • Gene expression signatures
  • HCC
  • Pathway analysis
  • Receptor tyrosine kinase

ASJC Scopus subject areas

  • Hepatology

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    Kocabayoglu, P., Lade, A., Lee, Y. A., Dragomir, A. C., Sun, X., Fiel, M. I., Thung, S., Aloman, C., Soriano, P., Hoshida, Y., & Friedman, S. L. (2015). β-PDGF receptor expressed by hepatic stellate cells regulates fibrosis in murine liver injury, but not carcinogenesis. Journal of Hepatology, 63(1), 141-147. [5540]. https://doi.org/10.1016/j.jhep.2015.01.036