Induction and contribution of beta platelet-derived growth factor signalling by hepatic stellate cells to liver regeneration after partial hepatectomy in mice

Liver Int. 2016 Jun;36(6):874-82. doi: 10.1111/liv.12933. Epub 2015 Sep 21.

Abstract

Background & aims: Hepatic stellate cells (HSCs) activate during injury to orchestrate the liver's inflammatory and fibrogenic responses. A critical feature of HSC activation is the rapid induction of beta platelet-derived growth factor (β-PDGFR), which drives cellular fibrogenesis and proliferation; in contrast, normal liver has minimal β-PDGFR expression. While the role of β-PDGFR is well established in liver injury, its expression and contribution during liver regeneration are unknown. The aim of this study was to determine whether β-PDGFR is induced during liver regeneration following partial hepatectomy (pHx), and to define its contribution to the regenerative response.

Methods: Control mice or animals with HSC-specific β-PDGFR-depletion underwent two-thirds pHx followed by assessment of hepatocyte proliferation and expression of β-PDGFR. RNA-sequencing from whole liver tissue of both groups after pHx was used to uncover pathways regulated by β-PDGFR signalling in HSCs.

Results: Beta platelet-derived growth factor expression on HSCs was up-regulated within 24 h following pHx in control mice, whereas absence of β-PDGFR blunted the expansion of HSCs. Mice lacking β-PDGFR displayed prolonged increases of transaminase levels within 72 h following pHx. Hepatocyte proliferation was impaired within the first 24 h based on Ki-67 and PCNA expression in β-PDGFR-deficient mice. This was associated with dysregulated growth in the β-PDGFR-deficient mice based on RNAseq with pathway analysis, and real-time quantitative PCR, which demonstrated reduced expression of Hgf, Igfbp1, Mapk and Il-6.

Conclusions: Beta platelet-derived growth factor is induced in HSCs following surgical pHx and its deletion in HSCs leads to prolonged liver injury. However, there is no significant difference in liver regeneration.

Keywords: liver regeneration; partial hepatectomy; pathway analysis; receptor tyrosine kinase.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Proliferation*
  • Hepatectomy
  • Hepatic Stellate Cells / metabolism*
  • Interleukin-6 / metabolism
  • Liver / growth & development*
  • Liver / surgery
  • Liver Regeneration*
  • Male
  • Mice
  • Mice, Knockout
  • Receptor, Platelet-Derived Growth Factor beta / metabolism*
  • Sequence Analysis, RNA
  • Signal Transduction

Substances

  • Interleukin-6
  • interleukin-6, mouse
  • Receptor, Platelet-Derived Growth Factor beta