Knockdown and knockout of β1-integrin in hepatocytes impairs liver regeneration through inhibition of growth factor signalling

Nat Commun. 2014 May 21;5:3862. doi: 10.1038/ncomms4862.

Abstract

The liver has a unique regenerative capability, which involves extensive remodelling of cell-cell and cell-matrix contacts. Here we study the role of integrins in mouse liver regeneration using Cre/loxP-mediated gene deletion or intravenous delivery of β1-integrin siRNA formulated into nanoparticles that predominantly target hepatocytes. We show that although short-term loss of β1-integrin has no obvious consequences for normal livers, partial hepatectomy leads to severe liver necrosis and reduced hepatocyte proliferation. Mechanistically, loss of β1-integrin in hepatocytes impairs ligand-induced phosphorylation of the epidermal growth factor and hepatocyte growth factor receptors, thereby attenuating downstream receptor signalling in vitro and in vivo. These results identify a crucial role and novel mechanism of action of β1-integrins in liver regeneration and demonstrate that protein depletion by nanoparticle-based delivery of specific siRNA is a powerful strategy to study gene function in the regenerating liver.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Proliferation / genetics*
  • ErbB Receptors / metabolism
  • Gene Knockdown Techniques
  • Hepatectomy
  • Hepatocyte Growth Factor
  • Hepatocytes / metabolism*
  • Integrin beta1 / genetics*
  • Integrin beta1 / metabolism
  • Liver / metabolism*
  • Liver / surgery
  • Liver Regeneration / genetics*
  • Mice
  • Mice, Knockout
  • Signal Transduction / genetics

Substances

  • HGF protein, mouse
  • Integrin beta1
  • Hepatocyte Growth Factor
  • EGFR protein, mouse
  • ErbB Receptors