1. Knockdown and knockout of β1-integrin in hepatocytes impairs liver regeneration through inhibition of growth factor signalling.
- Author
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Speicher T, Siegenthaler B, Bogorad RL, Ruppert R, Petzold T, Padrissa-Altes S, Bachofner M, Anderson DG, Koteliansky V, Fässler R, and Werner S
- Subjects
- Animals, ErbB Receptors metabolism, Gene Knockdown Techniques, Hepatectomy, Hepatocyte Growth Factor, Integrin beta1 metabolism, Liver surgery, Mice, Mice, Knockout, Signal Transduction genetics, Cell Proliferation genetics, Hepatocytes metabolism, Integrin beta1 genetics, Liver metabolism, Liver Regeneration genetics
- 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.
- Published
- 2014
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