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

Tobias Speicher, Beat Siegenthaler, Roman L. Bogorad, Raphael Ruppert, Tobias Petzold, Susagna Padrissa-Altes, Marc Bachofner, Daniel G. Anderson, Victor Koteliansky, Reinhard Fässler and Sabine Werner ()
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Tobias Speicher: Institute of Molecular Health Sciences
Beat Siegenthaler: Institute of Molecular Health Sciences
Roman L. Bogorad: David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology
Raphael Ruppert: Max-Planck-Institute of Biochemistry
Tobias Petzold: Max-Planck-Institute of Biochemistry
Susagna Padrissa-Altes: Institute of Molecular Health Sciences
Marc Bachofner: Institute of Molecular Health Sciences
Daniel G. Anderson: David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology
Victor Koteliansky: Skolkovo Institute of Science and Technology, ul. Novaya, d.100
Reinhard Fässler: Max-Planck-Institute of Biochemistry
Sabine Werner: Institute of Molecular Health Sciences

Nature Communications, 2014, vol. 5, issue 1, 1-13

Abstract: 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.

Date: 2014
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DOI: 10.1038/ncomms4862

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