Knockdown and knockout of β1-integrin in hepatocytes impairs liver regeneration through inhibition of growth factor signalling.
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.
Department of Biology, Institute of Molecular Health Sciences, ETH Zurich,8093, Switzerland.
Tobias
T
Speicher
Department of Biology, Institute of Molecular Health Sciences, ETH Zurich,8093, Switzerland.
Beat
B
Siegenthaler
David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA.
Roman L
RL
Bogorad
Department of Molecular Medicine, Max-Planck-Institute of Biochemistry, 82152 Martinsried, Germany.
Raphael
R
Ruppert
Department of Molecular Medicine, Max-Planck-Institute of Biochemistry, 82152 Martinsried, Germany.
Tobias
T
Petzold
Department of Biology, Institute of Molecular Health Sciences, ETH Zurich,8093, Switzerland.
Susagna
S
Padrissa-Altes
Department of Biology, Institute of Molecular Health Sciences, ETH Zurich,8093, Switzerland.
Marc
M
Bachofner
1] David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA [2] Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA [3] Division of Health Science Technology, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA.
Daniel G
DG
Anderson
Skolkovo Institute of Science and Technology, ul. Novaya, d.100, Skolkovo 143025, Russian Federation.
Victor
V
Koteliansky
Department of Molecular Medicine, Max-Planck-Institute of Biochemistry, 82152 Martinsried, Germany.
Reinhard
R
Fässler
Department of Biology, Institute of Molecular Health Sciences, ETH Zurich,8093, Switzerland.
Sabine
S
Werner
D000818:Animals; D049109:Cell Proliferation / Q000235:genetics*; D066246:ErbB Receptors / Q000378:metabolism; D055785:Gene Knockdown Techniques; D006498:Hepatectomy; D017228:Hepatocyte Growth Factor; D022781:Hepatocytes / Q000378:metabolism*; D019012:Integrin beta1 / Q000235:genetics* / Q000378:metabolism; D008099:Liver / Q000378:metabolism* / Q000601:surgery; D008115:Liver Regeneration / Q000235:genetics*; D051379:Mice; D018345:Mice, Knockout; D015398:Signal Transduction / Q000235:genetics
C553307:HGF protein, mouse; D019012:Integrin beta1; D017228:Hepatocyte Growth Factor; C541485:EGFR protein, mouse; D066246:ErbB Receptors