Knockdown and knockout of β1-integrin in hepatocytes impairs liver regeneration through inhibition of growth factor signalling
Open accessAbstract
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.
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Knockdown or knockout of integrin β1 impairs liver regeneration.
“The importance of CCN1/α6β1-induced senescence in regeneration is consistent with the observation that knockdown or knockout of integrin β1 impairs liver regeneration (73).”
From Senescent hepatic stellate cells promote liver regeneration through IL-6 and ligands of CXCR2 (2022) · cites this paper as [73]
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References 37 · Cited by 85
Research works printed but not linked: 7
- Borowiak, M. et al. Met provides essential signals for liver regeneration. Proc. Natl Acad. Sci.USA 101, 10608-10613 (2004).
- Huh, C. G. et al. Hepatocyte growth factor/c-met signaling pathway is required for efficient liver regeneration and repair. Proc. Natl Acad. Sci. USA 101, 4477-4482 (2004).
- Natarajan, A., Wagner, B. & Sibilia, M. The EGF receptor is required for efficient liver regeneration. Proc. Natl Acad. Sci. USA 104, 17081-17086 (2007).
- Musacchio, T. & Torchilin, V. P. siRNA delivery: from basics to therapeutic applications. Front. Biosci. (Landmark Ed.) 18, 58-79 (2013).
- Love, K. T. et al. Lipid-like materials for low-dose, in vivo gene silencing. Proc. Natl Acad. Sci. USA 107, 1864-1869 (2010).
- Bogorad, R. L. et al. Integrins are required for tumour progression, but not for tissue integrity and homeostasis in the liver. Nat. Commun; doi:10.1038/ ncomm4869. · DOI
- Bauer, M. et al. Beta1 integrins differentially control extravasation of inflammatory cell subsets into the CNS during autoimmunity. Proc. Natl Acad. Sci. USA 106, 1920-1925 (2009).
- Authors
- Speicher, T., Siegenthaler, B., Bogorad, R. L., Ruppert, R., Petzold, T., Padrissa-Altes, S., Bachofner, M., Anderson, D. G., Koteliansky, V., Fässler, R., & Werner, S.
- Affiliations
- ETH Zurich (CH)
- Koch Institute for Integrative Cancer Research At MIT (US)
- Max Planck Institute of Biochemistry (DE)
- Skolkovo Institute of Science and Technology (RU)
- Corresponding author
- Werner, Sabine
- Venue
- Nature Communications
- Published
- 2014-05-21
- Volume
- 5
- Issue
- 1
- Pages
- 3862-3862
- ISSN
- 2041-1723 (ISSN-L)
- OpenAlex
- W2049851849
- Cited by
- 85
- References
- 37
- Citations by year
- 2026: 3 · 2025: 7 · 2024: 4 · 2023: 9 · 2022: 3 · 2021: 10 · 2020: 7 · 2019: 8 · 2018: 5 · 2017: 6 · 2016: 12 · 2015: 6 · 2014: 5
- FWCI
- 5.04
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Nature Communications (publishedVersion)
- PubMed (publishedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Max Planck Digital Library (submittedVersion)
- MPG.PuRe (Max Planck Society) (submittedVersion)
- Funders
- National Science Foundation
- Deutsche Forschungsgemeinschaft
- Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung (310030_132884/1, 132884)
- Topics
- Health Sciences › Medicine › Hepatology › Liver physiology and pathology
- Health Sciences › Medicine › Immunology and Allergy › Cell Adhesion Molecules Research
- Health Sciences › Medicine › Surgery › Tissue Engineering and Regenerative Medicine
- Keywords
- beta1 integrin, liver regeneration, hepatocytes, partial hepatectomy, liver necrosis, hepatocyte proliferation, epidermal growth factor receptor, c-Met, receptor signaling, gene knockdown, integrin signaling, extracellular matrix remodeling
- MeSH terms
- Animals, Hepatectomy, Liver, Liver Regeneration, Signal Transduction, Hepatocyte Growth Factor, Mice, Knockout, Integrin beta1, Hepatocytes, Cell Proliferation, Mice, Gene Knockdown Techniques, ErbB Receptors
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