Hepatocyte growth factor/ c-met signaling pathway is required for efficient liver regeneration and repair
Open accessAbstract
Hepatocyte growth factor/scatter factor c-met signaling pathway is of central importance during development as well as in tumorigenesis. Because homozygous null mice for either hgf/sf or c-met die in utero, we used Cre/loxP-mediated gene targeting to investigate the function of c-met specifically in the adult liver. Loss of c-met appeared not to be detrimental to hepatocyte function under physiological conditions. Nonetheless, the adaptive responses of the liver to injury were dramatically affected. Mice lacking c-met gene in hepatocytes were hypersensitive to Fas-induced apoptosis. When injected with a low dose of anti-Fas antibody, the majority of these mice died from massive apoptosis and hemorrhagic necrosis, whereas all wild-type mice survived with signs of minor injury. After a challenge with a single necrogenic dose of CCl4, c-met conditional knockout mice exhibited impaired recovery from centrolobular lesions rather than a deficit in hepatocyte proliferation. The delayed healing was associated with a persistent inflammatory reaction, over-production of osteopontin, early and prominent dystrophic calcification, and impaired hepatocyte scattering/migration into diseased areas. These studies provide direct genetic evidence in support of the critical role of c-met in efficient liver regeneration and suggest that disruption of c-met affects primarily hepatocyte survival and tissue remodeling.
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Previous studies in transgenic mice have suggested that hepatocyte proliferation is not a key mechanism regulating wound closure following necro-inflammatory liver injury.
“Furthermore, previous studies in transgenic mice have suggested that hepatocyte proliferation is not a key mechanism regulating wound closure following necro-inflammatory liver injury”
From Multimodal decoding of human liver regeneration (2024) · cites this paper as [27]
Conditional knockout of the HGF receptor (Met) in mouse hepatocytes followed by CCl4-induced acute liver injury impaired centrilobular wound closure and restitution of normal tissue architecture, despite similar levels of hepatocyte proliferation compared with controls.
“Conditional knockout of the HGF receptor (Met) in mouse hepatocytes followed by CCl4-induced acute liver injury impaired centrilobular wound closure and restitution of normal tissue architecture, despite similar levels of hepatocyte proliferation compared with controls27”
From Multimodal decoding of human liver regeneration (2024) · cites this paper as [27]
Mice with hepatocellular-targeted deletion of MET have a high death rate at 48 h following PHx, whereas mice with whole body deletion of MET survive.
“Mice with hepatocellular-targeted deletion of MET are reported to have a high death rate at 48 h following PHx whereas surprisingly, mice with a whole body deletion of the receptor have been reported to survive [21], [22].”
From Synthesis of IL-6 by Hepatocytes Is a Normal Response to Common Hepatic Stimuli (2014) · cites this paper as [21]
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- Authors
- Huh, C.-G., Factor, V. M., Sánchez, A., Uchida, K., Conner, E. A., & Thorgeirsson, S. S.
- Affiliations
- National Institutes of Health (US)
- Laboratory of Experimental Carcinogenesis, Center for Cancer Research, National Cancer Institute, National Institutes of Health, 37 Convent Drive MSC 4262, Building 37, Room 4146A, Bethesda, MD 20892-4262
- ORCID
- Conner, Elizabeth A.
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2004-03-30
- Volume
- 101
- Issue
- 13
- Pages
- 4477-4482
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC384772
- OpenAlex
- W1978514461
- Cited by
- 750
- References
- 0
- Citations by year
- 2026: 16 · 2025: 29 · 2024: 17 · 2023: 24 · 2022: 19 · 2021: 25 · 2020: 33 · 2019: 41 · 2018: 31 · 2017: 44 · 2016: 30 · 2015: 41 · 2014: 39 · 2013: 54 · 2012: 50
- FWCI
- 23.99
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Hepatology › Liver physiology and pathology
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Drug-Induced Hepatotoxicity and Protection
- Health Sciences › Medicine › Rehabilitation › Wound Healing and Treatments
- Keywords
- hepatocyte growth factor, c-Met, liver regeneration, liver injury repair, hepatocyte apoptosis, Fas-mediated apoptosis, carbon tetrachloride hepatotoxicity, osteopontin, dystrophic calcification, hepatocyte migration, hepatocyte proliferation, conditional knockout mice, tissue remodeling
- MeSH terms
- Animals, Carbon Tetrachloride Poisoning, Cell Division, Exons, Liver, Liver Regeneration, Signal Transduction, Apoptosis, Hepatocyte Growth Factor, Mice, Knockout, fas Receptor, Proto-Oncogene Proteins c-met, Hepatocytes, Mice
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