Hepatocyte growth factor/c-met signaling pathway is required for efficient liver regeneration and repair.
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.
Huh
Chang-Goo
CG
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, USA.
Factor
Valentina M
VM
Sánchez
Aránzazu
A
Uchida
Koichi
K
Conner
Elizabeth A
EA
Thorgeirsson
Snorri S
SS
D000818:Animals; D017209:Apoptosis; D002252:Carbon Tetrachloride Poisoning; D002455:Cell Division; D005091:Exons / Q000235:genetics; D017228:Hepatocyte Growth Factor / Q000502:physiology*; D022781:Hepatocytes / Q000166:cytology / Q000502:physiology; D008099:Liver / Q000473:pathology; D008115:Liver Regeneration / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D019859:Proto-Oncogene Proteins c-met / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D015398:Signal Transduction; D019014:fas Receptor / Q000502:physiology
D019014:fas Receptor; D017228:Hepatocyte Growth Factor; D019859:Proto-Oncogene Proteins c-met