Hepatocyte growth factor/c-met signaling pathway is required for efficient liver regeneration and repair

CG Huh, VM Factor, A Sánchez… - Proceedings of the …, 2004 - National Acad Sciences
CG Huh, VM Factor, A Sánchez, K Uchida, EA Conner, SS Thorgeirsson
Proceedings of the National Academy of Sciences, 2004National Acad Sciences
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/lox P-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 …
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.
National Acad Sciences