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

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Abstract
Hepatocyte growth factor/scatter factorc-metsignaling pathway is of central importance during development as well as in tumorigenesis. Because homozygous null mice for eitherhgf/sforc-metdiein utero, we used Cre/loxP-mediated gene targeting to investigate the function ofc-metspecifically in the adult liver. Loss ofc-metappeared not to be detrimental to hepatocyte function under physiological conditions. Nonetheless, the adaptive responses of the liver to injury were dramatically affected. Mice lackingc-metgene 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-metconditional 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 ofc-metin efficient liver regeneration and suggest that disruption ofc-metaffects primarily hepatocyte survival and tissue remodeling.