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

TLDR

Hepatocyte growth factor/scatter factor c‑met signaling is central to development and tumorigenesis. The study aimed to investigate the function of c‑met specifically in the adult liver. Cre/loxP‑mediated gene targeting was used to generate hepatocyte‑specific c‑met knockout mice. Mice lacking hepatocyte c‑met displayed normal liver function but were hypersensitive to Fas‑induced apoptosis and had impaired recovery from CCl₄‑induced centrolobular injury, with delayed healing, persistent inflammation, excess osteopontin, dystrophic calcification, and reduced hepatocyte migration, demonstrating c‑met’s essential role in hepatocyte survival and tissue remodeling during liver regeneration.

Abstract

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.