The role of c-met in liver biology

肝细胞生长因子/散射因子c-met信号通路在发育和肿瘤发生过程中具有重要作用。由于hgf/sf或c-met的纯合子无效小鼠在子宫内死亡，我们使用Cre/loxP介导的基因靶向研究c-met在成年肝脏中的特异性功能。在生理条件下，c-met的丧失似乎对肝细胞功能无害。尽管如此，肝脏对损伤的适应性反应受到了显着影响。肝细胞c-met基因缺失的小鼠对Fas诱导的细胞凋亡高度敏感。当注射低剂量的抗Fas抗体时，这些小鼠中的大多数死于大规模细胞凋亡和出血性坏死，而所有野生型小鼠均存活，伴有轻微损伤的迹象。在用单次致坏死剂量的CCl 4激发后，c-met条件性基因敲除小鼠表现出小叶中心病变的恢复受损，而不是肝细胞增殖的缺陷。延迟愈合与持续性炎症反应、骨桥蛋白过度生成、早期和显著的营养不良性钙化以及肝细胞散入/迁移至病变区域受损相关。这些研究提供了直接的遗传学证据，支持c-met在有效的肝再生中的关键作用，并表明c-met的破坏主要影响肝细胞存活和组织重塑。

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.