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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Hepatocyte growth factor/c-met signaling pathway is required for efficient liver regeneration and repair
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Hepatocyte growth factor/c-met signaling pathway is required for efficient liver regeneration and repair

机译：肝细胞生长因子/ c-met信号通路是有效肝再生和修复所必需的

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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, overproduction 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. [References: 41]
机译：肝细胞生长因子/散射因子c-met信号通路在发育以及肿瘤发生中都至关重要。因为hgf / sf或c-met的纯合无效小鼠在子宫内死亡，所以我们使用Cre / loxP介导的基因靶向研究了c-met在成年肝脏中的功能。在生理条件下，c-met的丧失似乎对肝细胞功能无害。但是，肝脏对损伤的适应性反应受到显着影响。肝细胞中缺乏c-met基因的小鼠对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量细胞凋亡和出血性坏死，而所有野生型小鼠均存活，并受到轻度损伤。在用单次致死剂量的CCl4攻击后，c-met条件性基因敲除小鼠表现出从小叶中心病变的恢复受损，而不是肝细胞增殖不足。延迟的愈合与持续的炎症反应，骨桥蛋白的过量产生，营养不良早期和突出的钙化以及肝细胞散布/迁移到患病区域受损有关。这些研究为支持c-met在有效肝再生中的关键作用提供了直接的遗传证据，并表明c-met的破坏主要影响肝细胞存活和组织重塑。 [参考：41]

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