A Zimmermann
ABSTRACT
Abstract BACKGROUND: Hepatocyte regeneration proceeds along a sequence of distinctive phases and results in a precise reconstitution of the lost tissue mass. The molecular mechanisms regulating liver regeneration have recently been elucidated. METHODS: Important aspects of the regulatory steps of hepatocyte proliferation during regeneration are summarized. RESULTS: Hepatocytes normally remain in proliferative quiescence. Regeneration requires priming of hepatocytes to achieve competence for proliferation. This is the initiation phase, which is regulated by cytokines, including interleukin-6 and tumour necrosis factor-alpha. During the subsequent proliferation, the hepatocyte population is expanded (the expansion phase), it being chiefly regulated by hepatocyte growth factor and transforming growth factor-alpha. Upon sensing of the required cell mass, the proliferation response is terminated (termination phase) and is mainly mediated by transforming growth factor-beta and activins. These structured processes go in line with a remodelling response, resulting in the reconstruction of a vascularized liver lobule. CONCLUSIONS: Liver regeneration proceeds in a highly ordered fashion, critical steps being regulated by several molecular mechanisms acting in a characteristic timely sequence.