Advances in the regulation of liver regeneration.

Liver regeneration is known to be a process involving highly organized and ordered tissue growth triggered by the loss of liver tissue, and remains a fascinating topic. A large number of genes are involved in this process, and there exists a sequence of stages that results in liver regeneration, while at the same time inhibitors control the size of the regenerated liver. The initiation step is characterized by priming of quiescent hepatocytes by factors such as TNF-α, IL-6 and nitric oxide. The proliferation step is the step during which hepatocytes enter into the cell cycle's G1 phase and are stimulated by complete mitogens including HGF, TGF-α and EGF. Hepatic stimulator substance, glucagon, insulin, TNF-α, IL-1 and IL-6 have also been implicated in regulating the regeneration process. Inhibitors and stop signals of hepatic regeneration are not well known and only limited information is available. Furthermore, the effects of other factors such as VEGF, PDGF, hypothyroidism, proliferating cell nuclear antigen, heat shock proteins, ischemic-reperfusion injury, steatosis and granulocyte colony-stimulating factor on liver regeneration are also systematically reviewed in this article. A tissue engineering approach using isolated hepatocytes for in vitro tissue generation and heterotopic transplantation of liver cells has been established. The use of stem cells might also be very attractive to overcome the limitation of donor liver tissue. Liver-specific differentiation of embryonic, fetal or adult stem cells is currently under investigation.