Liver regeneration: the emergence of new pathways.

The present overview summarizes important knowledge having accumulated during the last years. The liver maintains a steady mass which is basically controlled by a delicate balance between cell gain and cell loss. However, reconstitution of the organ after tissue loss does not only involve replacement of target cells, but also complex remodeling processes resulting in the reconstruction of the typical tissue architecture. Most information in liver regeneration refers to hepatocytes. It is important to note that hepatocytes are not terminally differentiated cells, but cells situated in the G0 phase that can undergo proliferation upon appropriate stimulation. In most situations, hepatic stem cells are not significantly involved in this response. Hepatocyte regeneration is accomplished by a sequence of distinct phases: an initiation phase, rendering cells in a state of replicative competence; a proliferation phase, where expansion of the cell population occurs; and a termination phase, where cell growth is suppressed to terminate regeneration at a set point. These three phases are regulated by a whole group of factors, mainly cytokines, the significance of which has in part been defined by use of animal models with target gene deletions (gene knockouts). It seems that several mechanisms are capable to sense the critical cell mass which has to be achieved. Hepatocyte regeneration is accompanied by a complex remodeling of hepatic tissue, with a transient breakdown of the lobular architecture. In contrast to hepatocytes, less is known for the the regenerative replacement of bile ducts, blood vessels and hepatic stellate cells.