Liver regeneration.

Abstract

The liver can precisely regulate its growth and mass. Surgical resection of hepatic lobes or hepatocyte loss caused by viral or chemical injury triggers hepatocyte replication while enlarged liver mass is corrected by apoptosis. Hepatocytes have a great replicative capacity and are capable of repopulating the liver. However, "stem-like" cells proliferate when hepatocyte replication is blocked or delayed. Detailed studies of the mechanisms that regulate liver growth have been done in animals subjected to partial hepatectomy or chemical injury. Substantial progress has been achieved using appropriate transgenic and knockout mouse models for this work. Gene expression in the regenerating liver can be divided into several phases, starting with expression of a large number of immediate early genes. Hepatocytes need to be primed before they can fully respond to the growth factors HGF (Hepatocyte Growth Factor), TGFalpha (Transforming Growth Factor Alpha), and EGF (Epidermal Growth Factor) in vitro. Priming requires the cytokines TNF and IL-6 in addition to other agents that prevent cytotoxicity. Reactive Oxygen Species and glutathione content can determine whether the TNF effect on hepatocytes is proliferative or apoptotic. At least four transcription factors, NFkappaB, STAT3 (which are strongly induced by TNF), AP-1 and C/EBPbeta play major roles in the initiation of liver regeneration. In addition, extensive remodeling of the hepatic extracellular matrix occurs shortly after partial hepatectomy. Progression through the cell cycle beyond the initiation phase requires growth factors. The expression of Cyclin D1 probably establishes the stage at which replication becomes growth factor-independent and autonomous. Knowledge about the mechanisms of liver regeneration can now be applied to correct clinical problems caused by deficient liver growth.