Liver regeneration

The liver can precisely regulate its growth and mass. Surgical resection of hepatic lobes or hepatocyte loss caused by viral or chemical injury trigge rs hepatocyte replication while enlarged liver mass is corrected by apoptos is, Hepatocytes have a great replicative capacity and are capable of repopu lating the liver. However, "stem-like" cells proliferate when hepatocyte re plication is blocked or delayed. Detailed studies of the mechanisms that re gulate liver growth have been done in animals subjected to partial hepatect omy or chemical injury Substantial progress has been achieved using appropr iate transgenic and knockout mouse models for this work. Gene expression in the regenerating liver can be divided into several phases, starting with e xpression of a large number of immediate early genes. Hepatocytes need to b e primed before they can fully respond to the growth factors HGF (Hepatocyt e Growth Factor), TGF alpha (Transforming Growth Factor Alpha), and EGF (Ep idermal Growth Factor) in vitro. Priming requires the cytokines TNF and IL- 6 in addition to other agents that prevent cytotoxicity. Reactive Oxygen Sp ecies and glutathione content can determine whether the TNF effect on hepat ocytes is proliferative or apoptotic, At least four transcription factors, NF kappa B, STAT3 (which are strongly induced by TNF), AP-1 and C/EBP beta play major roles in the initiation of liver regeneration. In addition, exte nsive remodeling of the hepatic extracellular matrix occurs shortly after p artial hepatectomy, Progression through the cell cycle beyond the initiatio n phase requires growth factors. The expression of Cyclin D1 probably estab lishes the stage at which replication becomes growth factor-independent and autonomous. Knowledge about the mechanisms of liver regeneration can now b e applied to correct clinical problems caused by deficient liver growth.