[Frontiers in Bioscience 7, e301-314, July 1, 2002]


Anna Mae Diehl

Johns Hopkins University, Baltimore, MD


1. Abstract
2. Introduction
3. General mechanisms that regulate hepatocyte mass
3.1. Healthy adult livers
3.1.1. Continuous rejuvenation by hepatic progenitors
3.1.2. Replication of mature hepatocytes
3.2. During recovery from injury
3.2.1. Hyperplasia of mature hepatocytes
3.2.2. Stem cell hyperplasia
3.2.3. Hepatocyte hypertrophy
4. Animal models of liver regeneration
4.1. Partial hepatectomy
4.2. Toxin-induced liver injury
5. Regulation of regeneration after PH
5.1. Initiation of regeneration (G-1 phase of the cycle)
5.1.1. Injurious factors
5.1.2. Oxidant generation and protective adaptations
5.1.3. Preservation of differentiated functions
5.1.4. Release from replicative quiescence
5.2. Replication of genetic material (S phase)
5.2.1. Mitogenic factors
5.2.2. Mitogenic signaling
5.3. Cell division (G2-Mitosis (M) phase)
6. Down-regulation of the proliferative response
7. Summary of mechanisms that regulate hepatocyte proliferation after PH
8. Tissue repair and remodeling after PH
8.1. Cytokine microenvironment
8.2. Matrix deposition and lobular reorganization
9. Future applications of liver regeneration knowledge
9.1. Rescue from fulminant liver failure
9.1.1. Auxiliary heterotopic liver transplantation
9.1.2. Hepatocyte transplantation
9.1.3. Artificial liver assist devices
9.2. Treatment of decompensated cirrhosis
9.2.1. Small-for-size donors (split livers and living donors)
10. Summary
11. References


Unlike other vital organs, the liver typically regenerates after injury. Indeed, the very factors that cause liver injury initiate a reparative process in the residual liver that includes the induction of cytoprotective mechanisms, deletion of mortally wounded cells, repair of less damaged survivors, liver cell proliferation to replace the cells that died, the deposition of new matrix, and tissue remodeling to restore normal hepatic mass and architecture. During liver regeneration, the liver normally continues to perform vital, liver-specific functions. Unfortunately, the hepatic regenerative response sometimes becomes disrupted - either failing to occur or occurring in a disordered, or incomplete fashion. Abnormal regeneration contributes to the pathogenesis of fulminate liver failure, cirrhosis, and primary liver cancers. Research in the field of regenerative biology has identified several events that are required for liver regeneration. These include injury-induced changes in the hepatic microenvironment, the ability of surviving liver cells and/or their progenitors to proliferate, and a temporary suspension of homeostatic mechanisms that normally couple cell proliferation to programmed cell death. The signals that mediate these complex biologic responses are being detailed. A better understanding of the extra- and intracellular signals that prompt the injured liver to regenerate should suggest treatments to promote liver regeneration in patients with otherwise fatal liver diseases.