Analysis of liver development, regeneration, and carcinogenesis by genetic marking studies.

The mechanism of generating new hepatocytes and bile ductule cells in the liver has been controversial. Oval cells are found in the periportal region under some circumstances and may represent multipotent stem cells. The role of stem cells in generating new liver cells in normal and pathological conditions is unclear, however. Genetic marking can be used to determine the ability of a particular cell to replicate and to migrate. Cells of known lineage are marked at an initial time point, and their developmental potential determined by the cluster size, position, and phenotype of marked cells at a later time point. Recently, genetic marking studies have demonstrated that the hepatocyte itself is the source of new hepatocytes in the normal postnatal liver and that daughter cells do not migrate. These studies have also demonstrated that the hepatocyte can replicate extensively when stimulated. Finally, genetic marking studies suggest that either hepatocytes or oval cells can develop into a hepatocellular carcinoma or cholangiocarcinoma if a sufficient number of genetic mutations accumulate. The implications of these results for hepatic gene therapy, treatment of liver insufficiency states, and liver cancer are discussed. Future genetic marking studies may help to address some remaining questions in liver biology.