Transplanted reporter cells help in defining onset of hepatocyte proliferation during the life of F344 rats

Transplanted hepatocytes integrate in the liver parenchyma and exhibit gene expression patterns that are similar to adjacent host hepatocytes. To dete rmine the fate of genetically marked hepatocytes in the context of hepatoce llular proliferation throughout the rodent life span, we transplanted Fisch er 344 (F344) rat hepatocytes into syngeneic dipeptidyl peptidase IV-defici ent rats. The proliferative activity in transplanted hepatocytes was studie d in animals ranging in age from a few days to 2 yr. Transplanted hepatocyt es proliferated during liver development between 1 and 6 wk of age, each di viding an estimated two to five times. DNA synthesis in occasional cells wa s demonstrated by localizing bromodeoxyuridine incorporation. There was no evidence for transplanted cell proliferation between 6 wk and 1 yr of age. Subsequently, transplanted cells proliferated again, with increased sizes o f transplanted cell clusters at 18 and 24 mo of age. The proliferative acti vity of transplanted cells was greater in rats entering senescence compared with during postnatal liver development. In old rats, some liver lobules w ere composed entirely of transplanted cells. We conclude that hepatocyte pr oliferation in the livers of very young and old F344 rats is regulated in a temporally determined, biphasic manner. The findings will be relevant to m echanisms concerning liver development, senescence, and oncogenesis, as wel l as to cell and gene therapy.