Limited Contribution of Cells of Intact Extrahepatic Tissue Origin to Hepatocyte Regeneration in Transplanted Rat Liver

BACKGROUND: It is now well established that various adult somatic tissues harbor multipotent stem cells that can differentiate into a broad variety of cell types of all three germ layer origins. It remains controversial, however, whether they are a reservoir of cells utilized for emergent tissue repair or simply a vestige of evolution and, if the former is the case, to what extent they can potentially contribute to reconstitution of a specific organ. To get an insight in such a direction, we examined the extent of contribution of naive intact cells of extrahepatic origin to hepatocyte reconstitution in the transplanted liver with or without injury in the rat. METHODS: Liver from wild-type donor rats was transplanted to green fluorescent protein (GFP)-transgenic rats, and GFP-positive hepatocytes were examined with or without liver injury. RESULTS: The proportion of GFP-positive hepatocytes in the transplanted noninjured liver linearly increased by 0.0048% per week, that is, approximately 5 x 10(3) hepatocytes of extrahepatic origin were generated per day. Liver injury induced by treatment with 2-acetylaminofluorene and CCl4 or the additional application of hepatocyte growth factor did not further increase the percentage of GFP-positive hepatocytes. CONCLUSION: The present results indicate that cells derived from nonmanipulated extrahepatic tissues appreciably contribute, though limitedly, to hepatocyte reconstitution in the liver of the rat.