Liver damage in the rat induces hepatocyte stem cells from biliary epithelial cells

Background and Aims: When rat hepatocyte regeneration after partial hepatectomy is blocked by 2-acetylaminofluorene, a proliferation of biliary epithelia sends out ductules into the parenchyma. The ability of these neoductules to act as a significant progenitor compartment for hepatocytes is in dispute. This study aims to resolve this question by varying the amount of 2-acetylaminofluorene administered. Methods: Rats were fed 2- acetylaminofluorene for 6 days before and up to 7 days after partial hepatectomy was performed at a dose of either 2.5 (low) or 5 (high) mg · kg^-1 · day^-1. The response was monitored by the immunohistochemical expression of intermediate filaments and cytochrome P450 enzymes. Results: No regeneration by mature hepatocytes occurred with either dose, and new ductules expressed the biliary cytokeratins 7, 8, 18, and 19 and, in addition, vimentin. At the high dose, hepatocytic differentiation was infrequent, whereas apoptosis and intestinal differentiation were common. At the low dose, almost all ductules differentiated into hepatocytes within 14 days of hepatectomy. Conclusions: Biliary epithelium is an effective and substantiative hepatocyte progenitor compartment under appropriate conditions.