LIVER-DAMAGE IN THE RAT INDUCES HEPATOCYTE STEM-CELLS FROM BILIARY EPITHELIAL-CELLS

Background & Aims: When rat hepatocyte regeneration after partial hepa tectomy is blocked by 2-acetyl-aminofluorene, a proliferation of bilia ry epithelia sends out ductules into the pavenchyma. The ability of th ese neoductules to act as a significant progenitor compartment for hep atocytes is in dispute. This study aims to resolve this question by va rying the amount of 2-acetylaminofluorene administered. Methods: Rats were fed 2-acetylaminofluorene for 6 days before and up to 7 days afte r 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 immunohi stochemical expression of intermediate filaments and cytochrome P450 e nzymes. Results: No regeneration by mature hepatocytes occurred with e ither dose, and new ductules expressed the biliary cytokeratins 7, 8, 18, and 19 and, in addition, vimentin. At the high dose, hepatocytic d ifferentiation was infrequent, whereas apoptosis and intestinal differ entiation were common. At the low dose, almost all ductules differenti ated into hepatocytes within 14 days of hepatectomy. Conclusions: Bili ary epithelium is an effective and substantiative hepatocyte progenito r compartment under appropriate conditions.