Direct hyperplasia does not enhance the kinetics of liver repopulation in a new model of hepatocyte transplantation in the rat

Abstract

Background/Aims: We have recently developed a new model of extensive liver repopulation by transplanted hepatocytes following exposure to pyrrolizidine alkaloids. In the present study, the effect of 2/3 partial hepatectomy (PH) and that of a potent direct liver mitogen, lead nitrate, were compared in their ability to modulate the kinetics of liver repopulation. Methods: Fischer 344 rats deficient in enzymatic activity for dipeptidyl-peptidase IV (DPPIV −) were used as cell transplantation recipients. They were given 2 doses of the pyrrolizidine alkaloid retrorsine (30 mg/kg, i.p.), 2 weeks apart, followed 2 weeks later by transplantation of 2×10 6 hepatocytes (via the portal vein), freshly isolated from a normal congeneic DPPIV + donor. PH was carried out or a single injection of lead nitrate (100 μmol/kg, i.v.) was administered 2 weeks post-transplantation. Liver samples obtained at different time points post-treatment were processed histochemically for DPPIV activity. Results: The percent of liver sections occupied by DPPIV + hepatocytes was <1% at the time of PH or lead nitrate administration. In animals which underwent PH, it increased to 33.4±5.7% at 2 weeks and to 55.6±8.5% at 1 month. However, in animals receiving lead nitrate, these percentages were only 3.3±1.3% at 2 weeks and 16.2±3.9% at 1 month. Repeated injections of lead nitrate had no additional effect. Further experiments indicated that an acute mitogenic response to lead nitrate was present in transplanted cells, while resident hepatocytes were inhibited by retrorsine. Conclusions: These results indicate that direct mitogenic signals (such as those induced by lead nitrate), and compensatory signals (such as those elicited by PH), are not equally effective on kinetics of liver repopulation in this system. The possible reasons for these differential effects are discussed.