Liver repopulation by transplanted hepatocytes and risk of hepatocellular carcinoma

Background. Transplantation of isolated hepatocytes in rats treated with retrorsine (RS) results in massive repopulation of the host liver. In this study, the long-term fate of hepatocytes transplanted into RS-treated recipients was followed for up to two years. Methods. Dipeptidyl-peptidase type IV-deficient (DPPIV-) Fischer 344 rats were given two injections of RS (30 mg/kg), followed by transplantation of 2 million hepatocytes, isolated from a syngenic, DPPIV+ donor. Results. Extensive (91 +/- 7%) liver replacement by transplanted hepatocytes was observed in animals sacrificed 18 months posttransplantation. Similar levels of repopulation persisted at two years (87 +/- 5%). No evidence of preneoplastic and/or neoplastic evolution of the transplanted cell population was present in the RS-treated and repopulated livers at any time point considered. Furthermore, serum parameters related to hepatocyte function and integrity were in the normal range. In control groups given cell transplantation in the absence of prior treatment with RS, only small clusters of donor-derived, DPPIV+ hepatocytes were discerned. Conclusions. These results indicate that liver repopulation in this model is largely stable, persisting for up to two years and allowing for a normal liver function. In addition, no increased risk of neoplastic transformation appears to be associated with the process of liver repopulation for as long as over two thirds of the life span of the recipient animal.