Selective repopulation of mice liver after Fas-resistant hepatocyte transplantation

Hepatocyte transplantation has been proposed as a potential therapeutic met hod to treat irreversible liver failure and inherited hepatic disorders, al though transplanted cells do not easily reconstruct the liver tissue under intact conditions. This study was aimed at modulating the recipient liver c onditions to promote repopulation of the liver after hepatocyte transplanta tion. Hepatocytes isolated from male MRL-lpr/lpr (lpr) mice with a mutation of Fas antigen were transplanted in a number of 1 x 10(6) cells in female MRL-+/+ (wildtype mice) by intrasplenic injection. An agonistic anti-Fas an tibody (0.15 mg/kg) was administered intravenously 24 h after cell transpla ntation. We also administrated the antibody at 0.3 mg/kg 1 week after graft ing and at 0.6 mg/kg 2 weeks after transplantation. The liver specimens wer e taken at different time intervals for histological examination. The recon structed male lpr hepatocytes in the female wild-type mice were determined by a real-time quantitative PCR assay using the primers and probe for the s ry gene. The pathologic findings of the recipient livers after treatment wi th anti-Fas antibody revealed a large number of apoptotic hepatocytes. The grafted lpr hepatocytes were observed to reconstruct as much as 6.9% of the recipient liver in the anti-Fas antibody-treated group 3 months after tran splantation. In contrast, we observed the transplanted cells at lower than 0.1% in the nontreated livers. These findings demonstrated that repeated in duction of apoptosis in recipient hepatocytes shifts the environment of the liver to a regenerative condition. This method may be useful to promote th e reconstruction of transplanted hepatocytes in a recipient liver.