Background and Aims: Significant liver repopulation by hepatocyte transplantation will advance clinical applications. The aim of this study was to test the hypothesis that translocation of transplanted cells into liver plates will allow repeated cell transplantation for increasing the transplanted hepatocyte mass. Methods: Hepatocytes were transplanted via spleen from either F344 rats into syngeneic recipients deficient in dipeptidyl peptidase IV or from transgenic hepatitis B surface antigen- producing G26 mice with hepatitis B virus into nontransgenic congeneic recipients. Portosystemic shunting was shown by radiological methods. Results: Repeated hepatocyte transplantation led to progressively increased liver repopulation. Transplantation of 1.75 x 108 hepatocytes in three divided doses repopulated more than an estimated 5% of the host rat liver, with 3.8 x 106 ± 0.1 x 106 transplanted cells/cm3 liver. This was a tenfold or threefold mean increase in transplanted cell number compared with recipients of 2.0 x 107 or 7.5 x 107 cells transplanted in single sessions, respectively (P < 0.001). Repeated hepatocyte transplantation interfered with neither cell integrations in liver parenchyma nor secretory function of transplanted cells. Portal hypertension, portasystemic collaterals, or intrahepatic shunting were not observed in cell recipients. Conclusions: Repeated transplantation of hepatocytes in large numbers is safe and effective and should advance strategies for liver repopulation.
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