PROLIFERATIVE RESPONSE OF HEPATOCYTES TRANSPLANTED INTO SPLEEN OR SOLID SUPPORT

Understanding the regenerative behavior of transplanted hepatocytes is of great importance for developing and improving such novel therapeutic strategies as hepatocellular transplantation and ex vivo gene therapy. In this study the proliferative responsiveness of transplanted syngeneic rat hepatocytes was examined in relation to the timing of the administration of a mitogenic stimulus. For this purpose nuclear bromodeoxyuridine incorporation after partial hepatectomy was investigated during the early post-transplant phase. The response of intrasplenically transplanted hepatocytes was compared to that of liver cells engrafted in polytetrafluoroethylene solid supports that had been implanted intraperitoneally 4 weeks prior to transplantation. Nonstimulated, engrafted hepatocytes exhibited a labeling index of similar to 0-1% independent of the transplantation technique used. This ''spontaneous'' labeling index did not change with time. Partial hepatectomy, executed simultaneously with hepatocyte transplantation through either technique, did not result in significant alteration of this proliferation index. Delayed kinetics were found not to be responsible for this lack of responsiveness. When the mitogenic stimulus was given between 2 and g weeks post-transplantation, a significant increase in labeling index was observed in comparison to sham-treated control animals. Maximal labeling indices of similar to 3-4% were found if the stimulus took place at 4 weeks post-transplantation. Both the pattern and the extent of the proliferative response seen in liver cells engrafted in solid supports were similar to the ones found in intrasplenic hepatocytes, indicating adequate vascularization of the supports. This data provides the first description of proliferative response in hepatocytes transplanted by the solid support technique, which may offer an attractive alternative to the intrasplenic route. It further suggests that, in analogy with the in vitro situation, a lag time exists between hepatocyte isolation/transplantation and their maximal responsiveness to physiological stimuli. It is concluded that timing of the administration of a proliferative stimulus is important for obtaining a maximal response of transplanted hepatocytes during the early post-transplantation phase. (C) 1994 Academic Press, Inc.