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 therapeut ic strategies as hepatocellular transplantation and ex vivo gene thera py. In this study the proliferative responsiveness of transplanted syn geneic rat hepatocytes was examined in relation to the timing of the a dministration of a mitogenic stimulus. For this purpose nuclear bromod eoxyuridine incorporation after partial hepatectomy was investigated d uring the early post-transplant phase. The response of intrasplenicall y transplanted hepatocytes was compared to that of liver cells engraft ed in polytetrafluoroethylene solid supports that had been implanted i ntraperitoneally 4 weeks prior to transplantation. Nonstimulated, engr afted hepatocytes exhibited a labeling index of similar to 0-1% indepe ndent of the transplantation technique used. This ''spontaneous'' labe ling index did not change with time. Partial hepatectomy, executed sim ultaneously 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 res ponsiveness. When the mitogenic stimulus was given between 2 and g wee ks post-transplantation, a significant increase in labeling index was observed in comparison to sham-treated control animals. Maximal labeli ng 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, indicatin g adequate vascularization of the supports. This data provides the fir st description of proliferative response in hepatocytes transplanted b y the solid support technique, which may offer an attractive alternati ve to the intrasplenic route. It further suggests that, in analogy wit h the in vitro situation, a lag time exists between hepatocyte isolati on/transplantation and their maximal responsiveness to physiological s timuli. It is concluded that timing of the administration of a prolife rative stimulus is important for obtaining a maximal response of trans planted hepatocytes during the early post-transplantation phase. (C) 1 994 Academic Press, Inc.