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Rat Liver Repopulation by Transplanted Late Gestation Fetal Hepatocytes

Hepatocyte transplantation has the potential to be an effective therapy for liver failure. However, the application of this therapy has been hampered by identification of an appropriate cell population and limited understanding of the factors accounting for the ability of cells to repopulate injured liver. Late gestation (E19) fetal hepatocyte proliferation in the rat is mitogen‐independent in vivo and in vitro. Fetal hepatocytes also differ from adult hepatocytes with regard to ribosome biogenesis, translation control, gene expression and cell cycle regulation. Our current studies are based on the hypothesis that histone posttranslational modifications (PTMs) acting through effects on chromatin structure account for the fetal hepatocyte signaling phenotype and that this phenotype will result in a selective growth advantage for fetal cells in the injured adult liver microenvironment. Late gestation fetal hepatocytes were isolated using antibodies against hepatic and ductal cell surface markers. The engraftment and repopulating ability of these cells was assessed using the mitomycin C dipeptidyl peptidase IV (DPPIV) transplant model. Liver harvested at 4 and 42 weeks posttransplantation contained well defined donor hepatocyte and endothelial colonies. Morphologic and phenotypic analysis using antibodies against well characterized markers revealed the formation of ductal colonies by 10 months. The average size of the donor colonies increased so that by 10 months up to 30% of the liver was repopulated by donor‐derived cells. Characterization of the donor cells pretransplant revealed that a large subpopulation of the hepatocytes also expressed ductal markers. Transcriptomic analysis revealed that these cells represent a distinct subpopulation of less well differentiated hepatocytes. Mass spectrometry‐based profiling of 77 modifications across 26 lysines on Histones H1, H2A, H3 & H4 revealed 23 significant changes including differential methylation of H3K27, H3K36 and H4K20 as well as acetylation of H3K4 comparing fetal to adult hepatocytes. In contrast, only 5 sites were significant comparing the two subpopulations of fetal hepatocytes. In conclusion, late gestation fetal hepatocytes are capable of extensive long‐term liver repopulation. These cells possess a histone PTM profile that is distinct from that of adult hepatocytes and may contribute to the maintenance of a fetal hepatocyte phenotype upon transplantation.