The Fetal Hepatocyte Phenotype and Cell-Based Therapy for Liver Disease

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Growth and functional differentiation of the liver are critical to late gestation fetal metabolism, the perinatal transition and metabolic adaptation by the newborn. The biology of fetal liver development also has implications for regulation of fetal somatic growth, hepatic carcinogenesis, and cell-based therapy for liver disease. Our laboratory has long focused on late gestation liver development in the rodent. In doing so, we have identified a fetal hepatocyte phenotype that is defined by the signaling pathways that regulate fetal hepatocyte growth, proliferation and gene expression. More recently, we demonstrated the ability of late gestation fetal rat liver cells possessing a key hepatocyte marker, leucine amino peptidase (LAP), to repopulate an injured adult liver. This is a capacity not shared by adult rat hepatocytes. The present proposal is based on the central hypothesis that histone variants and histone posttranslational modifications (PTMs), acting through effects on chromatin structure, account for the signaling phenotype of late gestation fetal rat hepatocytes and the persistence of this phenotype following transplantation into the adult liver microenvironment. The long term goal of the project is to identify genetic and epigenetic mechanisms that account for the novel characteristics of fetal liver cells, thereby applying an understanding of fetal liver development to the development of cell-based therapy for liver disease. This goal will be pursued through three Specific Aims. Specific Aim 1 is to identify a fetal hepatocyte epigenetic signature by examining chromatin structure, histone variants and histone PTMs in liver during late fetal versus adult life. Specific Aim 2 is to characterize the functional relationship between histone variants, histone PTMs, chromatin structure and regulation of key growth-regulating genes in liver during the fetal to adult transition. This aim will test the hypothesis that specific histone variants and PTMs are associated with developmental changes in critical growth-regulating genes. In Specific Aim 3, we will assess the role of the epigenetic signature identified in Aims 1 and 2 in defining and maintaining the ability of late gestation fetal rat liver cells to repopulate an injured adult rat liver. This aim will test the hypothesis that a fetal hepatic epigenetic signature is characteristic of a subpopulation of fetal hepatocytes that possess both hepatocyte and bile ductular markers, and that this epigenetic signature is present both before transplantation and after engraftment. Completion of these aims will provide insight into molecular mechanisms that determine cell behavior in the developing liver while advancing the development of cell-based therapy for liver disease. The project is innovative in a number of aspects. We will generate new information regarding the epigenetic regulation of gene expression during liver development. In doing so, we will characterize a previously unidentified, multipotent cell population in fetal liver that can repopulate an injured adult liver. Finally, we will use innovative methods throughout these studies, thus advancing the ability to study epigenetic regulation in the context of mammalian developmental physiology.