STEM CELLS IN LIVER GROWTH AND REGENERATION

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The long-term objective of the proposed studies is to identify the contributions of different liver cell subpopulations to hepatic growth and regeneration. They seek to resolve a longstanding controversy about whether liver stem cells exist that, under conditions of extreme hepatic injury, can give rise to progeny capable of differentiating into new hepatocytes ("facultative" stem cells). These studies are based upon a novel transgenic mouse model in which hepatotoxic expression of urokinase- type plasminogen activator is targeted to hepatocytes by the albumin enhancer/promoter. Because of the methodological and paradigmatic importance of the rat to studies of liver growth, this transgenic model will be reproduced in this species. In these transgenic animals, clones of cells, derived from progenitor hepatocytes that physically deleted the transgene array, expand and eventually replace the entire transgene- expressing parenchyma. Thus, the adult liver of albumin-urokinase animals is a somatic chimera hepatocytes do not contain an intact transgene copy and thus they and their progeny cannot express the transgene, whereas remaining liver cells possess an unrearranged transgene. Liver of these animals subjected to condiitons predicted to activate the stem cell lineage (represented by "oval cell" proliferation) should display transgene reactivation if non-hepatocytic precursors (with an intact transgene) can give rise to hepatocytes. If only preexisting hepatocytes can give rise to new hepatocytes, transgene expression will not be reactivated. Thus, hepatic cell lineages in this model are genetically distinct; conclusions regarding cell lineage potential can be addressed using a stable marker instead of less reliable criteria such as morphology or patterns of gene expression. These studies further propose to characterize the oval cell population that appears spontaneously in albumin-urokinase animals, determine how this population responds to additional hepatic injury, and identify the effect on this response of ablating an hepatic accessory cell (the Ito cell), or a particular subgroup of the oval cell population (those expressing alphafetoprotein).