CELLULAR AND MOLECULAR BIOLOGY OF THE HEPATIC STEM CELL COMPARTMENT

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The research is focused on defining the cellular and molecular biology of the hepatic and pancreatic stem cell compartments in normal and neoplastic organs. We have recently reported that cell lines of nonparenchymal epithelial origin isolated from rat liver and pancreas express K8 and K14 but not K18 and K5, their normal partners in filament formation. However, upon spontaneous transformation and differentiation toward a hepatoblast- like progeny, K14 expression is abrogated and substituted by expression of K18. Immunocytochemical analysis of the cells in monolayer demonstrated that K8 as well as K14 were incorporated in the cellular cytoskeleton. Thus, in small nonparenchymal epithelial cell lines isolated from rat liver, K8 and K14 form the major intermediate filament network. Finally, we showed that a widely used antibody in studies of cell lineages in hepatic and pancreatic tissues and their neoplasms, the mouse monoclonal antibody OV-6, recognizes a common epitope in keratins 14 and 19. We further investigated if the expression of K14 could provide a lineage marker for this facultative stem cell compartment and its early progeny known as oval cells in the adult rat liver. Our results suggest that K14 and AFP are expressed in two different subpopulations of the early oval cell compartment. Similar results were obtained in an in vitro model in which spontaneous transformation of rat liver epithelial (RLE) cells appeared to mimic the process of early differentiation along the hepatic lineage in vivo. We demonstrated that undifferentiated RLE cells expressed K14 and vimentin, whereas transformation and differentiation to hepatoblast-like progeny resulted in an abrogation of K14 and vimentin expression and an induction of K18 and AFP. Taken together the in vivo and in vitro data indicate that K14 is expressed prior to AFP, when oval cells differentiate along hepatic as well as other cell lineages. Therefore, K14 expression may represent a valuable tool for studies on the mechanisms involved in the activation, proliferation and differentiation of the hepatic stem cell and oval cell compartments.