The identification of somatic stem cell populations in mammalian tissues has raised important questions about the specification, maintenance and control of differentiation of these cells during an organism’s lifespan. Investigation of the control of stem cell behavior will benefit greatly from the use of in vitro culture systems that allow a detailed analysis of the interplay of genetics and microenvironment in the regulation of plasticity and commitment of tissue derived stem cells. The focus of our laboratory has been to develop such a system for the mammalian liver. Our laboratory has isolated cells from the murine liver diverticulum that have properties of hepatic stem cells or hepatoblasts. In addition, we have developed culture conditions that allow the clonal growth of hepatoblasts and the propagation of these cells into a stable cell line (e.g. HBC-3). The availability of this cell line has allowed us to employ a genome-based analysis of hepatocytic and cholangiocyte differentiation in vitro. These studies have identified new stem cell markers and candidate genes involved in genetic control of stem cell maintenance and differentiation. In addition, we have used genetically marked HBC-3 cells to investigate the plasticity of these cells using blastocyst injection chimeras and we have shown that these cells maintain their commitment to the hepatic lineage within these animals. An understanding of the molecular mechanisms controlling the differentiation potential of hepatic stem cells may greatly increase our ability to utilize such cells in experimental therapies for the treatment of chronic liver disease. Several projects are currently being pursued in our laboratory. 1. We are studying the role of the WNT/beta-catenin pathway in the maintenance of the hepatic stem cell phenotype. 2. We are investigating the role of the TGFbeta/BMP and Notch signaling pathways in the control of cell fate decisions by bipotent hepatic stem cells. 3. We are exploring the role of miRNAs in hepatic stem cell differentiation.
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