Regulating Hepatic Progenitor Cell Proliferation

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DESCRIPTION (provided by applicant): Despite progress in stem cell research numerous challenges persist including 1) maintaining the stem cells in a proliferative state and 2) directing their commitment into a specific mature cell. While we are beginning to understand the processes involved in cell differentiation there is a large body of unanswered questions with respect to the post-natal role of these cellular populations. It is postulated that there are intra- and extracellular signals that are necessary for most stem cell populations to continue self-renewal. Further comprehension into the pathways by which a select stem or progenitor cell undergoes proliferation and subsequent differentiation will provide insights into advancing the field of tissue engineering and organogenesis. We have previously identified a hepatic progenitor cell that persists into adulthood. After initially isolating the hepatic progenitor cell there is a period of dormancy prior to cell proliferation and colony formation. From a therapeutic standpoint it is necessary to understand the pathways and intermediate mediators involved with regulating proliferation and survival of these hepatic progenitor cells in an effort to develop clinical applications. The proposed series of experiments in this research plan will broaden our understanding of critical signals involved in stimulating and/or inhibiting hepatic progenitor cell proliferation. Our specific aims are as follows: (1) Study hepatic progenitor cell proliferation and characterize the role of cyclin proteins, cyclin dependent kinases and cyclin kinase inhibitors during proliferation; (2) Study the role of intracellular mediators including Ras, p38 mitogen-activated protein kinase (p38MAPK), MEK 1/2, ERK 1/2, AKT, p70s6k, and phosphoinositide 3-kinase (PI3K) in regulating cell cycle progression and proliferation of hepatic progenitor cells; and (3) Study downstream effects of inhibitory cell cycle mediators on hepatic progenitor cell proliferation. Our research efforts with an adult derived liver progenitor cell population are critical steps in understanding how stem cell subpopulations can be translated into therapies. To develop novel clinical strategies we need to understand the signaling pathways that trigger the growth of these cells and leads to their maturation into functional cells.