REGULATION OF HUMAN HEMATOPOIETIC STEM CELL CYCLE INDUCTION

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The goals of this project are to define methods to induce primitive, quiescent human hematopoietic stem cells (HSC) to enter cell cycle, and to determine the associated phenotyping and molecular changes that occur in vitro and in vivo. Cell cycle induction of both CD45+/CD34+/lin- and CD45+/CD34-/lin cells will be evaluated in side-by-side comparisons in vitro and in vivo in immune deficient mice. Bone marrow recovered from long-term engrafted beige/nude/xid (bnx) mice CD34 at the cell surface. We hypothesize that the human HSC engrafted in the bone marrow of bnx mice lose by activation of the human stem cells in vivo, following sublethal irradiation of the mice. We have demonstrated that sublethal irradiation leads to an increase in the number of human CD34+ cells in the marrow of immune deficient murine marrow microenvironment. We hypothesize that the inductive signals from the sublethally irradiated cells and will result in cell cycle induction in both CD34+/lin- and Cd34-/lin- cells We will use human stem cells engrafted in bnx and NOD/SCID mice to test this hypothesis. We have previously demonstrated that reduction that reduction in levels now extend those studies to define in vitro methods to induce cell cycle entry in human CD34-/lin-stem cells, to facilitate whether individual human CD34+/lin- and CD34-/lin- cells can be transduced in vitro and retain the capacity to give rise to multi-lineage hematopoiesis in vitro. Tracking of individual, marked human HSC from the CD34+/lin and CD34-/lin-PCR method that we developed. The planned studies will establish an in vivo correlation. between human techniques to promote rapid cell cycle entry and transduction of both types of stem cells, and will demonstrate which hematopoietic lineages can be derived from individual, transduced stem cells from each population.