description) Important physiological events in hematopoietic stem and progenitor cell biology include the movement of these rare cells from organ to organ and through the blood. Very little is known regarding what directs this migration and homing under normal unperturbed conditions, during stress and during transplantation. Even less is known about the cellular and intracellular signaling events mechanistically mediating this migration and homing. While mobilization of hematopoietic stem and progenitor cells from marrow to blood is induced after infusion of certain cytokines little information is available on the mechanisms of this induced-mobilization. It is the investigator's hypothesis that regulation of migration, homing and mobilization involves a combination of cytokine/cytokine receptor directed effects and that members of the chemokine family of cytokines and their receptors are intimately involved in modulation of these events. Candidate chemokines/chemokine receptors for these effects include: macrophage inflammatory protein (MIP)-1alpha/C-C Chemokine receptor (CCR) 1, interleukin (IL)-8 and MIP-2/C-X-C chemokine receptor (CXCR)2, and stromal derived factors (SDF)-1alpha and -1beta/CXCR4 (=LESTR/FUSIN/HUMSTR). Moreover, the investigators believe that Thrombopoietin (TPO) and its receptor c-mpl can interact to modulate the effects of certain chemokine and chemokine receptors or alternatively chemokine/chemokine receptor interactions can modulate TPO effects. The following aims are proposed: (1) Evaluate the influence in vitro on primary hematopoietic stem and progenitor cells and their subsets of selected chemokines and their respective receptors, alone and in combination with TPO and its receptor c-mpl for stimulation, enhancement, or suppression of chemotaxis in a modified checkerboard assay and of integrin-mediated adherence to fibronectin and other extracellular matrix (ECM) proteins. (2) Determine intracellular signal transduction events associated with chemotaxis and integrin receptor-mediated adherence to fibronectinin response to chemokines, TPO and their receptors by using the human growth factor-dependent cell line, M07e. (3) Analyze the influence of chemokines, TPO and their receptors on homing and short- and long-term engraftment of primary murine hematopoietic stem and progenitor cells into lethally irradiated mice and of human stem and progenitor cells into NOD-SCID mice using marked or fluorescent labeled cells. Also, assess chemokine- and TPO-induced mobilization of stem and progenitor cells from control mice, mice lacking chemokine receptors or c-mpl, and mice transplanted with cells lacking or over-expressing chemokine receptors or c-mpl. These studies should help improve our understanding of stem/progenitor cell migration, homing and mobilization, information of importance to stem and progenitor cell behavior and transplantation.
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