Successful hematopoietic transplantation depends upon the unexpected capacity of intravenously infused hematopoietic stem cells (HSC) to home to and engraft the bone marrow (BM) of fully or partially myeloablated patients. Current clinical practice in hematopoietic stem cell transplantation has begun to shift toward the use of """"""""mobilized peripheral blood"""""""" (MPB) as a source of engrafting cells. Mobilization of HSC and hematopoietic progenitors from the BM to the bloodstream can be induced in patients or in normal donors following administration of cytoreductive agents and hematopoietic cytokines, either alone or in combination. Thus, the innate ability of stem and progenitor cells to migrate to and from BM, blood, and other tissues, is currently exploited for the treatment of diverse diseases, and yet, the mechanisms and regulators of these events are largely unclear. The experiments described in this application are therefore designed to improve our understanding of the molecular mediators and biological significance of HSC migration in the context of both normal homeostasis, and in the special settings of induced mobilization and transplantation. These studies will (1) clarify the role of migration in the normal function of HSC, (2) evaluate the influence of HSC proliferation on HSC migration, (3) identify adhesion and chemokine receptors that mediate blood to BM and BM to blood HSC homing, and (4) characterize the interactions between stem cells and other cells that promote HSC expansion or migration or determine the localization of HSC within particular tissues. These questions will be addressed using rigorously purified cell populations, sensitive quantitative assays, and large-scale genomic analysis. Given the substantial clinical importance of HSC migration to and from BM, the insights gained through these approaches may quickly translate into clinical applications that will ultimately improve the efficiency of HSC mobilization for PBPC harvest and hematopoietic engraftment following transplantation.
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