Chemokine induced hematopoietic stem cell mobilization

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Hematopoietic cytokines elevate levels of stem progenitor cells in peripheral blood defining a new standard of care for patients with hematological and solid tumor malignancies receiving peripheral blood hematopoietic stem cell grafts. However, peripheral blood stem cell transplantation (PBSCT) is not without issues, related to efficacy, logistics, expense and cell yield, particularly in some patient populations, and in the partially matched related donor and sublethal conditioning regimen settings. Hematopoietic stem cell (HSC) mobilization can be accomplished more rapidly and with improved efficacy by chemokines that bind the CXCR2 chemokine receptor. Moreover, chemokine-induced mobilization of HSC is synergistic with hematopoietic growth factor-induced HSC mobilization. Chemokine-induced HSC mobilization and synergy with G-CSF offer new paradigms for autologous and allogeneic PBSCT. Mechanisms responsible for stem cell mobilization either with growth factors or chemokines are largely unknown. Elucidation of the immediate molecular and biochemical events leading to release and migration of HSC may permit direct mobilization, bypassing the chemokine and/or growth factor receptors. Our hypothesis are 2-fold: First that neutrophils mediate CXCR2-ligand induced HSC mobilization, and second that the HSC population mobilized by CXCR2 ligands alone or in combination with G-CSF posses intrinsic properties that allow for more rapid hematological reconstitution and can be defined phenotypically. To more fully understand these mechanisms at the cellular, biochemical and molecular level we propose a comprehensive plan to investigate the biochemical and molecular events initiated at the CXCR2 receptor by the ligands Gro-beta and a novel isoforms that we have identified, Gro-beta-T, that lead to HSC mobilization and to further define the nature of the hematopoietic graft mobilized that is responsible for superior reconstituting capacity. Investigation will focus on the CXCR2 receptor and intracellular signaling pathways leading to production and activation of matrix metalloproteinase-9, which we have implicated in the biomechanism of action of CXCR2 chemokines. We will focus on defining the cell cycle status, adhesion molecule expression and homing characteristics of the chemokine- induced HSC graft in order to understand its superior reconstituting potential. Understanding the molecular mechanisms of mobilization will lead to the development of novel and more predictable and efficacious regimens, and faster and safer protocols, measurable in improvement in patient morbidity and mortality, particularly in the allogeneic setting, and define new standards of care for patients with autoimmune disease, non-malignant hematological diseases and patients undergoing tolerance induction for organ transplantation.