Peripheral blood stem cell mobilization:: The CXCR2 ligand GROβ rapidly mobilizes hematopoietic stem cells with enhanced engraftment properties

Chemokines direct the movement of leukocytes, including hematopoietic stem and progenitor cells, and can mobilize hematopoietic cells from marrow to peripheral blood where they can be used for transplantation. In this review, we will discuss the stem cell mobilizing activities and mechanisms of action of GRO beta, a CXC chemokine ligand for the CXCR2 receptor. GRO beta rapidly mobilizes short- and long-term repopulating cells in mice and/or monkeys and synergistically enhances mobilization responses when combined with the widely used clinical mobilizer, granulocyte colony-stimulating factor (G-CSF). The hematopoietic graft mobilized by GRO beta contains significantly more CD34(neg), Sca-1(+), c-kit(+), lineage(neg) (SKL) cells than the graft mobilized by G-CSF. In mice, stem cells mobilized by GROP demonstrate a competitive advantage upon long-term repopulation analysis and restore neutrophil and platelet counts significantly faster than cells mobilized by G-CSF. Even greater advantage in repopulation and restoration of hematopoiesis are observed with stem cells mobilized by the combination of GROP and G-CSF. GRO beta-mobilized SKL cells demonstrate enhanced adherence to vascular cell adhesion molecule-1 and VCAM(pos) endothelial cells and home more efficiently to bone marrow in vivo. The marrow homing ability of GRO beta-mobilized cells is less dependent on the CXCR4/SDF-1 axis than cells mobilized by G-CSF. The mechanism of mobilization by GRO beta requires active matrix metalloproteinase-9 (MMP-9), which results from release of pro-MMP-9 from peripheral blood, and marrow neutrophils, which alters the stoichiometry between pro-MMP-9 and its inhibitor tissue inhibitor of metalloproteinase-1, resulting in MMP-9 activation. The efficacy and rapid action of GRO beta and lack of proinflammatory activity make it an attractive agent to supplement mobilization by G-CSF. In addition, GRO beta may also have clinical mobilizing efficacy on its own, reducing the overall time and costs associated with peripheral blood stem cell transplantation. (c) 2006 International Society for Experimental Hematology.