The chemokine GRObeta mobilizes early hematopoietic stem cells characterized by enhanced homing and engraftment.

Mobilized peripheral blood hematopoietic stem cells (PBSCs) demonstrate accelerated engraftment compared with bone marrow; however, mechanisms responsible for enhanced engraftment remain unknown. PBSCs mobilized by GRObeta (GRObeta(Delta4)/CXCL2(Delta4)) or the combination of GRObeta(Delta4) plus granulocyte colony-stimulating factor (G-CSF) restore neutrophil and platelet recovery faster than G-CSF-mobilized PBSCs. To determine mechanisms responsible for faster hematopoietic recovery, we characterized immunophenotype and function of the GRObeta-mobilized grafts. PBSCs mobilized by GRObeta(Delta4) alone or with G-CSF contained significantly more Sca-1(+)-c-kit(+)-lineage(-) (SKL) cells and more primitive CD34(-)-SKL cells compared with cells mobilized by G-CSF and demonstrated superior competitive long-term repopulation activity, which continued to increase in secondary and tertiary recipients. GRObeta(Delta4)-mobilized SKL cells adhered better to VCAM-1(+) endothelial cells compared with G-CSF-mobilized cells. GRObeta(Delta4)-mobilized PBSCs did not migrate well to the chemokine stromal derived factor (SDF)-1alpha in vitro that was associated with higher CD26 expression. However, GRObeta(Delta4)-mobilized SKL and c-Kit(+) lineage(-) (KL) cells homed more efficiently to marrow in vivo, which was not affected by selective CXCR4 and CD26 antagonists. These data suggest that GRObeta(Delta4)-mobilized PBSCs are superior in reconstituting long-term hematopoiesis, which results from differential mobilization of early stem cells with enhanced homing and long-term repopulating capacity. In addition, homing and engraftment of GRObeta(Delta4)-mobilized cells is less dependent on the SDF-1alpha/CXCR4 axis.