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Granulocyte colony-stimulating factor (G-CSF)–induced hematopoietic stem cell mobilization is widely used for clinical transplantation; however, the mechanism is poorly understood. We report here that G-CSF induced a reduction of the chemokine stromal cell–derived factor 1 (SDF-1) and an increase in its receptor CXCR4 in the bone marrow (BM), whereas their protein expression in the blood was less affected. The gradual decrease of BM SDF-1, due mostly to its degradation by neutrophil elastase, correlated with stem cell mobilization. Elastase inhibition reduced both activities. Human and murine stem cell mobilization was inhibited by neutralizing CXCR4 or SDF-1 antibodies, demonstrating SDF-1–CXCR4 signaling in cell egress. We suggest that manipulation of SDF-1–CXCR4 interactions may be a means with which to control the navigation of progenitors between the BM and blood to improve the outcome …