G-CSF induces stem cell mobilization by decreasing bone marrow SDF-1 and up-regulating CXCR4

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  • An Erratum to this article was published on 01 August 2002

Abstract

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 of clinical stem cell transplantation.

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Figure 1: G-CSF decreases SDF-1 protein within the BM but not in the blood.
Figure 2: G-CSF transiently increases SDF-1 protein in the BM and increases SDF-1 mRNA expression by osteoblasts.
Figure 3: Degradation of SDF-1 by elastase and supernatants from G-CSF–treated human and murine BM.
Figure 4: Inhibition of elastase reduces SDF-1 degradation and mobilization.
Figure 5: G-CSF up-regulates CXCR4 expression on BM cells before their mobilization.
Figure 6: Anti-CXCR4 and anti–SDF-1 prevent G-CSF–induced mobilization of human and murine hematopoietic cells.

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Acknowledgements

Supported by grants from The Israel Science foundation and the Ares Serono Group (to T. L.), The Germany MINERVA grant and ICRF (to I. P.), the Gabriella Rich Center for Transplantation Biology (to T. P.) and the French National Agency for AIDS Research (to F. A.-S.).

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Correspondence to Tsvee Lapidot.

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