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Blood. 2004 Jan 1;103(1):110-9. Epub 2003 Sep 4.

Neutrophil-derived MMP-9 mediates synergistic mobilization of hematopoietic stem and progenitor cells by the combination of G-CSF and the chemokines GRObeta/CXCL2 and GRObetaT/CXCL2delta4.

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  • 1Department of Microbiology and Immunology and the Walther Oncology Center, Indianapolis, IN 46202, USA.


Mobilized peripheral blood stem cells (PBSCs) are widely used for transplantation, but mechanisms mediating their release from marrow are poorly understood. We previously demonstrated that the chemokines GRObeta/CXCL2 and GRObetaT/CXCL2Delta4 rapidly mobilize PBSC equivalent to granulocyte colony-stimulating factor (G-CSF) and are synergistic with G-CSF. We now show that mobilization by GRObeta/GRObetaT and G-CSF, alone or in combination, requires polymorphonuclear neutrophil (PMN)-derived proteases. Mobilization induced by GRObeta/GRObetaT is associated with elevated levels of plasma and marrow matrix metalloproteinase 9 (MMP-9) and mobilization and MMP-9 are absent in neutrophil-depleted mice. G-CSF mobilization correlates with elevated neutrophil elastase (NE), cathepsin G (CG), and MMP-9 levels within marrow and is partially blocked by either anti-MMP-9 or the NE inhibitor MeOSuc-Ala-Ala-Pro-Val-CMK. Mobilization and protease accumulation are absent in neutrophil-depleted mice. Synergistic PBSC mobilization observed when G-CSF and GRObeta/GRObetaT are combined correlates with a synergistic rise in the level of plasma MMP-9, reduction in marrow NE, CG, and MMP-9 levels, and a coincident increase in peripheral blood PMNs but decrease in marrow PMNs compared to G-CSF. Synergistic mobilization is completely blocked by anti-MMP-9 but not MeOSuc-Ala-Ala-Pro-Val-CMK and absent in MMP-9-deficient or PMN-depleted mice. Our results indicate that PMNs are a common target for G-CSF and GRObeta/GRObetaT-mediated PBSC mobilization and, importantly, that synergistic mobilization by G-CSF plus GRObeta/GRObetaT is mediated by PMN-derived plasma MMP-9.

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