Journal
BLOOD
Volume 103, Issue 1, Pages 110-119Publisher
AMER SOC HEMATOLOGY
DOI: 10.1182/blood-2003-04-1115
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Funding
- NATIONAL HEART, LUNG, AND BLOOD INSTITUTE [R01HL069669] Funding Source: NIH RePORTER
- NHLBI NIH HHS [HL69669] Funding Source: Medline
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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 GRObeta(T)/CXCL2(Delta4) rapidly mobilize PBSC equivalent to granulocyte colony-stimulating factor (G-CSF) and are synergistic with G-CSF. We now show that mobilization by GRObeta/GRObeta(T) and G-CSF, alone or in combination, requires polymorphonuclear neutrophil (PMN)-derived proteases. Mobilization induced by GRObeta/GRObeta(T) is associated with elevated levels of plasma and marrow matrix metal loproteinase 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/GRObeta(T) 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/GRObeta(T)-mediated PBSC mobilization and, importantly, that synergistic mobilization by G-CSF plus GRObeta/GRObeta(T) is mediated by PMN-derived plasma MMP-9.
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