Neutrophil-derived MMP-9 mediates synergistic mobilization of hematopoietic stem and progenitor cells by the combination of G-CSF and the chemokines GROβ/CXCL2 and GROβT/CXCL2Δ4

Louis M. Pelus, Huimin Bian, Andrew G. King, Seiji Fukuda

Research output: Contribution to journalArticle

147 Scopus citations

Abstract

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 GROβ/CXCL2 and GROβT/CXCL2Δ4 rapidly mobilize PBSC equivalent to granulocyte colony-stimulating factor (G-CSF) and are synergistic with G-CSF. We now show that mobilization by GROβ/GROβT and G-CSF, alone or in combination, requires polymorphonuclear neutrophil (PMN)-derived proteases. Mobilization induced by GROβ/GROβT 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 GROβ/GROβT 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 GROβ/GROβT-mediated PBSC mobilization and, importantly, that synergistic mobilization by G-CSF plus GROβ/GROβT is mediated by PMN-derived plasma MMP-9.

Original languageEnglish (US)
Pages (from-to)110-119
Number of pages10
JournalBlood
Volume103
Issue number1
DOIs
StatePublished - Jan 1 2004

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ASJC Scopus subject areas

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

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