4.5 Article

Degradation of BM SDF-1 by MMP-9: the role in G-CSF-induced hematopoietic stem/progenitor cell mobilization

Journal

BONE MARROW TRANSPLANTATION
Volume 42, Issue 9, Pages 581-588

Publisher

NATURE PUBLISHING GROUP
DOI: 10.1038/bmt.2008.222

Keywords

G-CSF-induced HSPC mobilization; metalloproteinases; chemotactic activity; proteolytic degradation; osteoblast; poor mobilizer

Funding

  1. Science and Technology Development Program of Tianjin [06YFSYSF01900]
  2. Natural Sciences Foundation of Tianjin [06YFJMSC08500, 08JCYBJ6200]
  3. Scientific Research Foundation of the State Human Resource Ministry for Returned Chinese Scholars, China

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The major involvement of chemokines and proteolytic enzymes has recently been discovered in the mobilization process. Here, we report that the degradation of BM stromal cell-derived factor (SDF-1) by matrix metalloproteinase (MMP)-9 is important in G-CSF-mediated hematopoietic stem/progenitor cells (HSPCs) mobilization. In this study, the SDF-1 concentration in healthy donors BM plasma decreased significantly after 5 days of G-CSF administration, with no obvious change of SDF-1 in the peripheral blood. We also observed a similar result by immunohistochemical staining on the BM biopsy slides. In vitro, mobilized BM plasma exhibited decreased chemotactic effect on CD34(+) cells, compared with steady-state BM plasma. MMP-9 protein and mRNA increased dramatically in the BM plasma in accordance with SDF-1 decrease. MMP-9 enriched supernatant from HT1080 cell-conditioned medium upregulated CXCR4 expression and the migration of BM CD34(+) cells toward SDF-1. SDF-1 was a substrate for MMP-9, furthermore, SDF-1 also stimulated MMP-9 proteolytic enzyme activity of BM CD34(+) cells, which facilitate HSPCs migration. In BALB/c mice, HSPCs mobilization was significantly inhibited by anti-SDF-1 antibodies or MMP inhibitor, o-phenanthroline. In conclusion, the degradation of BM SDF-1 by MMP-9 is a vital step in mobilization.

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