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Exp Hematol. 2010 Sep;38(9):823-35. doi: 10.1016/j.exphem.2010.05.002. Epub 2010 May 13.

MT1-MMP association with membrane lipid rafts facilitates G-CSF--induced hematopoietic stem/progenitor cell mobilization.

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1
Department of Medicine, University of Alberta, Edmonton, Alberta, Canada.

Abstract

OBJECTIVE:

Soluble matrix metalloproteinases (MMPs) facilitate the egress of hematopoietic stem/progenitor cells (HSPC) from the bone marrow (BM) during granulocyte colony-stimulating factor (G-CSF)-induced mobilization. Because membrane-type (MT)1-MMP, which is localized on the leading edge of migrating cells, activates the latent forms of soluble MMPs, we investigated its role in HSPC mobilization.

MATERIALS AND METHODS:

We examined the effect of G-CSF on the expression of MT1-MMP and its activities (proMMP-2 activation and migration) in hematopoietic cells. We also investigated the subcellular localization of MT1-MMP and the signaling pathways that regulate its expression and function in hematopoietic cells after exposure to G-CSF.

RESULTS:

We found that G-CSF increases MT1-MMP transcription and protein synthesis in hematopoietic cells; proMMP-2 activation in cocultures of HSPC with BM fibroblasts; chemoinvasion across reconstituted basement membrane Matrigel toward a stromal cell-derived factor-1 gradient, which is reduced by small interfering RNA silencing of MT1-MMP; and localization of MT1-MMP to membrane lipid rafts through a mechanism that is regulated by the phosphatidylinositol 3-kinase signaling pathway. Disruption of raft formation (by the cholesterol-sequestering agent methyl-beta-cyclodextrin) abrogated phosphatidylinositol 3-kinase phosphorylation and MT1-MMP incorporation into lipid rafts resulting in reduced proMMP-2 activation and HSPC migration.

CONCLUSION:

G-CSF-induced upregulation of MT1-MMP in hematopoietic cells and its enhanced incorporation into membrane lipid rafts contributes to proMMP-2 activation, which facilitates mobilization of HSPC.

PMID:
20471446
DOI:
10.1016/j.exphem.2010.05.002
[Indexed for MEDLINE]
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