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Phenotypic Analysis and Isolation of Murine Hematopoietic Stem Cells and Lineage-committed Progenitors
12:03

Phenotypic Analysis and Isolation of Murine Hematopoietic Stem Cells and Lineage-committed Progenitors

Published on: July 8, 2012

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

Neeta Shirvaikar1, Leah A Marquez-Curtis, Andrew R Shaw

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

Experimental Hematology
|May 18, 2010
PubMed
Abstract

Insights

Granulocyte colony-stimulating factor (G-CSF) mobilizes hematopoietic stem cells (HSCs) by upregulating membrane-type 1 matrix metalloproteinase (MT1-MMP). This enhances proMMP-2 activation and HSC migration.

Area of Science:

  • Hematology
  • Cell Biology
  • Biochemistry

Background:

  • Soluble matrix metalloproteinases (MMPs) are crucial for hematopoietic stem/progenitor cell (HSPC) egress from the bone marrow during G-CSF-induced mobilization.
  • Membrane-type (MT)1-MMP, located at the leading edge of migrating cells, activates latent soluble MMPs, suggesting a key role in HSPC mobilization.

Purpose of the Study:

  • To investigate the role of MT1-MMP in G-CSF-induced HSPC mobilization.
  • To examine how G-CSF affects MT1-MMP expression, activity, and localization in hematopoietic cells.

Main Methods:

  • Assessed G-CSF effects on MT1-MMP expression and activity (proMMP-2 activation, migration) in hematopoietic cells.
  • Investigated MT1-MMP subcellular localization and regulatory signaling pathways (PI3K) after G-CSF exposure.
  • Utilized small interfering RNA (siRNA) for MT1-MMP silencing and methyl-beta-cyclodextrin to disrupt lipid rafts.

Main Results:

  • G-CSF increased MT1-MMP transcription and protein synthesis in hematopoietic cells.
  • MT1-MMP facilitated proMMP-2 activation and chemoinvasion of HSPC, which was reduced by MT1-MMP silencing.
  • G-CSF promoted MT1-MMP localization to membrane lipid rafts via the PI3K pathway; raft disruption reduced MT1-MMP activity and HSPC migration.

Conclusions:

  • G-CSF upregulates MT1-MMP in hematopoietic cells, enhancing its lipid raft incorporation.
  • This MT1-MMP upregulation and raft localization contribute to proMMP-2 activation.
  • These processes collectively facilitate the mobilization of hematopoietic stem/progenitor cells.

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