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Stromal-derived factor 1-induced megakaryocyte migration and platelet production is dependent on matrix

W J Lane1, S Dias, K Hattori

  • 1Division of Hematology-Oncology, Weill Medical College of Cornell University, Ithaca, NY 10021, USA.

Blood
|December 9, 2000
PubMed

Insights

Mature megakaryocytes (MKs) migrate and release platelets by expressing matrix metalloproteinase-9 (MMP-9), a process stimulated by stromal-derived factor 1 (SDF-1) and its receptor CXCR4. MMP inhibitors may treat blood disorders.

Area of Science:

  • Hematology
  • Cell Biology
  • Molecular Biology

Background:

  • Thrombopoietin (TPO) is known to influence megakaryocytopoiesis, but the precise mechanisms and locations of platelet production remain unclear.
  • Mature megakaryocytes (MKs) express the stromal-derived factor 1 (SDF-1) receptor, CXCR4, and SDF-1 induces their migration through endothelial cells, enhancing platelet production.

Purpose of the Study:

  • To investigate the role of matrix metalloproteinases (MMPs) in megakaryocyte migration and platelet production.
  • To determine if SDF-1 induces MMP expression in MKs and if MMPs are essential for MK migration and platelet release.

Main Methods:

  • Purified mature human MKs and a megakaryocytic cell line were used to assess SDF-1-induced expression and release of MMP-9.
  • Neutralizing antibodies against MMP-9 and MMP-2 were employed to evaluate their role in MK migration.
  • Synthetic MMP inhibitors were used to assess their impact on platelet formation.
  • Adeno-SDF-1 was injected into mice to confirm findings in vivo, with subsequent analysis of platelet counts and MMP inhibitor effects.

Main Results:

  • SDF-1 stimulated the expression and release of gelatinase B (MMP-9) by mature MKs and a megakaryocytic cell line.
  • Neutralization of MMP-9, but not MMP-2, inhibited SDF-1-induced MK migration through basement membrane.
  • MMP inhibitors blocked both MK migration and subsequent platelet formation.
  • In vivo administration of adeno-SDF-1 increased platelet counts in mice, an effect reversible by MMP inhibitors.

Conclusions:

  • Megakaryocyte (MK) mobilization involves sequential expression and activation of CXCR4 and MMP-9, leading to transendothelial migration and platelet release.
  • Matrix metalloproteinase-9 (MMP-9) plays a critical role in both MK migration and platelet formation.
  • Matrix metalloproteinase (MMP) inhibitors show potential therapeutic value for thrombotic and myeloproliferative disorders.

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