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Use of Matrix Metalloproteinase (MMP)-9 Knockout Mice Demonstrates that MMP-9 Activity Is not Absolutely Required for G-CSF or Flt-3 Ligand-Induced Hematopoietic Progenitor Cell Mobilization or Engraftment

Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, Nebraska, USA

Key Words. Matrix metalloproteinase • G-CSF • Flt-3 ligand • Cytokine-induced mobilization • Engraftment

Simon N. Robinson, Ph.D., Department of Genetics, Cell Biology and Anatomy, 986395 Nebraska Medical Center, Omaha, Nebraska 68198-6395, USA. Telephone: 402-559-4390; Fax: 402-559-7328; e-mail: snrobins{at}unmc.edu

Recombinant growth factors (GFs) are used to mobilize hematopoietic stem cells (HSCs) for autologous and allogeneic transplantation; however, little is known about the mechanism(s) critical to this process. Increased levels of serum matrix metalloproteinase (MMP)-9 are detected during mobilization by G-CSF in humans or interleukin (IL)-8 in primates and mice, suggesting a role for this molecule in mobilization. Further, antibodies to MMP-9 block IL-8-induced mobilization. To investigate the role of MMP-9, we compared G-CSF and Flt-3 ligand (Flt-3L)-induced mobilization in wild-type (WT) and MMP-9 knockout (KO) mice. The absence of MMP-9 in the KO mice was confirmed by zymography, which also revealed that serum MMP-9 levels were elevated in WT mice following G-CSF administration. We report that MMP-9 KO mice did not have impaired G-CSF- or Flt-3L-induced hematopoietic progenitor mobilization, suggesting that MMP-9 is not an absolute requirement for this process. In addition, MMPs produced by HSCs have been demonstrated to be important for their transmigration; however, we demonstrate that the engraftment of MMP-9-deficient bone marrow HSCs was not impaired in sublethally irradiated WT recipients. We conclude that while MMP-9 may play an important role in GF-induced hematopoietic progenitor mobilization and engraftment in WT animals, compensatory upregulation of enzymes with a similar activity profile to MMP-9 may obscure the impact of MMP-9 deficiency in the KO model.

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