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.
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.
Robinson
Simon N
SN
Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha 68198, USA. snrobins@unmc.edu
Pisarev
Vladimir M
VM
Chavez
Jennifer M
JM
Singh
Rakesh K
RK
Talmadge
James E
JE
D000818:Animals; D001854:Bone Marrow Cells / Q000378:metabolism; D016026:Bone Marrow Transplantation; D005269:Femur / Q000378:metabolism; D018093:Gelatinases / Q000097:blood; D016179:Granulocyte Colony-Stimulating Factor / Q000378:metabolism*; D006412:Hematopoietic Stem Cells / Q000378:metabolism; D006801:Humans; D016209:Interleukin-8 / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000235:genetics* / Q000378:metabolism / Q000502:physiology*; D008565:Membrane Proteins / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D011994:Recombinant Proteins / Q000378:metabolism; D013154:Spleen / Q000378:metabolism; D013997:Time Factors; D015854:Up-Regulation
D016209:Interleukin-8; D008565:Membrane Proteins; D011994:Recombinant Proteins; C084881:flt3 ligand protein; D016179:Granulocyte Colony-Stimulating Factor; D018093:Gelatinases; D020780:Matrix Metalloproteinase 9