title: Importance of recruitment of bone marrow-derived CXCR4+ cells in post-infarct cardiac repair mediated by G-CSF.
abstract: OBJECTIVE
  Granulocyte-colony stimulating factor (G-CSF) accelerates repair following myocardial infarction (MI). Recently, the beneficial effects of post-MI administration of G-CSF were reported to be mediated by direct activation of the Jak-Stat pathway in cardiomyocytes. Our aim was to test the hypothesis that bone marrow-derived cells recruited into the infarcted myocardium are the primary mediators of the beneficial effects by G-CSF.
  
  
  RESULTS
  MI was induced using a 30-min ischemia-reperfusion protocol (day 0) in 40 rabbits treated with G-CSF (10 microg/kg/day from days 3 to 7) or saline. Another 40 rabbits received the same G-CSF or saline protocol but also received AMD3100 (200 microg/kg/day), a specific inhibitor of CXCR4. On day 28 post-MI, left ventricular ejection fractions and end-diastolic dimensions were significantly better in the G-CSF group than in the control saline group, and the scar area/left ventricular wall area ratio was significantly smaller in the G-CSF group. G-CSF administration also led to increased mobilization of CXCR4+ bone marrow cells, including RAM11+ macrophages, into infarcted areas. And within those areas there was significant upregulation of expression of stromal cell-derived factor (SDF)-1, a chemoattractant of circulating CXCR4+ cells, as well as of the collagenase matrix metalloproteinase-1. AMD3100 significantly inhibited all of these beneficial effects of G-CSF, but did not affect the upregulation of SDF-1 or phospho-Stat3.
  
  
  CONCLUSIONS
  Recruitment of CXCR4+ cells into infarcted myocardial tissues via stimulation of the CXCR4/SDF-1 axis plays a critical role in the beneficial effects of G-CSF.
authors.affiliation: Department of Cardiology, Regeneration Medicine and Bioethics, Gifu University Graduate School of Medicine, 1-1 Yanagido, Gifu 501-1194, Japan.
authors.forename: Yu
authors.initials: Y
authors.lastname: Misao
authors.forename: Genzou
authors.initials: G
authors.lastname: Takemura
authors.forename: Masazumi
authors.initials: M
authors.lastname: Arai
authors.forename: Takamasa
authors.initials: T
authors.lastname: Ohno
authors.forename: Hirohito
authors.initials: H
authors.lastname: Onogi
authors.forename: Tomoyuki
authors.initials: T
authors.lastname: Takahashi
authors.forename: Shinya
authors.initials: S
authors.lastname: Minatoguchi
authors.forename: Takako
authors.initials: T
authors.lastname: Fujiwara
authors.forename: Hisayoshi
authors.initials: H
authors.lastname: Fujiwara
mesh_terms: D000818:Animals; D001596:Benzylamines; D001854:Bone Marrow Cells / Q000473:pathology*; D054377:Chemokine CXCL12; D019743:Chemokines, CXC / Q000378:metabolism; D000080027:Cyclams; D016179:Granulocyte Colony-Stimulating Factor / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D006439:Hemodynamics / Q000187:drug effects; D006571:Heterocyclic Compounds / Q000494:pharmacology; D007958:Leukocyte Count; D008297:Male; D020781:Matrix Metalloproteinase 1 / Q000378:metabolism; D009203:Myocardial Infarction / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology; D011817:Rabbits; D019718:Receptors, CXCR4 / Q000032:analysis* / Q000037:antagonists & inhibitors; D050796:STAT3 Transcription Factor / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
chemical_list: D001596:Benzylamines; D054377:Chemokine CXCL12; D019743:Chemokines, CXC; D000080027:Cyclams; D006571:Heterocyclic Compounds; D019718:Receptors, CXCR4; D050796:STAT3 Transcription Factor; D042461:Vascular Endothelial Growth Factor A; D016179:Granulocyte Colony-Stimulating Factor; D020781:Matrix Metalloproteinase 1; C088327:plerixafor