Importance of recruitment of bone marrow-derived CXCR4+ cells in post-infarct cardiac repair mediated by G-CSF

doi:10.1016/j.cardiores.2006.05.002

Cardiovascular Research 2006 71(3):455-465; doi:10.1016/j.cardiores.2006.05.002

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Importance of recruitment of bone marrow-derived CXCR4⁺ cells in post-infarct cardiac repair mediated by G-CSF

Yu Misao^a, Genzou Takemura^a, Masazumi Arai^a, Takamasa Ohno^b, Hirohito Onogi^a, Tomoyuki Takahashi^c, Shinya Minatoguchi^a, Takako Fujiwara^d and Hisayoshi Fujiwara^a^,*

^aDepartment of Cardiology, Regeneration Medicine and Bioethics, Gifu University Graduate School of Medicine, 1-1 Yanagido, Gifu 501-1194, Japan
^bDepartment of Oriental Medicine, Gifu University Graduate School of Medicine, Gifu, Japan
^cDepartment of Gene Therapy and Regenerative Medicine, Gifu University Graduate School of Medicine, Gifu, Japan
^dDepartment of Food Science, Kyoto Women's University, Kyoto, Japan

^* Corresponding author. Tel.: +81 58 230 6520; fax: +81 58 230 6521. Email address: gifuim-gif{at}umin.ac.jp

Objective: Granulocyte-colony stimulating factor (G-CSF) acceleratesrepair following myocardial infarction (MI). Recently, the beneficialeffects of post-MI administration of G-CSF were reported tobe mediated by direct activation of the Jak–Stat pathwayin cardiomyocytes. Our aim was to test the hypothesis that bonemarrow-derived cells recruited into the infarcted myocardiumare the primary mediators of the beneficial effects by G-CSF.

Methods and results MI was induced using a 30-min ischemia–reperfusionprotocol (day 0) in 40 rabbits treated with G-CSF (10 µg/kg/dayfrom days 3 to 7) or saline. Another 40 rabbits received thesame G-CSF or saline protocol but also received AMD3100 (200 µg/kg/day),a specific inhibitor of CXCR4. On day 28 post-MI, left ventricularejection fractions and end-diastolic dimensions were significantlybetter in the G-CSF group than in the control saline group,and the scar area/left ventricular wall area ratio was significantlysmaller in the G-CSF group. G-CSF administration also led toincreased mobilization of CXCR4⁺ bone marrow cells, includingRAM11⁺ macrophages, into infarcted areas. And within those areasthere was significant upregulation of expression of stromalcell-derived factor (SDF)-1, a chemoattractant of circulatingCXCR4⁺ cells, as well as of the collagenase matrix metalloproteinase-1.AMD3100 significantly inhibited all of these beneficial effectsof G-CSF, but did not affect the upregulation of SDF-1 or phospho-Stat3.

Conclusion Recruitment of CXCR4⁺ cells into infarcted myocardialtissues via stimulation of the CXCR4/SDF-1 axis plays a criticalrole in the beneficial effects of G-CSF.

KEYWORDS Myocardial infarction; G-CSF; CXCR4/SDF-1 axis; Post-infarct repair; AMD3100

Time for primary review 15 days

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