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

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. Methods and results: MI was induced using a 30-min ischemia-reperfusion protocol (day 0) in 40 rabbits treated with G-CSF (10 mu g/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 mu g/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 metalloprotemase-1. AMD3100 significantly inhibited all of these beneficial effects of G-CSF, but did not affect the upregulation of SDF-1 or phospho-Stat3. Conclusion: 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. (c) 2006 European Society of Cardiology. Published by Elsevier B.V. All rights reserved.