Abstract 942: Bone Marrow-Derived CXCR4+ Cells Mobilized by Macrophage Colony-stimulating Factor Participate in the Prevention of Cardiac Dysfunction after Myocardial Infarction in Mice
Background: Myocardial infarction (MI) is accompanied by inflammatory responses that lead to the recruitment of leukocytes and subsequent myocardial damage, healing, and scar formation. The monocyte (Mo)/macrophage (Mϕ) lineage might affect this process through 2 possible mechanisms; cytokine secretion by activated Mo/Mϕ and neovascularization by this lineage-derived endothelial cell progenitor cells (EPCs). Since macrophage colony-stimulating factor (M-CSF) has been shown to stimulate differentiation and proliferation of this lineage, and be upregulated in experimental MI models, we examined the effect of exogenous M-CSF administration on left ventricular (LV) dysfunction and remodeling in a murine MI model.
Methods and Results: MI was produced by left coronary artery ligation in C57BL/6J mice. Recombinant human M-CSF (500 μg/kg/day, n=27) or saline (control, n=26) was administered for 5 consecutive days after the induction of MI. Histology and echocardiogram revealed significant reduction of infarct size (p<0.05) and scar formation (p<0.05), and improvement of LV function (%FS; p<0.05) at 14 days after MI in M-CSF group. Immunohistochemistry showed M-CSF significantly increased macrophage infiltration (F4/80) and neovascularization (CD31), but not myofibroblast accumulation (α-SMA). Further, the stromal cell-derived factor (SDF)-1 was upregulated in the infarcted area of both M-CSF and control groups, whereas CXCR4+ cells were increased only in M-CSF group. Real-time RT-PCR analysis showed downregulation of M-CSF receptor (c-fms) in the myocardium of M-CSF group; this suggests bone-marrow-derived cells are responsible for the beneficial effect of M-CSF. Flow cytometric analysis showed that M-CSF increased the number of monocytes (Mac-1+/Gr-1−) and CXCR4+ cells, but not EPCs (CD34+/Flk-1+) in the peripheral circulation. MI was also produced in mice whose bone marrow was replaced with that of GFP mice, and increased number of GFP+ cells was detected in the border area in M-CSF group.
Conclusion: These findings suggest that M-CSF prevents cardiac dysfunction and remodeling after MI through the recruitment of CXCR4+ cells into the infarcted myocardium by the SDF-1/CXCR4 axis activation.