Mesenchymal stem cell migration in a murine model of myocardial infarction

Aims: Mesenchymal stem cell (MSC)-based therapies are presently under investigation for the treatment of myocardial infarction (MI). However, for MSCs to regenerate the wounded myocardium, tissue specific homing is crucial. We sought out to determine whether amplifying the cytokine signals released by the ischemic myocardium can enhance the recruitment of intravenously (IV) administered bone marrow-derived MSCs. Methods and results: First, cytokines released by ischemic myocardium 24 hours after left anterior descending (LAD) coronary artery ligation in BALB/c mice were analysed for their potential to increase MSC migration and proliferation in vitro . Of the cytokines that were at least 5-fold upregulated during ischemia (HGF, VEGF, IL-6, MCP-1, GM-CSF and CXCL-16), in our in vitro studies only HGF and VEGF proved to promote both MSC proliferation and migration. Injection of 60µl of HGF 40ng/ml or VEGF 8ng/ml into the infarct border zone at the time of MI significantly increased the number of IV-injected MSCs in the infarct (from 1±0.5 cells/high power field (HPF) to 11±4 cells/HPF; p<0.001 and 7±4 cells/HPF; p=0.013 respectively). Left-ventricle ejection fraction (LVEF) was monitored 6 months after the MI using ECG-triggered contrast Micro-CT imaging. The progressive decrease in LVEF (to 19±1%) was attenuated by treatment with IV-injected MSCs and HGF (29±6%; p=0.003) or VEGF (28±4%; p=0.004). Conclusion: Our data show that the increase in MSC number due to HGF and VEGF injections attenuates negative LV remodeling after MI.