Abstract 10711: Dual Stem Cell Therapy After Myocardial Infarction Acts Specifically by the Cxcr4-sdf1 Axis
Background: Dual stem cell therapy comprising stabilization of cardiac SDF-1 by DPP-IV-inhibition and G-CSF based stem cell mobilization may improve therapy of myocardial infarction since it finally leads to increased heart function and enahnced survival. However, it remains unclear, whether this new approach works specifically by the SDF1-CXCR4- axis.
Methods: We induced myocardial infarction in C57BL/6 mice by surgical occlusion of the left descending artery. Animals were then treated with G-CSF +/- the DPP-IV inhibitor Diprotin A. Saline treated animals served as controls. Antagonization of CXCR-4 was performed by application of AMD3100. FACS analyses were used to determine stem cell populations in the myocardium after 6 days. Histology was performed to examine capillary density after 6 days and infarct size 30 days after AMI. Cardiac function was assessed using a Millar-Tip catheter system. Survival was analyzed by Kaplan-Meier-method for 30 days (n=20 in each group). Myocardial perfusion was measured by single photon emission computed tomography (SPECT).
Findings: First, we established in a titration scheme the optimal dosage of AMD3100 (1,25mg/kg) that is sufficient to block CXCR-4 but is not mobilizing stem cells in a relevant extent. Based on these findings, AMD3100 inverted the beneficial effect of G-CSF and Diprotin A concerning the homing of circulating stem cells, cardiac remodeling (infarct size), heart function and survival (Kaplan-Meier curves). Additionally, G-CSF and Diprotin A application significantly improved neovascularization (represented by CD31 positive capillaries in the borderzone). Besides, dual stem cell therapy stimulated myocardial blood flow (SPECT analysis) which was antagonized by AMD. Finally G-CSF + Diprotin A administration effectively increased the amount of resident cardiac stem cells (FACS) which was reversed by AMD3100 as well.
Interpretation: Dual stem cell therapy mainly works by the SDF1-CXCR4-axis. This gives final proof that the extent of stem cell homing which is associated with increased myocardial perfusion and enhancement of resident cardiac stem cells is decisive for the success of this new therapeutic approach.
- © 2011 by American Heart Association, Inc.