Abstract 19915: Role of Myocardial CXCR4 Expression in Mesenchymal Stem Cell Mediated Repair in Myocardial Infarction
Introduction: Stromal cell-derived factor (SDF)-1 binding to CXCR4 inhibits cell death. Mesenchymal stem cells (MSC) engraftment after acute myocardial infarction (AMI) inhibits cardiac myocyte (CM) cell death and MSC express SDF-1. We wanted to determine the importance of cardiac myocyte CXCR4 (CM-CXCR4) expression on MSC mediated repair after AMI.
Methods: CM-CXCR4 null mice were generated using tamoxifen inducible cardiac specific cre by crossing the CXCR4 floxed with the MCM-cre mouse. All studies were performed in littermates who did (CM-CXCR4 null) or did not (WT) receive tamoxifen at least 3 weeks before AMI. No differences were observed at baseline or 21 d after AMI between the CM-CXCR4 null and WT. Mice underwent AMI and were randomly selected to receive either 100,000 GFP positive MSC or saline via tail vein injection 1 d later.
Results: In saline treated mice there was no difference between WT and CM-CXCR4 null in any parameters measured. There was a similar level of MSC engraftment in WT and CM-CXCR4 null mice following MSC infusion. MSC engraftment led to a significant reduction (44%) of TUNEL positive CM in WT but only a 23% reduction in CM-CXCR4 null mice (p<0.01). Decreased CM death was reflected at day 21 in a 39% increase in cardiac myosin-positive area within the infarct zone in WT compared to a 9% increase in CM-CXCR4 null mice (p<0.05). Consistent with improved CM survival, MSC infusion led to a 90% (p<0.05) increase in ejection fraction in WT compared to a 37% (p=NS) increase in CM-CXCR4 null mice despite similar levels of an increase (16%) in vascular density in the absence or presence of CM-CXCR4.
Conclusions: CM- CXCR4 expression is critical for the MSC mediated inhibition of myocyte apoptosis post-MI; in the absence of CM-CXCR4 expression there is a significant loss of functional benefit in MSC mediated repair despite equal increases in vascular density between groups.
- © 2010 by American Heart Association, Inc.