Myocardial CXCR4 Expression Is Required for Mesenchymal Stem Cell Mediated Repair Following Acute Myocardial Infarction
Background—Over-expression of SDF-1 in injured tissue leads to improved end-organ function. In this study we quantify the local trophic effects of mesenchymal stem cell (MSC) SDF-1 release on the effects of MSC engraftment in the myocardium after acute myocardial infarction (AMI).
Methods and Results—Conditional cardiac myocyte CXCR4 (CM-CXCR4) null mice were generated using tamoxifen inducible cardiac specific cre by crossing CXCR4 floxed with MCM-cre mouse. Studies were performed in littermates with (CM-CXCR4 null) or without (control) tamoxifen injection 3 weeks before AMI. One day after AMI mice received 100,000 MSC or saline via tail vein. We show αMHC-MerCreMer and the MLC-2v promoters are active in cardiac progenitor cells (CPC). MSC engraftment in WT mice decreased TUNEL+ CM (-44%, p<0.01), increased CPC recruitment (100.9%, p<0.01) and increased cardiac myosin positive area (39%, p<0.05) at 4, 7 and 21 d after AMI, respectively. MSC in WT resulted in 107.4% (p<0.05) increase in ejection fraction compared to 25.9% (p=NS) increase in CM-CXCR4 null mice. These differences occurred despite equivalent increases (16%) in vascular density in response to MSC infusion in WT and CM-CXCR4 null.
Conclusions—These data demonstrate that the local trophic effects of MSC require CPC- and CM-CXCR4 expression and are mediated by MSC SDF-1 secretion. Our results further demonstrate and quantify for the first time a specific paracrine mechanism of MSC engraftment. 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.
- Received November 25, 2011.
- Accepted May 23, 2012.
- Copyright © 2012, American Heart Association, Inc. All rights reserved. Unauthorized use prohibited