Myocardial CXCR4 expression is required for mesenchymal stem cell mediated repair following acute myocardial infarction.

Myocardial CXCR4 expression is required for mesenchymal stem cell mediated repair following acute myocardial infarction.

Dong Feng; Harvey James; Finan Amanda; Weber Kristal; Agarwal Udit; Penn Marc S

Circulation

2012

2012-07

BACKGROUND: Overexpression of stromal cell-derived factor-1 in injured tissue leads to improved end-organ function. In this study, we quantify the local trophic effects of mesenchymal stem cell (MSC) stromal cell-derived factor-1 release on the effects of MSC engraftment in the myocardium after acute myocardial infarction. METHODS AND RESULTS: Conditional cardiac myocyte CXCR4 (CM-CXCR4) null mice were generated by use of 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 acute myocardial infarction. One day after acute myocardial infarction, mice received 100,000 MSC or saline via tail vein. We show alpha-myosin heavy chain MerCreMer and the MLC-2v promoters are active in cardiac progenitor cells. MSC engraftment in wild-type mice decreased terminal deoxynucleotidyltransferase-mediated dUTP nick-end labeling positive CM (-44%, P\textless0.01), increased cardiac progenitor cell recruitment (100.9%, P\textless0.01), and increased cardiac myosin-positive area (39%, P\textless0.05) at 4, 7, and 21 days after acute myocardial infarction, respectively. MSC in wild-type mice resulted in 107.4% (P\textless0.05) increase in ejection fraction in comparison with 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 wild-type and

Animals; Apoptosis/physiology; Cardiac/cytology/physiology; Cell Movement/physiology; Chemokine CXCL12/*metabolism; Coronary Circulation/physiology; CXCR4/*genetics/metabolism; Gene Expression/physiology; Green Fluorescent Proteins/genetics; Inbred C57BL; Knockout; Mesenchymal Stem Cell Transplantation/*methods; Mesenchymal Stem Cells/*metabolism; Mice; Myocardial Infarction/genetics/pathology/*therapy; Myocardium/cytology; Myocytes; Paracrine Communication/physiology; Receptors; Ventricular Remodeling/physiology

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