Abstract 17141: Stem Cell Factor Gene Transfer in a Swine Model of Ischemic Cardiomyopathy is accompanied by decreased apoptosis and proliferating cKit+ cell
Background: Stem cell factor (SCF), a ligand of the c-kit receptor, is a critical cytokine which contributes to cell migration, proliferation, and survival. Because SCF expression increases after myocardial infarction (MI), cKit+ progenitor cells may be recruited to the site of injury, play key roles in gain of function and myocardial repair. The aim of this study was to identify key pathways involved in cardiac gain of function in a large animal model of MI.
Methods and Results: A transmural MI was created by implanting an embolic coil in the left anterior descending coronary artery in Yorkshire pigs. One week after the MI, the pigs received direct intramyocardial injections of either a recombinant adenovirus encoding for SCF, (Ad.SCF, n=9) or β-gal (Ad.β-gal, n=6) into the infarct border area. At three months post-MI, ejection fraction increased by 12% after Ad.SCF therapy, whereas it decreased by 4.2% (P=0.004) in pigs treated with Ad.β-gal. Preload-recruitable stroke work was significantly higher in pigs after SCF treatment (Ad.SCF, 55.5±11.6 mmHg vs Ad.β-gal, 31.6±12.6 mmHg, P=0.005), indicating enhanced cardiac function after SCF gene therapy. One week post SCF gene delivery c-kit+ cells were histologically detected in the peri-infarct zone. Some relatively isolated cKit+/CD45+ and cKit+/VEGFR2+ cells were detected. Much greater populations of cKit+/CD45- and cKit+/VEGFR- cells were detected suggesting that many progenitors had origins other than bone marrow. Furthermore, detailed 3D microscopic analyses revealed pairs of partially superimposed nuclei with either one or both cell membranes expressing ckit. Rare cardiomyocytes, in the peri-infarct zone were undergoing cell cycling. These results are consistent with both cell division and fusion between one or more cKit+ cells. At this same time point, there was also reduced apoptosis in the peri-infarct zone. Three months after SCF gene delivery increased capillary density was apparent suggesting that SCF may enhance angiogenesis.
Conclusion: Local over-expression of SCF post-MI induces the recruitment of c-kit+ cells at the infarct border area and results in improved cardiac function in a pre-clinical model of ischemic cardiomyopathy.
Author Disclosures: K. Fish: None. K. Ishikawa: None. J. Aguero: None. L. Tilemann: None. D. Jeong: None. L. Liang: None. L. Fish: None. E. Yaniz-Galende: None. K. Zsebo: Employment; Significant; 100% gross income. Ownership Interest; Significant; 2%. H. Roger: Ownership Interest; Significant; Celladon.
- © 2014 by American Heart Association, Inc.