Stem Cell Factor Gene Transfer Improves Cardiac Function After Myocardial Infarction in Swine

Abstract

Background Stem cell factor (SCF), a ligand of the c-kit receptor, is a critical cytokine which contributes to cell migration, proliferation, and survival. It has been shown that SCF expression increases after myocardial infarction (MI) and may be involved in cardiac repair. The aim of this study was to determine whether gene transfer of membrane-bound human SCF improves cardiac 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 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% relative to baseline 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. Histological analyses confirmed the recruitment of c-kit+ cells as well as a reduced degree of apoptosis one week after Ad.SCF injection. In addition, increased capillary density compared to pigs treated with Ad.β-gal was found at three months and suggests an angiogenic role of SCF. Conclusions Local over-expression of SCF post-MI induces the recruitment of c-kit+ cells at the infarct border area acutely. In the chronic stages, SCF gene transfer was associated with improved cardiac function in a pre-clinical model of ischemic cardiomyopathy.

Left Ventricular Unloading Using an Impella CP Improves Coronary Flow and Infarct Zone Perfusion in Ischemic Heart Failure

“…These data are consistent with previously published reports using a similar approach to induce ischemic HF. 13,15 At 2 weeks after MI, coronary angiograms revealed TIMI 2 flow in 8 animals and TIMI 3 flow in 2 animals (1 each in Impella and SNP groups) in the LAD.…”

Stimulatory Effects of Mesenchymal Stem Cells on cKit + Cardiac Stem Cells Are Mediated by SDF1/CXCR4 and SCF/cKit Signaling Pathways

“…Based on previous reports 23, 37 , but also due to the white-spotting phenotype that is often produced from mutations in the cKit and SCF loci, we expected that the SCF/cKit signaling pathway would affect CSCs mobilization by MSCs. However, we did not find evidence that modulation of SCF/cKit is sufficient to control CSC mobilization.…”

Plasma stem cell factor levels are associated with risk of cardiovascular disease and death

“…SCF is the ligand for c-kit, a receptor expressed by many types of SC [1]. Moreover, local injection of SCF, as well as cardiomyocyte-specific overexpression of SCF, has improved cardiac function after MI in mice [10,29,30]. A number of studies have reported evidence for cardiomyocyte renewal in the adult mammalian heart [3,27,28], but their origin, rate of turnover and physiological significance remains controversial.…”

“…Stem cell factor plays a critical role in regulating the maintenance and expansion of hematopoietic SC in the BM where it is expressed by stromal cells and released through the action of matrix metalloproteinase 9 (MMP-9) [4][5][6]. Adult c-kit-positive cardiac SC are required for regeneration and repair in mouse models of myocardial damage [9], and SCF gene transfer has been shown to improve cardiac function after myocardial infarction (MI) in swine [10]. Adult c-kit-positive cardiac SC are required for regeneration and repair in mouse models of myocardial damage [9], and SCF gene transfer has been shown to improve cardiac function after myocardial infarction (MI) in swine [10].…”