Preclinical Evaluation of the Engineered Stem Cell Chemokine Stromal Cell-Derived Factor 1-alpha Analogue in a Translational Ovine Myocardial Infarction Model
Rationale: Following myocardial infarction (MI) there is an inadequate blood supply to the myocardium and the surrounding borderzone becomes hypocontractile.
Objective: To develop a clinically translatable therapy, we hypothesized that in a preclinical ovine model of MI, the modified endothelial progenitor stem cell (EPC) chemokine, engineered stromal cell-derived factor 1-alpha analogue (ESA), would induce EPC chemotaxis, limit adverse ventricular remodeling, and preserve borderzone contractility.
Methods and Results: Thirty six adult male Dorset sheep underwent permanent ligation of the left anterior descending coronary artery, inducing an anteroapical infarction and were randomized to borderzone injection of saline (n=18) or ESA (n=18). Ventricular function, geometry, and regional strain were assessed using cardiac magnetic resonance imaging and pressure-volume catheter transduction. Bone marrow was harvested for in-vitro analysis, and myocardial biopsies were taken for mRNA, protein and immunohistochemical analysis. ESA induced greater chemotaxis of EPCs compared to saline (p<0.01), and was equivalent to recombinant stromal cell-derived factor 1-alpha (p=0.27). Analysis of mRNA expression and protein levels in ESA treated animals revealed reduced MMP-2 in the borderzone (p<0.05), with elevated levels of TIMP-1 and elastin in the infarct (p<0.05), while immunohistochemical analysis of borderzone myocardium showed increased capillary and arteriolar density in the ESA group (p<0.01). Animals in the ESA treatment group also had significant reductions in infarct size (p<0.01), increased maximal principle strain in the borderzone (p<0.01), and a steeper slope of the end systolic pressure volume relationship (p=0.01).
Conclusions: The novel, biomolecularly-designed peptide ESA induces chemotaxis of EPCs, stimulates neovasculogenesis, limits infarct expansion, and preserves contractility in an ovine model of MI.
- endothelial progenitor cells
- cardiac magnetic resonance imaging
- ventricular wall stress
- reverse remodeling
- Received October 21, 2013.
- Revision received December 19, 2013.
- Accepted December 23, 2013.