Objectives: The functional impairment of endothelial progenitor cells (EPCs) constitutes an important barrier for therapeutic angiogenesis. Here, we tested the hypotheses that a secreted version of acidic fibroblast growth factor (sp-FGF1) gene transfer may achieve functional improvement of EPCs and that autologous transplantation of sp-FGF1-modified EPCs can facilitate neovascularization in a porcine model of chronic myocardial ischemia.
Methods and results: EPCs were cultured from porcine peripheral blood and transduced with a recombinant adeno-associated virus encoding the sp-FGF1 gene (Td/FGF1-EPC). EPC function was evaluated 3 days after the gene transfer. In vitro, the sp-FGF1-modified EPCs displayed enhanced migration, tube formation and survival. Chronic myocardial ischemia was induced by the placement of an ameroid constrictor around the left circumflex coronary artery (LCx). Four weeks after ameroid placement, coronary angiography was performed and the cells were administered through the stenotic LCx. Myocardial perfusion defects were significantly reduced in animals transplanted with Td/FGF1-EPC compared to animals that received non-transduced EPCs or PBS (P<0.05) as assessed by SPECT 4 weeks after cell transplantation. Furthermore, the vascular density of ischemic myocardium was significantly increased in Td/FGF1-EPC transplanted animals (P<0.05). In addition, FGF1 protein expression was only detected in Td/FGF1-EPC transplanted animals.
Conclusions: The functional activities of EPCs were enhanced by sp-FGF1 gene transfer. Transplantation of this gene modified EPCs promoted neovascularization in a porcine model of chronic myocardial ischemia, indicating the therapeutic potential of this cell-based gene therapy strategy for the treatment of ischemic diseases.