Abstract 16769: Sequential Treatment With Sustained-release of Basic Fibroblast Growth Factor Followed by Transplantation of Human Induced Pluripotent Stem Cell-derived Cardiac Tissue Improved Left Ventricular Function in a Rat Chronic Myocardial Infarction Model

Backgrounds: Cell-based therapy using human induced pluripotent stem (iPS) cell-derived Cardiac Tissue Sheets (CTSs) including cardiomyocytes and vascular cells shows promise for cardiac regeneration following myocardial infarction (MI). However, severe ischemia limits engraftment of cells after transplantation and it is still challenging to show functional advantages especially for chronic MI. Recently, we have generated Human iPS cell-derived Cardiac Tissue with 15-layered CTSs (HiCT-15) by inserting gelatin hydrogel (GH) microspheres between each CTS to overcome the stacking limitation of hypoxia. On the other hand, sustained-release of basic fibroblast growth factor (bFGF) using GH is known to improve left ventricular (LV) function in chronic MI through induction of angiogenesis. Here we aimed to take advantage of bFGF to enhance engraftment and efficiency of HiCT-15 in a rat chronic MI model. Methods: Studies were conducted in male athymic nude rats (12-16 weeks old) 4 weeks after ligation of the proximal left anterior descending coronary artery. GH sheets (GHSs) with or without bFGF (100μg) were implanted to MI models to evaluate the effect of bFGF-GHS on chronic scar tissue. Four weeks later, HiCT-15 with bFGF (100μg) were transplanted to the rats received bFGF-GHS treatment. Cardiac functions were evaluated with echocardiogram. Results: Four weeks after treatment, bFGF-GHS significantly improved cardiac contractile function accompanied with neovascularization. Immunohistochemical studies revealed that bFGF-GHS increased collagen III/I ratio indicating attenuation of solid scar tissue. Quantitative RT-PCR results showed a decrease of collagen I expression within border ischemic zone. HiCT-15 transplantation following bFGF-GHS treatment further promoted systolic function compared to the baseline of bFGF-GHS treatment. The beneficial effects sustained 12 weeks till sacrifice. Conclusion: Sustained-release of bFGF altered collagen distribution and increased angiogenesis in ischemic myocardium, thereby enhanced the efficiency of HiCT transplantation. The sequential treatment of sustained-release of bFGF and HiCT may be a promising treatment for heart failure due to chronic pathology such as ischemic cardiomyopathy.