Cell Therapy in Hypertrophied and Remodeled Left Ventricle

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Cell Therapy in Hypertrophied and Remodeled Left Ventricle ABSTRACT The recent report of increased arrhythmic potential in hearts of non-human primates that received cell therapy causes serious concerns in field of cardiac stem cell therapy. Although the beneficial effects of human induced pluripotent stem cell (hiPSC) cellular therapy in hearts with post myocardial infarction (MI) have been recently reported in large animal studies, there could be additional benefits in applying a highly functional prefabricated cardiac muscle tissue equivalent over the MI surface. The specific aims (SA) are: SA1. To fabricate the larger and thicker human cardiac muscle patch (hCMP) using the hiPSC - cardiomyocytes (CM), - smooth muscle cells (SMC) and – endothelial cells (EC). We will fabricate a new type of larger and thicker hCMP and characterize its vascular, electrical, and mechanical properties in vitro. To increase the engraftment rate, we will generate hiPSC lines by engineering the hiPSC, in which human HLA Class I and/or Class II protein expression have been knocked out (HLA-KO -hCMP) by the gene editing technology. To reduce the arrhythmogenic potential, we will generate hiPSC lines by engineering the hiPSC to overexpress the gap junction protein: Cx43 (Cx43-hCMP). SA2. Using an immuno-suppressed porcine model of post-infarction LV remodeling, we will examine whether the transplantation of a prefabricated hCMP will result in better functional outcomes in reductions in LV scar bulging and wall stress, and improvements in myocardial bioenergetics and contractile function as compared to standard cell injection. We will compare the electrical stability of hearts with or without hCMP transplantation by continuously monitoring ECG for 8 weeks in vivo, and by conducting ex vivo dual optical mapping studies of electrical propagation. We will develop the completely non-invasive NMR technology that will provide unprecedented levels of sensitivity and signal-to-noise ratio (SNR) for P-31 NMR spectroscopy measuring the myocardial ATP hydrolysis rate with a precision of micro moles/s per gram of myocardium in a large bore magnet, which can be applied clinically. The findings of the studies will advance our understanding of the mechanisms of functional benefits of cell therapy in hearts with post-infarction LV remodeling, which can lead to better diagnostic and therapeutic modalities for CHF patients.