Mycardial Repair Using Human iPSC Derived Cardiac Muscle Patch

描述（由申请人提供）：尽管最近已经报道了细胞治疗对心肌梗死后左室重构（MI）心脏的有益作用，但在心肌梗死表面应用预制心肌组织等效物可能会有额外的益处。我们的目标是开发一种“心肌贴片”，通过将人类心肌细胞、内皮细胞和来源于人类诱导多能干细胞（hiPSC）的平滑肌细胞包裹在3D多孔纤维蛋白生物材料中形成。心肌贴片能有效预防左室梗死瘢痕膨出，减轻BZ壁应力，改善心肌生物能量学。心血管生理学中最重要的问题之一是ATP的产生和利用的速度如何在体内心脏中被调节，以及这种速度的限制如何导致衰竭心脏的收缩功能障碍。准确评价心肌ATP周转率（ADP+Pi）

DESCRIPTION (provided by applicant): Although the beneficial effects of cellular therapy in hearts with post myocardial infarction LV remodeling (MI) have been reported recently, there could be additional benefit in applying a prefabricated cardiac muscle tissue equivalent over the surface of myocardial infarct. We aim to develop a "cardiac muscle patch", formed by entrapping human cardiac myocytes, endothelial cells and smooth muscle cells that derived from human induced pluripotent stem cells (hiPSC) in a 3D porous fibrin biomaterial. A "cardiac muscle patch" could effectively prevent LV infarct scar bulging, reduce the BZ wall stress and improve the myocardial bioenergetics. One of the most significant problems in cardiovascular physiology is how the rate of ATP production and utilization is regulated in the in vivo heart and how the limitation of this rate may contribute to contractile dysfunction in failing hearts. The accurate evaluation of myocardial ATP turnover rates (ADP+Pi ATP), has generally not been successful because the level of myocardial free inorganic phosphate (Pi) in the in vivo heart is too low to be measured directly. We aim to demonstrate a novel double saturation transfer (MRS-MST) method enabling us to calculate the ATP hydrolysis rate without measuring Pi levels, which overcomes the primary barrier in determining the ATP turnover rate in vivo. Although reports of human brain function imaging at high field (>7Tesla, [T]), have generated significant novel findings that advance the field of neuroscience, cardiac MRI and spectroscopy for humans at 7T is nonexistent because of the lack of coil engineering. The specific aims (SA) are: SA1. To fabricate and characterize the human cardiac muscle patch (hcMP). We will differentiate human induced pluripotent stem cells (hiPSC) into cardiomyocytes (CM), endothelial cells (EC), and smooth muscle cells (SMC); and use these cardiac cells to fabricate an hcMP and characterize the mechanical properties of the hcMP during baseline and in response to pacing. SA2. To examine novel delivery of CM-, EC- and SMC-hiPSC for myocardial repair using an immuno-suppressed swine model of post infarction LV remodeling. We will examine whether the transplantation of a prefabricated hcMP will result in reductions in LV scar bulging and wall stress, and improvements in myocardial bioenergetics and contractile function. We will also compare the electrical stability of hearts with or without C transplantation by using a Loop Recorder to monitor EKGs 24/7 for 8 weeks, and by conducting a PES study. SA3.To examine myocardial bioenergetics in a high field magnet with previously unattainable levels of capability, sensitivity and spatial localization. 3a) To demonstrate a novel NMR MRS-MST technology that can measure the myocardial ATP turnover rate in the in vivo heart. 3b) To develop the first body coil for a 7T/125 CM large-bore magnet that can be used to perform 1H- and 31P- cardiac NMR studies for measurements of myocardial function, perfusion, and ATP turnover rate; The success of this coil will enable these methods to be readily applied in a clinical setting and provide an entirely new and valuable method for monitoring myocardial function, metabolism, and perfusion in the human heart.