Selection and Electromechanical Maturation of Ventricular Mycocytes from hiPSs

Human induced pluripotent stem cells (hiPSCs) represent a potentially inexhaustible source of human cardiomyocytes, and the Penn/UW Consortium has recently developed methods that greatly improve the efficiency of hiPSC generation, making these cells an even more attractive candidate for the development of autologous cell-based cardiac therapies. However, existing preparations of hiPSC-derived cardiomyocytes suffer from two major limitations. First, while large quantities of unambiguous cardiomyocytes can be derived from hiPSCs, those myocytes include cells with distinct ventricular, atrial and nodal action potential properties. Second, even hiPSC-derived ventricular myocytes are immature and show inadequate capacity for force generation and significant electrophysiological mismatch with adult myocardium, limiting their utility for applications in cardiac repair. Hence, the overall goals of this ancillary project will be to obtain mature ventricular cardiomyocytes from hiPSCs and to apply novel, high-throughput methods for assessing and promoting their electromechanical maturation. In Aim 1, we will develop a genetic selection system suitable for the scaled production and enrichment of ventricular cardiomyocytes from multiple human iPSC lines. Our group was the first to develop and validate a cardiac subtype-specific genetic label in human ESCs and here will leverage that experience, as well as available expertise in efficient hiPSC generation, scaled production of hiPSC-derived cardiomyocytes and cardiac electrophysiology. In Aim 2, we will use novel techniques to assess and manipulate the electromechanical phenotype of hiPSC-derived cardiomyocytes. Our group has developed microfabricated tissue gauges, which will be used to directly and non-invasively measure the force generated by hiPSC-derived cardiomyocytes. When combined with optical voltage recordings, this technology will allow us to comprehensively and non-invasively assess the changing functional properties of these myocytes over time. It will also be used to compare the phenotype of subtype-enriched populations from Aim 1 and to test the hypothesis that the maturation of ventricular iPSC-CMs can be enhanced by pulsatile electrical conditioning and/or changes in their mechanical environment. 

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