Charles Murry, MD, PhD

Comparative Analysis of Human iPS Cells to Generate Vascularized Cardiac Tissue Constructs
University of Washington, Seattle, WA
Charles Murry, MD, PhD – $50,000

Most pediatric hyperthrophic cardiomyopathies and many dilated cardiomyopathies have a genetic basis, and the only definitive treatment is cardiac transplantation, which is limited by organ availability. Stem cells provide a novel source of cardiomyocytes that can be transplanted to repair the cardiomyopathic heart. Embryonic stem (ES) cells can robustly generate cardiomyocytes, and transplanting ES cell-derived human cardiomyocytes prevents heart failure in cardiac injury models. However, ES cells are ethically controversial and may face immune rejection. Cellular reprogramming of adult fibroblasts to "induced pluripotent stem (iPS) cell" state has the ability to differentiate into many different cell types and potentially removes the immune barriers for transplantation. The long term goals of this study are to derive iPS cells from pediatric cardiomyopathy patients with defined mutations, and then use iPS cell-derived cardiomyocytes to understand cardiomyopathy, screen new drugs for its treatment, and to develop genetic correction strategies using homologous recombination. The study will first characterize the cardiovascular differentiation potential of three different human iPS cell lines. This will involve directing the differentiation of iPS cells to cardiomyocytes and endothelium using protocols established for human ES cells, and comparing yields, purities and gene expression patterns of the resulting cardiovascular cells to results from well-characterized human ES cell lines. Then human iPS cell-derived cardiomyocytes and vascular cells will be used to generate 3-dimensional tissue engineered constructs of vascularized human myocardium that can be used for assessing contractile function and potentially for therapeutic applications. These studies will form the basis for derivation of cardiovascular cells from patients with pediatric cardiomyopathy, shedding light on disease mechanisms and possibly establishing a novel therapeutic platform.