Reprogramming of adult human fibroblasts into induced pluripotent stem (iPS) cells has generated significant excitement in the fields of regenerative medicine and stem cell biology. IPS cells avoid the ethical issues surrounding human embryonic stem (hES) cells, and also have the potential for being patient- and diseasespecific. However, at present the field is still in its infancy and significant concerns still exist over the efficiency, safety, and efficacy of iPS cell-based derivatives. This Stanford-Gladstone porposal on IPS Cells for the Understanding and Treatment of Heart Disease will investigate the following aspects: Specific Aim 1: To generate iPS cells from adult human adipose stromal cells (hASCs) using non-viral minicircle plasmids. Specific Aim 2: To compare human adipose stromal cell-derived induced pluripotent stem (hASC-iPS) cells and hES cells using network pathway analyses. Specific Aim 3: To significantly enhance the yield of hASC-iPS cells by mlRNA reprogramming approach. Specific Aim 4: To assess the fate of IPS cell-derived cardiomyocytes (iPSC-CMs) in vivo using novel molecular imaging technology. Specific Aim 5: To demonstrate that transplantation of iPSC-CMs in an infarcted heart model will lead to beneficial improvements in cardiac contractility, perfusion, and viability. To tackle these questions, we have assembled a team of interdisciplinary investigators. This team has broad expertise in areas such as stem cell biology, genetics, microRNA, surgery, small & large animal models, immunology, molecular imaging, and bioinformatics. Importantly, this team already has a rich history of collaborations already. Thus, we are confident that significant advances can be made over the next 7 years that will translate into iPS cell-based clinical therapies.