The use of cell therapies for heart disease has increased steeply over recent years. Initial results suggest modest positive effects on cardiac function but with limited graft survival. We predict that progress will require a focused approach to understanding of the biological mechanisms. To achieve this goal we have formed a multi-disciplinary consortium of labs at the University of Minnesota that includes specialists in embryonic and iPS cell biology, cardiac development, cardiac physiology, myocardial repair, in vivo imaging and large animal research technology. The research plan includes three synergistic and overlapping projects. The first will better define development of hematopoietic and cardiac progenitor cells from ES and iPS cells, by exposing cells to selected environments to mimic the effects of normal development, and by directing differentiation by the overexpression of specific transcription factors. These studies will clarify the developmental relationship between progenitor cells with common hematopoietic and vasculogenic properties (hemangioblasts) and those with cardiogenic and vasculogenic properties (cardiac progenitors). They will also provide a pipeline of cells, and of relevant developmental biology information, for the other projects. The second project will utilize the unique decellularized heart model available at the University of Minnesota to investigate the mechanisms for cardiac colonization by progenitor cells of different developmental stages. The role of resident cells will be established by comparison of the decellularized model with the perfused heart model. Furthermore, the role of systemic factors will be established by comparing both of these to in vivo models. The third project will build on the results of the first two to establish protocols for the performance of successful immunocompatible grafts. We will use either individual-specific iPS cells to produce the graft, or a tissue graft and hematopoietic graft derived from the same cell source. Grafts may be of cells, recellularized tissue patches, or recellularized entire hearts. The most promising protocols will be tested using a swine model of postinfarction left ventricular remodeling, which is well established at the University. The function of grafts will be monitored using novel magnetic resonance methods which will allow the accurate tracking of cells and measurement of important physiological parameters. Collectively, these strategies will utilize novel models to define the mechanisms that govern the regeneration of heart and blood by progenitor cell populations as a prelude for new cell-based regenerative medicine therapies.