In clinical trials, functional benefits of cell therapy for repair of the damaged heart have been moderate and variable. Frequently, only a small fraction of transplanted cells engrafts in injured myocardium. This limits therapeutic efficacy and may explain variability of results. There is a need for improved understanding of therapeutic mechanisms and for improved selection of candidates. Specific noninvasive imaging techniques, which go beyond assessment of structure and function of the heart, are promising new means for improving cell therapy.In this proposal, we aim at developing image-based strategies to facilitate stem cell engraftment. The myocardial microenvironment is considered to be a critical contributor to engraftment. It constitutes a suitable target for molecular imaging. Our central hypothesis is that molecular-targeted radionuclide imaging prior to cell delivery can characterize an optimal biologic environment which is supportive of cell engraftment after delivery, and thus predictive of successful myocardial regeneration. This hypothesis will be tested in 3 specific aims, using an array of noninvasive imaging techniques to characterize myocardial biology, to track stem cells and to determine functional and structural effects of cell delivery.Aim 1 will define the role of tissue perfusion and viability for successful engraftment of bone-marrow derived stem cells. Aim 2 will investigate the role of neurohumoral activation after ischemic damage for successful cardiac stem cell engraftment. And in aim 3, knowledge derived in a rat model in aims 1 and 2 will be translated to a large animal model and clinical camera systems.These studies will provide unique new insights into myocardial regeneration. They will also deliver imaging techniques for assistance in therapeutic decision making. The ultimate goal of the project is to optimize cell therapeutic benefit based on imaging of individual disease biology.