Due to the limited regenerative capacity of the heart, an ischemic event often leads not only to myocardial infarction but also to post-infarction remodeling and the development of congestive heart failure. Most therapeutic techniques are aimed at limiting infarct size by restoration of vessel patency and reducing myocardial work. Recently, mesenchymal stem cells (MSCs), derived from bone marrow, have been transplanted in infarcted myocardium to regenerate and repair damaged myocardium with the hope of restoring normal cardiac function. Since ischemic heart disease is the largest cause of morbidity and mortality in the Western world, therapeutic methods designed to regenerate irreversibly injured myocardium could have enormous health care benefits. However, many of the mechanisms of myocardial regeneration from MSCs have not yet been elucidated. Recently, our group has demonstrated the ability to label MSCs with agents that are visible by Magnetic Resonance Imaging (MRI). The ability to track the fate of MSCs after transplantation, using the high spatial and temporal resolution of MRI, will enable us to optimize protocols (e.g., timing of injection, location of injection, and mode of delivery) and study therapeutic response of stem cell transplantation using non-invasive techniques such as MR tagging. Ultimately, the transplantation of stem cells in patients will require techniques, such as MRI, that can monitor noninvasively tissue migration and evaluate the impact on infarct size and cardiac function. Another concern with clinical transplantation in patients is whether autologous MSCs provide the same degree of robust engraftment as allogenic MSCs. Because a readily available supply of autologous MSCs could be provided using cell culture and freezing techniques analogous to blood banks, allogenic MSC transplantation would be preferable to autologous MSC transplantation. Thus, in this research project, we propose to determine the optimal protocols for labeled-MSC delivery using non-invasive MR imaging techniques in a swine model of myocardial infarction. Furthermore, we will determine in our animal model whether the allogenic MSCs used for transplantation elicit an immunogenic response that in turn will decrease therapeutic efficacy compared to autologous MSCs. Because these studies will be developed in a large animal model, these techniques will be readily transferable to future studies in patients with ischemic heart disease.
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