The proposed research will determine how autologous cell therapy for myocardial infarction (MI) can be impaired by age and the MI itself, and how this impairment can be avoided. We and others have demonstrated that implantation of mouse bone marrow cells (BMCs) into mouse hearts after myocardial infarction (MI) can prevent the decline in cardiac function that would otherwise occur. However, while such experiments typically use young healthy donor mice, MI patients undergoing autologous cell therapy tend to be older and have had an MI. We have recently observed that BMCs from old donor mice lack this therapeutic capacity. Furthermore, in several age groups, we have compared healthy donor mice with those that have themselves had an MI, and find that BMCs from donors with MI are also therapeutically impaired. We will answer the following questions: What causes this age- and infarct-related impairment of the BMCs? Do the negative effects of donor age and disease work through different mechanisms? How can these negative effects be prevented in our experimental model? Most importantly, can such a solution be directly applied to current clinical autologous BMC therapy of the aged, post-MI patient population? Our general hypothesis is that MI increases the inflammatory state of the bone marrow and adds a deleterious component to the otherwise-beneficial bone marrow, whereas age decreases the beneficial component. Specifically, we will test the hypothesis that MI causes a systemic inflammatory response that increases the number or activation state of inflammatory cells in the bone marrow. The hyper-inflammatory BMCs are deleterious to the myocardium, and the problem can be circumvented by removing these cells prior to implantation. We will also test the hypothesis that donor age reduces the beneficial component of the bone marrow responsible for the BMCs' therapeutic effect, in contrast with the proposed increase in the deleterious component caused by donor MI. The data generated in this R21 will be used as the basis of more long-term research proposals, aimed at understanding the mechanistic details of how different age and disease states differentially affect the therapeutic capacity of cells in the bone marrow, and how these potential problems can be avoided in clinical cell therapy procedures. PUBLIC HEALTH RELEVANCE: Bone marrow cell delivery to the heart is a promising new treatment for heart attacks and heart failure that is the subject of intense clinical and preclinical testing. Because these cells are taken from the patient's own bone marrow, we will study how the therapeutic potential of bone marrow cells can be decreased in older individuals and those with heart disease. We will also attempt to prevent these problems by removing specific cells that we predict have accumulated in the bone marrow as a result of the age and disease.