We have recently identified and characterized a cardiac stem cell (CSC) in the adult human heart. Human CSCs express the stem cell antigens c-kit, MDR1 and Sca-1-like alone or in various combinations. Therefore, one of the major objectives of this application is to determine whether the expression of distinct stem cell epitopes has a functional counterpart resulting in different degrees of CSC growth and differentiation. A number of in vitro assays will be implemented to demonstrate the self-renewal property of these cells and their ability to give rise to committed progenies. This information is crucial for the recognition of the most appropriate autologous CSC preparation to be employed in the treatment of the diseased human heart. To achieve this goal, the effects of the type, duration and severity of the cardiac disease, and the age and gender of the patient on his/her own resident CSC classes will be defined by in vitro protocols to detect the best cell(s) to be employed in each case. To demonstrate whether the criteria introduced in the separations of the CSC categories are valid, the selected CSC populations will be injected in infarcted immunodeficient rats and the extent of myocardial regeneration promoted by each CSC class will be measured. Another important aspect of this research is to determine whether these strategies that may lead to the repair of the acutely damaged heart are equally effective, less effective or completely ineffective in the regeneration of chronic scarred myocardium. Additionally, we will address the issue whether the utilization of CSCs is preferable to the use of cells already committed to the myocyte, endothelial cell and smooth muscle cell lineages or a pool of CSCs and partially differentiated cells provides a greater and faster regenerative response. The committed cells may have a reduced capacity to proliferate but may acquire more rapidly the adult phenotype. Ultimately, CSC/progenitor cell therapy will be established on an individual basis to maximize the efficacy of this novel approach for the management of heart failure in each case.