The general goal of this proposal is to gain a better understanding of the origin, identity, and biological properties of mammalian cells that when properly stimulated are capable of regenerating the adult and senescent myocardium. This objective is based on the premise that adult and senescent myocardium contains a small population of cells with the characteristics and behavior of cardiac stem cells (CSCs): they are clonogenic, self-renewing and multipotent. The progeny of a single CSC isolated from an aging myocardium can differentiate into myocytes, smooth muscle and endothelial cells. When injected or activated in a post-ischemic myocardium, these cells reconstitute a functional ventricular wall. A decrease in their number and/or function might be one of the causal factors in the altered performance of the old and senescent heart. Nothing is known about the origin of the CSCs. Data from animals and humans show a continuous trafficking of these cells between myocardium and extra-myocardial tissues. The bone marrow contains a population of cells with similar characteristics and a several other extra-cardiac cell types have been shown able to differentiate into cardiocytes. We will test the hypothesis that CSCs appear late in development, reach the myocardium through the circulation, and are constantly replenished to allow a continuous turnover of the normal and pathological heart. Once we have established the origin of the CSCs and determined their cardiogenic potential, we initiate the dissection of the genetic regulators of their differentiation, starting by identifying the role of """"""""stem cell marker genes"""""""" in the production of the cardiogenic phenotype. We will continue by testing the hypothesis that differentiation of CSCs in large measure recapitulates early cardiac ontogeny and requires the down regulation of the canonical Wnt pathway as well as the upregulation of members of the TGFbeta family of regulators, namely certain bone morphogenetic protein (BMPs) genes.
Three Specific Aims will be pursued: 1.- To ascertain the origin and relationship among the different adult cells capable of producing the cardiogenic lineages and to compare their myocardial regenerating potential in the post-ischemic heart. 2.- To elucidate the role of """"""""stem cell marker genes"""""""" on the myocardial regenerating capability of the CSCs. 3.- To initiate the dissection of the signaling pathways responsible for the maintenance of the differentiated state of the CSCs and their differentiation under normal conditions, in aging and in response to ischemia. The information obtained from these experiments will be used to devise more effective ways of fostering myocardial regeneration through the coaching of the CSCs.
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