Current therapeutics applied to patients with heart failure, with the exception of cardiac transplantation, fail to address the quantitative deficiency of cardiomyocytes that compromises ventricular performance in many of these individuals. A successful biotechnological strategy to add new cardiomyocytes to the damaged heart would meet a major clinical need. The investigators propose to identify or engineer cardiogenic cells that, following transplantation to the myocardial wall, are capable of proliferation, differentiation, and correct pattern formation in a manner sufficient to improve cardiac function. The approach is novel, systematic and multidisciplinary, and will be constructed upon an expanding foundation of new knowledge concerning molecular mechanisms of cardiogenesis in mammalian and amphibian embryos, and of myogenic repair in adult skeletal muscles. The experimental plans have been designed to take maximum advantage of emerging technologies and powerful model systems. The participating investigators have expertise in diverse areas of science relevant to this research including biophysics, developmental biology, molecular genetics, and clinical cardiology, but they work within a single institution and this joint proposal is enhanced by pre-existing and ongoing scientific relationships. The investigators propose to gain, in parallel, a more detailed understanding of the biology of skeletal myogenic stem cells (satellite cells) and how they contrast with myogenic precursor cells (cardioblasts) from the developing heart, specifically in the context of tissue regeneration. Putative cardiogenic cells will be isolated from early embryos or from embryoid bodies in culture, or engineered by transdifferentiation of skeletal myogenic cells. Each candidate cell type will be characterized comprehensively with respect to its repertoire of expressed genes, and its capacity to promote effective cardiogenic tissue repair following transplantation into ectopic locations or into the myocardial wall of cardiomyopathic animals. Each round of testing will be followed by the application of enhancing strategies, chosen on the basis of results acquired from preceding analyses within each of the separate components of this proposal, and designed to optimize the tissue repair process. In this iterative manner, the investigators expect to gain knowledge that ultimately will foster the development of cell transplantation strategies to promote myocardial repair in human patients afflicted with heart failure.
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