The purification, renewal and differentiation of native cardiac progenitors would form a mechanistic underpinning for unravelling steps for both cardiac lineage formation and regeneration, and their links to forms of congenital and adult cardiac diseases. Taking advantage of a developmental lineage marker for undifferentiated cardiogenic precursors as a requirement for a heart-specific origin, we have identified in the post-natal heart a novel cardiac cell type. The LIM-homeodomain transcription factor isle t-1 (isl1) marks a cell population that makes a substantial contribution to the embryonic heart. Tamoxifen-inducible Cre/lox technology enables selective marking of this progenitor cell population including its progeny, at a defined time, and purification to relative homogeneity. Co-culture studies with neonatal myocytes indicate that isl1+ cells display a highly efficient conversion to a mature cardiac phenotype. Our hypothesis is that isl1 is a unique marker to isolate a population of cardiac precursors f rom the intact heart that can differentiate in vitro into functioning myocytes and to generate cardiogenic precursors from mouse embryonic stem cell systems during cardiogenesis. Our specific aims are: 1) To determine therapeutic efficacy of isl1+ cardiobl asts by transplantation into normal and diseased myocardium utilizing mouse models. 2) To establish optimal conditions for generation and differentiation of isl1+ progenitors in the mouse embryonic stem cell system. 3) To identify specific molecular pathwa ys that drive the differentiation of isl1+ cardioblasts into specific cardiomyocyte cell lineages. (Laugwitz K-L, Moretti A, Lam J, Gruber P, Chen Y, Woodard S, Lin L, Cai C-L, Lu M, Reth M, Platoshyn O, Yuan J, Evans S & Chien KR. Postnatal isl1+ card ioblasts enter fully differentiated cardiomyocyte lineages. Nature 433: 647-653 (2005).
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