S13-03 HOX transcription factor regulation of adult stem/progenitor cell behavior in response to injury

The purification, renewal and differentiation of native cardiac progenitors would form a mechanistic underpinning for unraveling steps for cardiac cell lineage formation, and their links to forms of congenital and adult cardiac diseases. Previously, we have reported the identification of isl1+ cardiac progenitors in postnatal rat, mouse and human myocardium (1). The discovery of native cardioblasts represents a genetically based system to identify steps in cardiac cell lineage formation and maturation in development and disease. A pivotal role for isl1+ progenitors in cardiovascular lineage diversification has also recently been reported by our laboratory (2), where muscle and endothelial lineage diversification arises from a single celllevel decision of a multipotent isl1(+) cardiovascular progenitor cell (MICP) that lies upstream of the post-natal isl1+ post-natal progenitor (2). The discovery of ES cell-derived MICPs suggests a strategy for cardiovascular tissue regeneration via their isolation, renewal and directed differentiation into specific mature cardiac, pacemaker, smooth muscle and endothelial cell types. Toward this goal, we have recently identified the Wnt/b-catenin pathway as a major component by which cardiac mesenchymal cells modulate the prespecification, renewal, and differentiation of isl1+ cardiovascular progenitors (3). This microenvironment can be reconstituted by a Wnt3a-secreting feeder layer with ES cell-derived, embryonic, and postnatal isl1+ cardiovascular progenitors. In vivo activation of b-catenin signaling in isl1+ progenitors of the secondary heart field leads to their massive accumulation, inhibition of differentiation and outflow tract (OFT) morphogenic defects. In addition, the mitosis rate in OFT myocytes is significantly reduced following bcatenin deletion in isl1+ precursors. Agents that manipulate Wnt signals can markedly expand isl1+ progenitors from human neonatal hearts, a key advance toward the cloning of human isl1+ heart progenitors. An update on the lineage fate map of islet heart progenitors into differentiated progeny (atrial, ventricular, smooth muscle, endothelial, SA nodal, AV nodal, etc.), including the recent characterization of a novel subset of reversible, bipotent Isl1+ atrial progenitors (4), will be provided. Challenges and opportunities in moving these discoveries towards a more therapeutic application will also be highlighted.