Notch signaling respecifies the hemangioblast to a cardiac fate

To efficiently generate cardiomyocytes from embryonic stem (ES) cells in culture it is essential to identify key regulators of the cardiac lineage and to develop methods to control them. Using a tet-inducible ES cell line to enforce expression of a constitutively activated form of the Notch 4 receptor, we show that signaling through the Notch pathway can efficiently respecify hemangioblasts to a cardiac fate resulting in the generation of populations consisting of more than 60% cardiomyocytes. Microarray analyses revealed that this respecification is mediated, in part, through the coordinated regulation of the BMP and Wnt pathways by Notch signaling. Together, these findings have uncovered a potential novel role for the Notch pathway in cardiac development and in doing so provide a new approach for generating large numbers of cardiac progenitors from ES cells.