| Heart failure is one of the leading causes of morbidity and mortality in the United States today. Medical advances have significantly improved a patient's prognosis, but remain limited due to our failure to improve cardiac output and contractility. Cardiac cell therapy has the potential to address these functional deficits. While ESC/iPSCs-derived cardiomyocytes are ideal candidates for cell therapy, development of an efficient method for the generation of cardiac progenitors or cardiomyocytes is paramount.;Through a series of in vitro and in vivo experiments, we addressed multiple signals and pathways that are involved in the induction and expansion of cardiac progenitors. We identified a large number of factors that affect the efficiency of cardiac differentiation, and determined the timing and roles that certain Wnt and TGF-b family members play in the specification of cardiac progenitors in vitro. In addition, we uncovered a previously unrecognized role of fibronectin in the induction of cardiac mesoderm in vitro and in vivo. We showed that fibronectin acts as a morphogen by modulating Wnt signaling through an integrin-dependent mechanism. Lastly, we discovered an intricate balance between Notch and Wnt signaling that controls the proliferation and differentiation decision of cardiac progenitors through direct transcriptional control of numerous prodifferentiation cues. Expanding on the Notch-Wnt interaction, we demonstrated the generalizability of this interaction to numerous stem cells and cancer cells, elucidating detailed mechanisms behind this novel post-translational control of beta-catenin by the Notch Receptor. |
