Cardiovascular disease is the most prevalent disease, and mammalian hearts only have a very limited ability to regenerate, which prevents functional repair and restorations of diseased hearts.Stem cell therapies, including using embryonic stem cells (ESCs), induced pluripotent stem cells (iPS), and cardiac progenitor cells, have been implicated in heart repairs.Yet, how to induce differentiation of these cells into needed, fully functional cell types remains a major challenge.Understanding the underlying molecular mechanisms by which the cardiac progenitor cell formation, self-renewal, and differentiation are controlled is essential for developing stem cell therapy for cardiovascular diseases.The fibroblast growth factor (FGF) family consists of 18 receptor-binding members that regulate a broad spectrum of cellular activities.The FGF signaling axis has been implicated in heart progenitor development, recruitment, and differentiation;disruption of FGF signaling leads to severe defects in heart development.Yet, the molecular mechanism by which the FGF regulates cardiogenesis is not fully understood.Tissue-specific ablation of FGF receptor substrate 2α(Frs2α) in heart progenitor cells leads to premature differentiation of the cells in mice.Using embryoid body (EB) cultures of mouse embryonic stem cells (ESCs), we demonstrate that FGF signaling promotes mesoderm differentiation in ESCs, but inhibits cardiomyocyte differentiation of the mesoderm cells at later stages.Furthermore, inhibiting FRS2()-mediated signals increases autophagy and that activating autophagy promotes myocardial differentiation and vice versa.Thus, the results indicate that FRS2α-mediated signals prevent premature differentiation of heart progenitor cells through suppressing autophagy.The findings provide the first evidence that autophagy plays a role in heart progenitor differentiation, suggest a new venue to regulate stem/progenitor cell differentiation into cardiomyocytes, and shed new light on novel heart repair strategies based on stem cell therapies.