Cellular Biology FRS2 -Mediated FGF Signals Suppress Premature Differentiation of Cardiac Stem Cells Through Regulating Autophagy Activity

Rationale: Although the fibroblast growth factor (FGF) signaling axis plays important roles in heart development, the molecular mechanism by which the FGF regulates cardiogenesis is not fully understood. Objective: To investigate the mechanism by which FGF signaling regulates cardiac progenitor cell differentiation. Methods and Results: Using mice with tissue-specific ablation of FGF receptors and FGF receptor substrate 2 (Frs2 ) in heart progenitor cells, we demonstrate that disruption of FGF signaling leads to premature differentiation of cardiac progenitor cells in mice. Using embryoid body cultures of mouse embryonic stem cells, we reveal that FGF signaling promotes mesoderm differentiation in embryonic stem cells but inhibits cardiomyocyte differentiation of the mesoderm cells at later stages. Furthermore, we also report that inhibiting FRS2 -mediated signals increases autophagy and that activating autophagy promotes myocardial differentiation and vice versa. Conclusions: The results indicate that the FGF/FRS2 -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. (Circ Res. 2012;110:e29-e39.)