The fibroblast growth factor signaling axis controls cardiac stem cell differentiation through regulating autophagy

Abstract

The fibroblast growth factor (FGF) signaling axis plays important roles in heart development. Yet, the molecular mechanism by which the FGF regulates cardiogenesis is not fully understood. Using genetically engineered mouse and in vitro cultured embryoid body (EB) models, we demonstrate that FGF signaling suppresses premature differentiation of heart progenitor cells, as well as autophagy in outflow tract (OFT) myocardiac cells. The FGF also promotes mesoderm differentiation in embryonic stem cells (ESCs) but inhibits cardiomyocyte differentiation of the mesoderm cells at later stages. Furthermore, inhibition of FGF signaling increases myocardial differentiation and autophagy in both ex vivo cultured embryos and EBs, whereas activation of autophagy promotes myocardial differentiation. Thus, a link between FGF signals preventing premature differentiation of heart progenitor cells and suppression of autophagy has been established. These findings provide the first evidence that autophagy plays a role in heart progenitor differentiation, and suggest a new venue to regulate stem/progenitor cell differentiation.

Figure 1. The FGF signaling axis inhibits premature differentiation of cardiac progenitor cells by suppressing autophagy. Binding of the FGF to the FGFR activates the FGFR tyrosine kinase, which then activates the AKT and MAPK kinase pathways in a FRS2α-dependent manner, suppresses autophagy, and inhibits differentiation of cardiac progenitor cells. Disruption of FGF signaling by deletion of Frs2α, or suppression of FGFR, PtdIns3K, or MAPK kinase activity promotes autophagy and differentiation of cardiac progenitor cells. Consistently, stimulation of autophagy promotes cardiac progenitor differentiation; suppression of autophagy prevents the differentiation. Although disruption of FGF signaling suppresses cardiac progenitor proliferation, whether autophagy directly plays a role in regulating cardiac progenitor proliferation remains to be investigated.