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Epicardium and myocardium separate from a common precursor pool by crosstalk between bone morphogenetic protein– and fibroblast growth factor–signaling pathways
Circulation Research, 07/28/09

van Wijk B et al. – Data show that fibroblast growth factor (FGF) signaling via mitogen-activated protein kinase kinase (Mek)1/2 is dominant over bone morphogenetic protein (BMP) signaling via Smad and is required to separate epicardial lineage from precardiac mesoderm. Thus, myocardial differentiation requires BMP signaling via Smad and FGF signaling inhibition at the Mek1/2 level. These findings are clinically relevant for development of regeneration-based therapies for heart disease.

• Study to elucidate the signaling pathways involved in lineage separation leading to differentiation of myocardial and (pro)epicardial cells at the inflow of the developing heart
• 3D reconstructions of Tbx18 gene expression patterns to elucidate developing epicardium in relation to developing myocardium
• Use of DiI tracing to show (pro)epicardium separates from same precursor pool as inflow myocardium

• In vitro, lineage separation is regulated by a crosstalk between BMP and FGF signaling
• BMP signaling via Smad drives differentiation toward myocardial lineage, inhibited by FGF signaling via Mek1/2
• Embryos exposed to recombinant FGF2 in vivo show enhanced epicardium formation
• Misbalance between FGF and BMP by Mek1/2 inhibition and BMP stimulation causes developmental arrest of epicardium and enhances myocardium formation at heart inflow

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