J021 Regulation of cardiac progenitor cells during development

Abstract

Cardiac progenitor cells of the second heart field (SHF) contribute to the poles of the elongating embryonic heart. Failure or perturbation of SHF development leads to congenital heart defects. Recent studies have demonstrated the existence, in the postnatal heart, of resident cardiac progenitor cells that specifically express the transcription factor Islet1, a SHF marker, and that have the potential to differentiate into cardiomyocytes, smooth muscle and endothelial cells. Interestingly, several evidences suggest that these residual progenitor cells arise from the SHF. Through analysis of a transgene integration site position effect we have identified the transcriptional repressor Hes1 as a novel regulator of SHF development. Hes1, a target gene of the Notch signaling pathway, is expressed SHF progenitor cells. Analysis of E15.5 Hes1-/- embryos reveals outflow tract alignment defects (ventricular septal defects and overriding aorta). At earlier developmental stages, Hes1-/- embryos display SHF proliferation defects, cardiac neural crest cells reduction and fail to completely extend the outflow tract. Thus these data reveal a role for Hes1, and potentially Notch signaling, in SHF development. Given the importance of Isl1 as a marker of resident progenitor cells in the later heart we are analysing the role of known and novel regulators of the SHF (Hes1, Fgf10 and Tbx1) in the regulation of myocardial progenitor cell fate and in the definition of the critical niche occupied by residual cardiac progenitor cells in the forming and definitive heart. In Fgf10-/- mice, outflow tract alignment occurs normally. However, Fgf10-/- hearts are highly dysmorphic. We thus hypothesize that Fgf10 deletion may affect the proliferative capacities of SHF progenitors in order to maintain the residual progenitor cells pool in the fetal heart. Initial results have revealed that whereas Fgf10-/- hearts undergo heart tube extension normally, proliferation is impaired. Together, our results identify Hes1 as a novel regulator of SHF progenitor cell deployment and reveal a potential role of Fgf10 in regulating cardiac progenitor cell fate and cardiac growth during the fetal period. This study will increase our understanding of the molecular mechanisms governing the maintenance and differentiation of cardiac progenitor cells.