0245 : Dissecting progenitor cell contributions to the developing heart

Abstract

Cardiac progenitor cells of the second heart field (SHF) contribute to the poles of the elongating embryonic heart. Perturbation of SHF development leads to a spectrum of congenital heart defects. Recent evidence suggests that distinct regions of the heart are pre-patterned in the SHF. For example the dell22q11.2 or DiGeorge syndrome gene Tbx1 is required in the SHF for development of the inferior wall of the embryonic outflow tract, giving rise to subpulmonary myocardium. Characterization of the expression of an enhancer trap transgene at the Hes1 locus, encoding a transcriptional repressor, has identified a complementary Notch-dependent Hes1 + TBX1 – subpopulation of SHF cells giving rise to future subaortic myocardium. Using transcriptomic analysis we have characterized the genetic signatures of future subaortic and subpulmonary myocardium and identified Pparg among the genes enriched in future subpulmonary myocardium. Genetic and explant analyses have shown that Hes1 controls the molecular signature of future subaortic myocardium through direct transcriptional repression of Ppar g. Our results reveal that distinct genetic regulatory networks control different progenitor cell contributions to the developing heart. We also investigated the potential role of Hes1 in the maintenance of residual SHF progenitors in the fetal heart. Our initial results have identified Hes1 + cells in the fetal heart and suggest that Hes1 deletion impacts negatively on residual progenitor cell numbers. Together, our study identifies a role for Hes1 in the regulation of cardiac progenitor cell fate and maintenance in the definitive heart of clinical importance for heart repair.