Defining the genetic program pre-specifying early cardiac progenitor cells fate

Abstract

During gastrulation, cardiac progenitors (CPs) are identified by the expression of the transcription factor Mesp1. Previous studies have demonstrated that CPs are already spatiotemporally restricted to specific cardiac lineages by that stage. Thus, the heart is built from distinct CPs that display different potential. Recent transcriptional analyses have uncovered the molecular heterogeneity of CPs. In order to understand how CP heterogeneity affects their fate in the adult heart, our aim is to define and modulate the mouse genetic program or “heart code” driving CP specification. We are focusing, in particular, on homeodomain transcription factors that are heterogeneously expressed in CPs. To this end, our objectives are to identify CP sub-populations by defining the spatiotemporal pattern of homeodomain genes during gastrulation and their final cardiac contributions. The role of the homeodomain genes in regulating the pre-specification of CPs are assessed by modulating their expression and analyzing how it impacts CP subpopulations in vivo and in vitro. Our promising preliminary results have already pinpointed the spatial heterogeneity of homeodomain gene expression during gastrulation and have suggested an important role for Lhx1 in Mesp1 + progenitors to correctly form head structures. Together these results will allow the dynamic characterization of heterogeneity within CPs and the identification of putative factors that could trigger the differentiation toward one particular cardiac cell type. These studies have important implications for better understanding the etiology of congenital cardiac malformations and should be the starting point of further applications for improving cell therapy during cardiac repair.