In cell biology, an important challenge is to understand how progenitors are deployed to build an organ and by which mechanisms are driven cell fate decisions and lineage diversification. The heart is the first organ formed during development and represents a good model to address these questions. To ensure the harmonious morphogenesis of the heart, progenitors need to be specified, patterned and migrate at the right time and at the correct place. Any defects during this critical stage of development leads to congenital heart diseases, which represent the first cause of severe birth malformations. Because heart and head muscle development are tightly linked some rare syndromes affect both muscles. The mechanisms leading to these syndromes are still not completely understood.
Previous studies have shown that, already at the time of gastrulation, cardiac and head muscle progenitors are regionally restricted, contributing to a particular heart region and also restricted in their lineage with very few progenitors able to contribute to more than one cell type. We have in addition found that all progenitors are not homogenous, expressing the transcription factor Mesp1 at different time points. Left ventricular progenitors for example express Mesp1 a day earlier than atrial progenitors showing, that cardiac progenitors are much more heterogeneous than previously thought. Using lineage tracing and transcriptomics at the single cell level, we have uncovered how the heart is built from distinct progenitors with different potential. It provides a description of distinct progenitor populations with different molecular signature and that localized differently in the embryo.
Our next challenges are now to understand how cardiac progenitor heterogeneity affects their cellular and regional fate by:
1) Defining the molecular program or “Heart-code” driving cardiac progenitor specification.
2) Understanding the different types of cell behavior during cardiac progenitor migration.
3) Identifying the different environmental signals affecting the different cardiac progenitor populations.
We are currently investigating mouse cardiac progenitor specification in vivo as well as in vitro, using the embryonic stem cell model. Our goal is to integrate the spatial position of the progenitors, their temporal expression of key transcripts, the neighboring extrinsic signals and their cell behavior. These approaches will allow the dynamic characterization of heterogeneity within cardiac progenitors and identification of putative signaling pathways 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 studies to understand how the regionalization and the choice of differentiation into a particular cardiovascular lineage is achieved, which have important implications for improving cell therapy during cardiac repair.
Together with the team of Stephane Zaffran (particularly Laurent Argiro, research engineer), we have recently developed the gastruloids model (van den Brick, 2014; Beccari et al. 2018) and showed that it can model the earliest steps of cardiac and head muscle development, from mouse embryonic stem cells.
In addition, and in a more long-term perspectives, the goal of our team will be to dissect the mechanisms of specification toward a head skeletal muscle or heart muscle fate. By investigating the specification of the cardio-pharyngeal mesoderm that form both the heart and head/neck muscles in normal and pathophysiological conditions. We want to better understand the etiology of congenital diseases that affect both the head and the heart, including the human DiGeorge syndrome.