Heart development

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.

The mammalian heart has a complex organization with four different regions and different cell fates (cardiomyocytes, pacemaker, endocardial, smooth muscle and epicardial cells). Its development has been shown to start at the time of gastrulation from a pool of progenitors that express the transcription factors Mesp1. 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 will lead to congenital heart diseases, which represent the first cause of severe birth malformations.

Previous studies have shown that, already at the time of gastrulation, cardiac 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, with a particular focus on homeodomain genes.

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.

ATIP


Swedlund, B.  et al. 2019

Cardiopharyngeal Progenitor Specification: Multiple Roads to the Heart and Head Muscles

During embryonic development, the heart arises from various sources of undifferentiated mesodermal progenitors, with an additional contribution from ectodermal neural crest cells. Mesodermal cardiac...
Cold Spring Harbor perspect Biol - issue: - volume: - pages: .

Lescroart, F.  et al. 2018

Hox and Tale transcription factors in heart development and disease

Hox genes are highly conserved transcription factors with critical functions during development, in particular for patterning the antero-posterior axis of the embryo. Their action is very often...
Int. J. Dev. Biol. - issue: 11-12 - volume: 62 - pages: 837-846.

Zaffran, S.  et al. 2018

Ectopic expression of Hoxb1 induces cardiac and craniofacial malformations

Members of the large family of Hox transcription factors are encoded by genes whose tightly regulated expression in development and in space within different embryonic tissues confer positional...
Genesis - issue: 6-7 - volume: 56 - pages: e23221.

Rulands, S.  et al. 2018

Universality of Clone Dynamics During Tissue Development

The emergence of complex organs is driven by the coordinated proliferation, migration and differentiation of precursor cells. The fate behaviour of these cells is reflected in the time evolution their...
Nat Phys - issue: 14 - volume: 5 - pages: 469-474.

Lescroart, F.  et al. 2018

Defining the earliest step of cardiovascular lineage segregation by single-cell RNA-seq

Mouse heart development arises from Mesp1-expressing cardiovascular progenitors (CPs) that are specified during gastrulation. The molecular processes that control early regional and lineage...
Science - issue: 6380 - volume: 359 - pages: 1177-1181.

Chabab, S.  et al. 2016

Uncovering the Number and Clonal Dynamics of Mesp1 Progenitors During Heart Morphogenesis

The heart arises from distinct sources of cardiac progenitors that independently express Mesp1 during gastrulation. The precise number of Mesp1 progenitors that are specified during the early stage of...
Cell Reports - issue: 14 - volume: 1 - pages: 1-10.

Chiapparo, G.  et al. 2016

Mesp1 Controls the Speed, Polarity, and Directionality of Cardiovascular Progenitor Migration

During embryonic development, Mesp1 marks the earliest cardiovascular progenitors (CPs) and promotes their specification, epithelial-mesenchymal transition (EMT), and cardiovascular differentiation....
J Cell Biol - issue: 213 - volume: 4 - pages: 463-477.