Gene network controlling cardiac progenitors

 

The heart is one of the first organs formed during embryonic development and is composed of different regions (ventricles, atria, and outflow tract) and different cell types including contractile cardiomyocytes, vascular cells, and smooth muscle cells.

During embryonic development, the different heart regions and cardiovascular lineages arise from the differentiation of distinct cardiovascular progenitors.

The precise molecular mechanisms that promote the specification of cardiovascular progenitors from undifferentiated mesoderm cells and their differentiation toward the different lineage and heart regions remains largely unknown.

Our lab studies the mechanisms regulating the earliest step of cardiovascular progenitor specification and differentiation during mouse embryonic development and pluripotent stem cell differentiation.

Using embryonic stem cell differentiation, we demonstrated that Mesp1, a transcription factor, acts as a master regulator that promotes the specification, migration and the differentiation of the earliest cardiovascular progenitors (Cell Stem Cell 2008, Journal of Cell Biology 2011 and Journal of Cell Biology 2016).

To explore the early step of cardiovascular progenitor specification in vivo, we developed novel genetic strategies to temporally mark and follow the fate of single cardiac progenitor during the early step of gastrulation. We uncovered the existence of distinct populations of Mesp1 progenitors that contribute to different cell lineages and different regions of the heart. Despite their emergence at different time points during development and their contribution to different heart regions, the different Mesp1 progenitors present a very similar proliferative behaviour (Nature Cell Biology 2014 and Cell Reports 2016).

To assess the mechanisms associated with the early cardiovascular lineage segregation during embryonic development, we have performed single RNA-seq of Mesp1 progenitors at different time during gastrulation. We identified distinct populations of Mesp1 progenitors that correspond to progenitors committed to different cell lineages and regions of the heart, identifying the molecular features associated with early lineage restriction and regional segregation of the heart at the early stage of mouse gastrulation (Science 2018).

We are now dissecting the gene regulatory network and enhancer logic that regulate the early regional and lineage segregation of cardiovascular progenitors during heart development.

 

People

Benjamin Swedlund, PhD student
Xionghui Lin, postdoctoral fellow
Catherine Paulissen, technician

Selected publications

Mesp1 acts as a master regulator of multipotent cardiovascular progenitor specification. Bondue A, Lapouge G, Paulissen C, Semeraro C, Iacovino M, Kyba M & Blanpain C. Cell Stem Cell 2008, 3(1):69-84. Highlighted by a preview in Cell Stem Cell

Mesp1: a key regulator of cardiovascular lineage commitment. Bondue A, Blanpain C. Circ Res 2010 Dec 10;107(12):1414-27.

Defining the earliest step of cardiovascular progenitor specification during embryonic stem cell differentiation. Bondue A, Tännler S, Chiapparo G, Chabab S, Ramialison M, Paulissen C, Beck B, Harvey R, Blanpain C. J Cell Biol 2011 Mar 7;192(5):751-65.

Early lineage restriction and regionalization during heart development Lescroart F, Chabab S, Mathiah N, Paulissen C,  Achouri Y, Bondue A, Simons BD and Blanpain C. Nat Cell Biol. 2014  Sep;16(9):829-40.

Uncovering the Number and Clonal Dynamics of Mesp1 Progenitors during Heart Morphogenesis. Chabab S, Lescroart F, Rulands S, Mathiah N, Simons BD and Blanpain C. Cell Reports 2016 Jan 5;14(1):1-10. Cover article

Mesp1 controls the speed, polarity, and directionality of cardiovascular progenitor migration. Chiapparo G, Chabab S, Lescroart F, Li X, Paulissen C, Pitisci L, Bondue A, and Blanpain C. J Cell Biol. 2016 May 23;213(4):463-77. Highlighted by a preview in Journal of Cell Biology

Defining the earliest step of cardiovascular lineage segregation during gastrulation by single cell RNA-seq Lescroart F, Wang X, Lin X, Swedlund B, Gargouri S, Sànchez-Dànes A, Moignard V, Dubois C, Paulissen C, Kinston S, Göttgens B, Blanpain C Science. 2018 Mar 9; 359(6380):1177-1181. doi: 10.1126/science.aao4174. Epub 2018 Jan 25. Highlighted by perspectives in Science and Nature Reviews Cardiology.

Universality of clone dynamics during tissue development Rulands S, Lescroart F, Chabab S, Hindley CJ, Prior N, Sznurkowska MK, Huch M, Philpott A, Blanpain C,  and Simons BD. Nature Physics, 2018 May;14(5):469-474. Cover article