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Developmental biology - Heart Formation

Stem cell to functional heart: The Mesp1 gene

Mesp1 is the key gene in the earliest steps of cardiovascular cell development...

Researchers at the Université libre de Bruxelles and the University of Cambridge, have identified the role of Mesp1 as a key gene in the earliest steps forming cardiovascular lines. This discovery may help us better explain congenital heart defects.

The heart is the first organ to form during development, with four different regions (2 ventricles and 2 atria), containing unique cells which perform specialized functions: (1) beating cardiomyocytes to ensure pumping activity, (2) vascular cells that line the inner blood vessels and (3) pacemaker cells to set the heartbeat.
Unless progenitor cells forming the heart are specified at the correct time, migrate to the correct location, and differentiate into the correct cell types, severe malformations of the heart occur.

In human patients, these malformations are recognized as congenital heart diseases, and represent the most common cause of severe birth defects in newborn babies. Previous studies have shown that heart progenitor cells arise from different pools of cells expressing the Mesp1 gene.

However, it was unclear how progenitors are distinguished at the molecular level, and what molecular mechanisms promote specification into a particular cardiac type or location.

In a new study published in an early release of Science, researchers led by Professor Cédric Blanpain, Laboratory of Stem Cells and Cancer, Université libre de Bruxelles, Belgium, and Professor Berthold Göttgens, the Universtity of Cambridge, identified the role of Mesp1 in the earliest step of cardiovascular lineage segregation using single cell molecular profiling and lineage tracking.

Fabienne Lescroart and colleagues isolated Mesp1 expressing cells at different stages of embryonic development and performed single cell transcriptomic analysis to identify any molecular features associated with region and cell type. They were able to demonstrate that different early populations of cardiac progenitors are molecularly unique.
Mesp1 is a transcription factor. To determine its role in regulating cardiovascular differentiation and heterogeneity of early heart progenitor cells, researchers performed single cell molecular profiling on those cells after deleting Mesp1. These experiments showed that Mesp1 is required for cells to exit their pluripotent state and induce cardiovascular gene expression programs.

Bioinformatic analysis identified among these early Mesp1 progenitor cells, distinct populations corresponding to specific cell lineages and regions of the heart, thus identifying molecular features associated with early lineage restriction and regional segregation. While progenitor cells were not thought to be differentiated, this new analysis showed that cardiovascular progenitors are "primed" or pre-specified to give rise to either (1) cardiac muscle cells or (2) vascular cells.

Researchers also found that different cells are born at different times and located at specific locations even at this very early stage of development.

Finally, researchers identified the earliest branching point between cardiac and vascular cell lines, showing that Notch1 marks the earliest progenitors committed to a vascular lineage.

Understanding thee molecular features associated with early cardiovascular lineage commitment and heart regions is important to designing new strategies to instruct cardiovascular progenitor cells to adopt cardiac or vascular identity from different heart regions that can be used for cellular therapy of cardiac diseases.
"Future studies will be required to determine whether the paradigm of early lineage segregation identified here controls formation of other cell lineages in different organs and tissues. It will also be important to determine whether the molecular features uncovered here play a role in congenital cardiac malformations and can be used to push cardiovascular progenitors into a particular lineage, which can have important implications for improving cell therapy for cardiac repair."

Professor Cédric Blanpain, one of the senior authors of the study.

The other senior author Professor Bertie Gottgens states that: "Our new discoveries critically depended on recent technological innovations that now allow us to determine the gene activity profile of individual single cells. Not only can we study minute cell populations, which wasn't possible before, but we can also use the computer to separate the individual single cells into subgroups or cell types, based on their gene activity profiles. And from these newly discovered gene profiles, we can discover new candidate genes that may be exploited for developing new therapies to repair the heart, as referred to by Cedric".

Committing the heart
The heart is a complex organ composed of multiple cell types such as cardiomyocytes and endothelial cells. Cardiovascular cells arise from Mesp1-expressing progenitor cells. Lescroart et al. performed single-cell RNA-sequencing analysis of mouse wild-type and Mesp1-deficient cardiovascular progenitor cells at early gastrulation (see the Perspective by Kelly and Sperling). When Mesp1 was eliminated, embryonic cells remained pluripotent and could not differentiate into cardiovascular progenitors. During gastrulation, the different Mesp1 progenitors rapidly became committed to a particular cell fate and heart region. Notch1 expression marked the earliest step of cardiovascular lineage segregation.
Science, this issue p. 1177; see also p. 1098

Mouse heart development arises from Mesp1-expressing cardiovascular progenitors (CPs) that are specified during gastrulation. The molecular processes that control early regional and lineage segregation of CPs have been unclear. We performed single-cell RNA sequencing of wild-type and Mesp1-null CPs in mice. We showed that populations of Mesp1 CPs are molecularly distinct and span the continuum between epiblast and later mesodermal cells, including hematopoietic progenitors. Single-cell transcriptome analysis of Mesp1-deficient CPs showed that Mesp1 is required for the exit from the pluripotent state and the induction of the cardiovascular gene expression program. We identified distinct populations of Mesp1 CPs 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.

Authors: Fabienne Lescroart, Xiaonan Wang, Xionghui Lin, Benjamin Swedlund, Souhir Gargouri, Adriana Sŕnchez-Dŕnes, Victoria Moignard, Christine Dubois, Catherine Paulissen, Sarah Kinston, Berthold Göttgens, Cédric Blanpain.

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Jul 4, 2018   Fetal Timeline   Maternal Timeline   News   News Archive

An embryonic heart looping into its four chambers. Each color is derived from early labeling of a specific cardiac progenitor cell expressing the gene Mesp1. Image credit: Fabienne Lescroart.

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