CLICK ON weeks 0 - 40 and follow along every 2 weeks of fetal development
Mesp1 gene leads to a functioning heart
Researchers at the Université libre de Bruxelles, Belgium and the University of Cambridge, United Kingdom, have identified Mesp1 as the key gene in the earliest formation of cardiovascular cells. A discovery that may help explain some congenital heart birth defects.
The heart is the first organ that forms in a fetus. It contains four different regions (ventricles and atria), with different cells performing specialized functions. Beating cardiomyocytes ensure pumping, vascular cells line blood vessels, pacemaker cells set the heartbeat.
Unless progenitor ("beginner") cells "turn on" at the right time, migrate to the right location and differentiate into the correct cell type, potential mistakes can occur that later are identified as 'congenital heart defects,' the most common severe birth defects found in newborns.
Previous studies have shown a diverse range of heart progenitor cells rise out of pools of cells that express the gene Mesp1. However, it wasn't clear how to distinguish one progenitor cell from another on a molecular level.
In a new study published in Science, researchers led by Cédric Blanpain, Professor, Laboratory of Stem Cells and Cancer, Université libre de Bruxelles, Belgium, and Berthold Göttgens, Professor, University of Cambridge, United Kingdom (UK), are now able to identify the Mesp1 protein at the earliest steps of cardiovascular cell segregation into specialized heart cells. They did this by creating single cell molecular profiles and then confirmed that data through cell lineage tracking.
Fabienne Lescroart and colleagues isolated cells expressing Mesp1 at different stages of embryonic development and then analysed each single cell's transcriptomes — or set of all RNA molecules. These early cardiac progenitor cells had molecular features that could be associated with specific cardiac regions and cell types. Therefore, Lescroart's group demonstrated that different populations of cardiac progenitor cells are molecularly distinct early on (gastrulation) and can be identified as to which particular cardiac progenitor cells they will become.
To determine the role of Mesp1 regulation in early cardiovascular progenitor cells, researchers deleted the Mesp1 protein — thus revealing it is required to end a cell's pluripotent state in order to begin expression of cardiovascular genes. While cardiac progenitor cells are not yet fully differentiated, bioinformatic analysis revealed they are primed or pre-specified to become cardiac muscle and vascular (blood vessel) cells. Finally, the researchers identified the earliest branching point between the cardiac and vascular lineages, to show that Notch1 marks the early progenitor cells committed to the vascular lineage during early embryonic development. The protein Notch1 is a receptor protein that helps regulate cell-fate.
Researchers found these different cell populations are "born" at unique times as well as located in specific areas of the early fetus. Notch1 marks the early progenitor cells committed to the vascular line in early embryo development. Understanding molecular features associated with early cardiovascular lines will be important in designing strategies for potential cellular therapies in cardiac diseases.
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. Here, we performed single cell RNA-sequencing of WT 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.
All 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
The authors have no conflicts of interest or financial disclosures relevant to this manuscript.
Return to top of page
A mosaically labeled embryonic heart where each color is derived from the early labeling of
cardiac progenitor cells expressing the gene Mesp1. Image credit: Fabienne Lescroart