Scientists shed new light into early mechanisms governing cardiovascular specification

The mature heart is composed by different cell types, including contractile cardiac cells, vascular cells, smooth muscle cells as well as pacemaker cells.

During embryonic development as well as during embryonic stem cell differentiation, the different cardiovascular cell types arise from the differentiation of multipotent cardiovascular progenitors. The mechanism that promotes multipotent cardiovascular progenitor specification from undifferentiated mesoderm cell remains largely unknown.

Now, researchers from the Université Libre de Bruxelles lead by Cédric Blanpain (IRIBHM, Faculty of Medicine), shed new light into the early mechanism that governs cardiovascular specification. This research is published in July 3 issue of Cell Stem Cell.

Researchers uncover the key molecular switch that specifies undifferentiated mesodermal cells to become cardiovascular progenitors. The authors of this study found that a protein called Mesp1 acts a master regulator of multipotent cardiovascular progenitor specification. They showed that a very transient expression of a Mesp1, increase by more than 500% the differentiation of pluripotent stem cells into cardiac and vascular cells, which represent the greatest promotion of cardiovascular differentiation induced by a single factor. "When we look at the Mesp1 stimulated cells under the microscope, it was just amazing! It was looking like all cells became cardiac cells, and were spontaneously beating everywhere in the dish", comments Antoine Bondue, the first author of the paper.

To better understand the molecular mechanism by which Mesp1 promotes cardiovascular specification, researchers from ULB used a genome-wide analysis to identify which genes are regulated by Mesp1. They found that Mesp1 directly activated many previously identified key genes responsible for cardiovascular differentiation. "Mesp1 allows the coordinate expression of all these important cardiac genes at the right place and at the right time", comments Cédric Blanpain, the principal investigator of this study. Mesp1 also directly repressed genes promoting the acquisition of other possible cell identity during this developmental stage, ensuring the specificity in the promotion of cardiovascular cell identity induced by Mesp1. These results demonstrate that Mesp1 acts as a key regulatory switch during cardiovascular specification, residing at the top of the hierarchy of the gene network responsible for cardiovascular cell fate determination.

This new and exciting study from Cédric Blanpain Lab has also important clinical and pharmaceutical implications. Cardiovascular diseases are the primary cause of death in western countries. The method presented in this study may be used in the future to increase the source of cardiovascular cells for cellular therapy in humans, but also to generate the large amount of cardiovascular cells required for toxicology and drug screenings.