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The formation of heart valves finally determined

Picture of the endocardial cells of zebrafish heart after photoconversion(1) of the ventricle of the heart. The ventricle which is photoconverted appears in mauve while the atrium, which is not photoconverted, appears in green. This approach allowed the researchers to address cellular mechanisms associated with the formation of the heart valves.


(1) Photoconversion: the conversion of a substance from one form to another by using the energy supplied by light.

klf2a couples mechanotransduction and zebrafish valve morphogenesis through fibronectin synthesis.

Steed E(1,)(2,)(3,)(4), Faggianelli N(1,)(2,)(3,)(4), Roth S(1,)(2,)(3,)(4), Ramspacher C(1,)(2,)(3,)(4), Concordet JP(5,)(6,)(7), Vermot J(1,)(2,)(3,)(4).

Nat Commun May 25, 2016

May 25, 2016

The team of Julien Vermot is working on the mechanisms that regulate the formation of the heart valves. The researchers were able to show how heart valves are formed in response to changes in the extracellular matrix that is mediated by mechanical forces exerted by the heart muscle contractions. The researchers hope this discovery will help to better understand how to grow the heart valves in vitro. These results have been published on May 25, 2016 in the journal Nature Communications.


Heart valves are essential structures for heart function and blood flow propagation within our blood vessels. Their role is to force blood motion in one direction. During a human life, the heart beats more than 2.6 billion times. Heart valves are among the most mechanically stimulated structures of our body. During embryonic development, the formation of the heart valves depends on the forces exerted by the blood flowing on the internal wall of the heart called the endocardium. The team of Julien Vermot is focusing on the mechanisms that regulate the formation of heart valves in response to these mechanical forces. The team has recently shown that these forces activate mechanosensitive proteins that moduate heart valves maturation and growth (Heckel et al., 2015). However, they were still unsure how the mechanical forces coordinate the establishment of the heart valve in the embryonic heart.


Steps of the formation of the heart valves in the embryonic heart


To address this important question, the group of Julien Vermot is developing in vivo imaging techniques and image analysis methods allowing to assess valve formation at cellular resolution. They could thus observe the cell movements involved in the development of the heart valves. The researchers also used transcriptomic analysis to identify the genes controlling these movements.


Their results are striking: they found that the formation of the heart valves is achieved through unexpected coordinated cell movements that are extremelly robust and stereotyped from embryo to embryo. The researchers showed that these movements take place together with the formation of an extracellular matrix made of fibronectin. Fibronectins are glycoproteins present very early in embryonic development that are playing a role in cell migration. The team of Julien Vermot has also discovered that the regulation of cell movement necessary for the formation of the heart valve is controlled by klf2a (Krüppel-like factor 2a), a gene whose expression is activated by blood flow, and which is known for its protective role in arteries. Interestingly, they found that klf2a also controls the synthesis of fibronectin (see diagram).


Some hear valve pathologies arise early in life due to abnormal embryonic heart valve formation. In adults, many heart valve pathologies are associated with the late reactivation of embryonic genes. This work, along with efforts to identify the genetic links associated with heart valves pathologies, will help to better understand the developmental origins of congenital heart valve defect. Now-a-day, the cure for heart valve pathologies consists in valve replacements. The authors hope that their work will also lead to new directions for the improvement of the manufacturing processes of valves in vitro.


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