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The heart presents an

asymmetry in the inflow tract

that has not been described until now, according to researchers from the National Center for Cardiovascular Research (CNIC), who have created a

3D atlas of the process of formation of the heart in its embryonic phase

, a powerful tool that can help identify

how and where

congenital heart defects occur.

This has been highlighted by

Miguel Torres

, head of the Genetic Control of Organ Development and Regeneration group at the CNIC and director of the study published in Nature Cardiovascular Research, who points out that the work "will be of great help in understanding the development of the heart", and also for the study of the

formation of other organs and tissues

.

A fundamental question in developmental biology, as the CNIC researchers explain, is how tissues acquire their

complex shapes from simple geometries

, a process called morphogenesis.

This task is relatively accessible to organs that develop in a highly reproducible pattern, such as in

limbs or eyes

, and can be easily visualized;

however, it is

more difficult in organs such as the heart of mammals

, with extreme morphological variability and little access to video microscopy, according to the CNIC researchers.

divergences that converge

The development of the heart thus presents particularities, with respect to what is characteristic in the formation of other organs.

Thus, during early cardiogenesis

no two embryonic hearts

look very much alike, to the point of being so different that it is difficult to decide which is more advanced in development.

Over time, those first apparently divergent morphologies converge to

produce a typical newborn heart,

Torres explains.

The challenge is to capture the average evolution of cardiac tissue geometry from its wide range of natural variability and to be able to

discriminate between physiological

and abnormal morphological variations from a large enough sample.

"Only then would we be able to understand the properties of

physiological morphogenesis

and identify when and how abnormalities occur," explains this expert.

To create the dynamic 3D atlas now presented and to overcome the limitations in obtaining live images, the CNIC team acquired high-resolution images of a large collection

of mouse embryonic hearts

collected during key stages of their development and with high time density.

In this process, "we realized that the morphogenesis of the heart could not be isolated from that of the surrounding tissues, since the formation of the heart tube resembles a

geological fold produced in a continuous layer of the mesoderm

, that is, the layer cell that makes up the embryo, from the pericardial cavity," explains Torres.

Therefore, according to the first author of the study,

Isaac Esteban

, "we captured all the tissues of the

pericardial cavity

and the underlying foregut endoderm."

Subsequently, the researchers transformed the images into digital versions and, thanks to a

morphometric staging

system , arranged them in time, since the moment of obtaining the embryos does not necessarily correspond to the time of real morphological development.

CNIC scientists have employed a recently developed approach:

intersurface mapping

, which generates maps of corresponding points between similar shapes with a point density sufficient to reconstruct the entire surface of objects.

"This method made it possible to identify equivalent positions between groups of specimens at a similar stage and in consecutive stages of development," says Esteban.

They thus created a 3D temporal atlas that shows the

trajectory of the heart tube formation and the local morphological variability

at each stage.

early asymmetry

With this tool, a better quantitative study of the development of an organ can be carried out, as well as how the

defects associated with a genetic mutation

begin to develop .

"In the case of the heart, the observations so far have been rather qualitative. Now we can

develop a quantitative analysis

, which will no longer depend on the eye of the researcher, and also with our tool we have carried out a study not only of the global morphology of the heart but locally mapped," Torres stresses.

The professional highlights the importance of knowing the

new asymmetry not described until now

, despite the fact that there are many laboratories that have been studying the development of the heart since the beginning of the last century.

The CNIC researchers have also verified that this asymmetry in the inflow tract of the heart

occurs very early

.

The authors of this work also analyzed a

series of mutants

in which the well-known curvature of the embryonic heart to the right was altered and found that the new asymmetry now described was reversed in these mutant images, leading to the conclusion that "the asymmetry now described is related to the

normal asymmetry of the adult heart."

The information obtained by the CNIC team shows that the regions usually involved in cardiac malformations coincide with

regions of high morphological heterogeneity and/or high variability

in development time.

"This observation suggests that morphological variability may be the basis for the high natural incidence of congenital heart malformations, which affect

1% of live births,"

says Esteban.

From here one of the most relevant applications

of this work can be derived

, by identifying "hot spots of variability that can guide us in

locating where the defects associated

with malformations are produced", also taking into account the high rate of cardiac malformations at birth compared to other organs.

The heart is the first organ that comes into operation in embryonic development,

beginning to pump blood very early and such a rapid transition from a phase of undifferentiated precursors to an active organ, which already requires a certain architectural configuration, with the development of very drastic changes in a very short period can explain this high rate of malformations.

The generated methodology can be applied to the quantitative analysis of the morphogenesis of any organ or organoid.

The main limitation of the study is, according to Torres, the use of fixed images to reconstruct a dynamic process, which does not allow analysis of the cellular bases of tissue deformation.

The generated atlas, however, will be an essential basis for contributing to this knowledge and scientists are already working on incorporating cellular data into this new dynamic atlas of heart development.


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