First 3D mapping in the embryo

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3D light-sheet microscope image of a 12-week-old transparent human embryo eye. T
3D light-sheet microscope image of a 12-week-old transparent human embryo eye. The 6 oculomotor muscles responsible for eye movement and the 3 motor nerves (in white, green and red) were colorized using virtual reality software. ©Raphael Blain/Alain Chédotal, Institut de la Vision (Inserm/CNRS/Sorbonne Université)

Improving our knowledge of the development of the complex structures that make up the human head, and thus gaining a better understanding of the congenital anomalies that cause malformations: this is the challenge that a team of researchers from Inserm, CNRS and Sorbonne Université at the Institut de la vision, Université Claude Bernard Lyon 1 and Hospices civils de Lyon is well on the way to meeting. Thanks to an innovative technique that makes cranial structures transparent and then takes 3D photos of the cells that make them up, this research team has been able to establish the very first three-dimensional map of the embryonic human head. These results, to be published in Cell , have already led to a better understanding of how certain complex structures of the head are formed, such as the lacrimal and salivary glands or the arteries of the head and neck. They pave the way for new tools for studying embryonic development.

The head is the most complex structure in the human body. In addition to the muscles and skin that protect it, and the brain housed in the skull, it contains vessels, nerves and endocrine glands (which secrete hormones directly into the bloodstream), such as the pituitary gland, and exocrine glands (which secrete substances into the external environment), such as the salivary glands, which produce saliva, and the lacrimal glands, which secrete tears.

Current knowledge of the development of the human head and its complex structures is rudimentary, based on studies carried out mostly in the first half of the 20th century, using simple histological sections. Thus, although malformations of the head exist in around a third of babies with congenital anomalies, the mechanisms controlling the development of the human head are still poorly understood.

A research team led by Alain Chédotal, Inserm Research Director at the Institut de la Vision (Inserm/CNRS/Sorbonne Université) and Professor at the MéLiS Laboratory of Mechanisms in Integrative Life Sciences (Inserm/CNRS/Université Claude Bernard Lyon 1/Hospices civils de Lyon), and Yorick Gitton, CNRS Research Fellow also at the Institut de la Vision, have used an innovative microscopy method to shed new light on the development of the human head.

The technology implemented had previously been used in embryos by the team to study the development of other human organs [1] . It is called transparentization because it makes organs transparent to light. The transparentized sample is then imaged in 3D using a special microscope that scans with a thin sheet of laser light. This enables the cells that make up embryonic tissue to be located in situ.

The researchers were able to apply this technique to embryos at different stages of development, taken from the human tissue biobank set up as part of the HuDeCA (Human Developmental Cell Atlas) program coordinated by Inserm [2] . Thanks to the images obtained, they were able to draw up the first three-dimensional map of the human embryonic head [3] .

In a second phase, the research team used virtual reality to analyze the 3D images and virtually "navigate" through the embryos.

This has enabled us to discover previously unknown features of the development of cranial muscles, nerves and blood vessels, the skull and cranial exocrine glands," says Alain Chédotal. For example, the very early stages of development of the salivary and lacrimal glands had never before been studied in humans. Our work has enabled us to begin to visualize and better understand the mechanisms behind the development of these extremely anatomically complex structures," he adds.

The scientists have also set up a web interface ( ) providing access not only to the images obtained in this work, but also to 3D printing models and interactive 3D reconstructions of human embryos. This platform thus provides valuable resources that can also contribute to the training of medical students.

In future work, the research team will attempt to map all the cells in certain organs, such as the retina.

"At this stage, it’s as if we’d mapped the continents and countries, but still had to position the towns and inhabitants," explains Alain Chédotal, whose team will also be working with doctors to apply the technology to pathological samples.

"The new insights into human embryology provided by this work, as well as the new tools developed, have important implications for understanding craniofacial malformations and neurological disorders, as well as for improving diagnostic and therapeutic strategies," concludes the researcher.

[1] On this subject, see our press release of March 23, 2017:

[2] Launched in 2019, the cross-disciplinary HuDeCa program led by Inserm aims to build the first atlas of human embryonic and fetal cells. It also aims to structure human embryology research in France and develop databases. In the longer term, this program should serve as a foundation for understanding the origins of chronic diseases and congenital malformations.

[3] With the specific exception of the brain, which is not a structure studied in these works.