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Development of head-to-tail axis in early human embryos explored by University of Cambridge and Wellcome Sanger Institute

Molecular insights into the one of the least understood yet critical stages of the development in human embryos have been published by University of Cambridge and Wellcome Sanger Institute scientists.

Failure of development during days seven to 14 of embryogenesis is one of the major causes of early pregnancy loss.

An illustration of blastocyst implantation inside a uterus
An illustration of blastocyst implantation inside a uterus

While the period of pre-implantation, before the embryo implants in the womb on the seventh day, has been extensively studied in the lab, the period after this is mysterious as it has been inaccessible to study.

But after pioneering work by Professor Magdalena Zernicka-Goetz and her team, reported in 2016, to culture human embryos outside the body of the mother beyond implantation, they can now be studied up to day 14.

New findings provide the first evidence that a group of cells outside the embryo, known as the hypoblast, send a message to it, initiating the development of the head-to-tail body axis.

When this axis begins to form, the symmetrical structure of the embryo begins to change, with one end developing into the head end and the other the ‘tail’.

The research, published in the journal Nature Communications, shows the molecular signals involved in the formation of the body axis are similar to those in animals, despite the major differences in the positioning and organisation of the cells.

“We have revealed the patterns of gene expression in the developing embryo just after it implants in the womb, which reflect the multiple conversations going on between different cell types as the embryo develops through these early stages,” said senior author Prof Zernicka-Goetz, of the Department of Physiology, Development and Neuroscience.

“We were looking for the gene conversation that will allow the head to start developing in the embryo, and found that it was initiated by cells in the hypoblast – a disc of cells outside the embryo. They send the message to adjoining embryo cells, which respond by saying ‘OK, now we’ll set ourselves aside to develop into the head end’.”

Identification of the gene conversations in the developing embryo was achieved by sequencing the code in the thousands of messenger RNA molecules made by individual cells.

By capturing the evolving molecular profile of the developing embryo after implantation in the womb, they showed the progressive loss of pluripotency - which confers the ability of embryonic cells to give rise to any cell type - as the fates of each cell is determined.

Senior author Dr Roser Vento-Tormo, a group leader at the Sanger Institute, said: “By creating an atlas of the cells involved in human development and how they communicate with other cells, we can start to understand more about the cellular processes and mechanisms behind very early embryo growth, which has been much harder to study compared to other mammals. This freely available information can now be used by researchers around the world to help inform future studies.”

Prof Zernicka-Goetz added: “Our goal has always been to enable insights to very early human embryo development in a dish, to understand how our lives start. By combining our new technology with advanced sequencing methods we have delved deeper into the key changes that take place at this incredible stage of human development, when so many pregnancies unfortunately fail.”

The research, funded by Wellcome, was carried out with the oversight of the UK Human Fertilisation and Embryology Authority, and with permission from a local research ethics committee.

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