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Scientists at PDN shed light on the mechanisms of early pregnancy loss

last modified Nov 30, 2017 08:55 AM
Using a newly developed technique to culture mouse and human embryos in vitro beyond implantation, PDN researchers led by Magdalena Zernicka-Goetz show how alteration of the first morphological transformation can lead to pregnancy termination

How the mammalian embryo develops at the time it implants into the maternal womb is one of the great unsolved and yet crucial questions of embryology. It is unsolved because as embryos implant they become inaccessible from view and experimentation; and crucial because failed implantation development represents the major cause of early pregnancy loss in humans.

A team of scientists at the University of Cambridge led by Prof. Magdalena Zernicka-Goetz decided to tackle this question using novel techniques that they had recently developed to culture mouse and human embryos in vitro beyond implantation. Their findings provide the molecular explanation of how the stem cells that will form the future embryo undergo their first morphological transformation. Alterations in this process lead to failed embryo development both in mouse and human embryos, and therefore the conclusions of the study are relevant for understanding early pregnancy loss.

Just before implantation, mouse and human embryos contain a group of approximately 10 embryonic stem cells that will give rise to the entire organism. These stem cells are not organized in any particular way and they display a property known as “naïve pluripotency”, which means they have the unlimited potential to become any cell type of the future organism (e.g. neurons, muscle or bone). They are the “seed” that will start to develop as soon as the embryo implants (on day 5 in mice and day 7 in humans) to generate a living entity. The first task these cells need to achieve is to form a cavity, the amniotic cavity, which will protect the embryo from mechanical damage and the immune system of the mother. The Cambridge team focused on this specific event and tackled the question of how the amniotic cavity is formed.

Culturing mouse and human embryos beyond implantation in vitro the Cambridge team found that the state of unlimited potential was incompatible with the formation of the amniotic cavity. Cells had to pay a price to form the cavity, and that was to give away part of their potential. Failure to do so, completely abrogated amniotic cavity formation and the embryos failed to progress. This is the first time that the principles of experimental embryology are applied to human embryos developing beyond day 7 in vitro.

Professor Zernicka-Goetz says: “During the last years we have worked very hard to generate methods to crack open the black box of implantation development. Our goal was to enable studies of mammalian development in a laboratory dish beyond implantation as this is one of the most mysterious stages of our own development and yet this is when many pregnancies fail. It is this technology that now has allowed to go deeper into the mechanistic explanation of how changes in stem cell potential and the formation of embryonic structures are beautifully coordinated”.

In addition, the team cultured mouse and human embryonic stem cells in 3D scaffolds that recreate the formation of the amniotic cavity and the changes in pluripotency. Marta Shahbazi, the first author of the study says: “Embryonic stem cells are typically studied in 2D culture dishes, that do not recapitulate the complex 3D organization of the stem cells in the embryo so I decided to explore embryonic stem cell pluripotency in three dimensions. Our results show that specific properties of embryonic stem cells determine their capacity to form structures such as the amniotic cavity”. Mimicking embryo development with 3D cultures allowed the Cambridge team to determine the detailed molecular regulation of amniotic cavity formation. The team identified specific pluripotency factors that are responsible of inducing the expression of proteins that build the cavity.

Naiveversusnonnaive2.png
Pluripotency regulates mouse and human embryonic morphogenesis: cells that are in an unrestricted naive pluripotent state (marked by the expression of Nanog in yellow) fail to undergo proper morphogenesis and form the amniotic cavity (left structure). Loss of naive pluripotency (marked by the lack of Nanog expression) directs morphogenesis and amniotic cavity formation (right structure). Magenta labels Podocalyxin (luminal protein), cyan labels F-actin (cellular shapes) and blue labels nuclei.

 

Mouse and human embryos acquire radically different morphologies during early post-implantation development. By comparing mouse and human embryos and mouse and human embryonic stem cells, the researchers observed that the regulation of amniotic cavity formation by pluripotency factors was conserved in both species. These findings have potential implications for the use of embryonic stem cells to build tissues in vitro for regeneration.

This work is published today in the international scientific journal Nature, and it was funded by the Wellcome Trust and the European Research Council. It was possible thanks to the collaboration of the Cambridge team with experts working on different areas.

This research has been possible thanks to couples that underwent IVF treatment and decided to donate their surplus embryos to advance our understanding of the early phases of post-implantation human development. The research complies with the regulations of the UK Human Fertilisation and Embryology Authority.

Written by Martha Shahbazi