Embryo demonstrates a bias at the two-cell stage

When human embryos consist of only two cells, the cells are already biased towards contributing to either the placenta or the embryo, scientists suggest.

Seventy percent of IVF implantations fail, and this study, led by Professor Magdalena Zernicka-Goetz from the California Institute of Technology and the University of Cambridge, aimed to increase our knowledge on pre-implantation human development. Labelling one of the cells at the two-cell stage, the researchers tracked both cells as they divided and differentiated to assess a potential bias in contribution towards specific cell types.

Professor Zernicka-Goetz, corresponding author of the study published in Cell, told the Scientist Magazine: 'I was always interested in how cells decide their fate'.

Pre-implantation development starts at fertilisation and finishes when the embryo implants into the uterus on approximately day seven. This is crucial for the success of IVF as it coincides with the time when embryos are chosen for transfer. This stage is characterised by a series of sequential cell divisions and differentiation. After the fusing of two gametes, and starting as one cell, called the zygote, the human embryo is formed of a few hundred cells at the time of implantation. These cells belong to three different cell types: the ones that will form the placenta; some which give rise to the embryo and others that will become the yolk sac.

Following fertilisation, the zygote divides into two cells, which then become four, eight, 16 and so on. These early cells are considered both equal to one another and totipotent as they can generate all the cells forming the embryo and surrounding membranes. The first cell differentiation happens at the 8-16 cell stage, with cells situated on the outside of the embryo becoming the precursors of the placenta, while inner cells continue to differentiate to form the embryo and yolk sac.

Now, this study addressed whether cells as early as the two-cell stage are predetermined to contribute to the placenta or the embryo. Green fluorescent protein was used to label one of the two-cells and follow the descendants of each daughter cell through development. At the stage when the embryo has acquired the three lineages, the researchers quantified the contribution of labelled and unlabelled cells to each cell type through microscopy. Professor Zernicka-Goetz claimed: 'Only one of the two cells is truly totipotent, meaning it can give rise to body and placenta, and the second cell gives rise mainly to placenta.'

'This is the first study to do some nice cell tracking in a human embryo at those early stages,' added Professor Nicolas Platcha, an embryologist from the University of Pennsylvania, who was not involved in the work.

Obtaining donated embryos at the zygote stage is rare, as embryos are now frozen at later stages. The authors acknowledge this as a major limitation of such research. They overcame this limitation by using time-lapse imaging recordings, which IVF clinics produce to monitor the progress and quality of embryo development, highlighting the need for collaboration between researchers and IVF clinics.

Better understanding of human embryo development at an early stage could lead to the development of new ways to address IVF embryo implantation failure.