What will each cell become? Dr Yorgos Nikas/Science Photo Library

Talk about getting a head start. Cells in an embryo begin deciding their future only two days after conception, when the embryo is made up of just four seemingly identical cells. The discovery could help improve IVF success rates and how we use stem cells.

Once a human sperm has fertilised an egg, the resulting embryo begins tumbling down the fallopian tube on its way to the uterus, where it will implant around a week later. As it travels, it starts to divide: first into two cells, then four, then eight.


By the time the embryo implants in the uterus lining, it has become a blastocyst, made up of hundreds of cells, some of which will become the placenta, and some the fetus. We know that around this stage – days eight to 16 after fertilisation – the cells have taken on a range of varying roles, but it has been unclear when our cells first decide what it is that they should become.

Now, thanks to high-resolution screening techniques, single cells have been sequenced just after fertilisation, measuring which genes are being actively expressed. This showed that embryonic cells start to differ from one another at the four-cell stage.

After just two cell divisions, these seemingly identical cells have each acquired a distinct genetic signature that indicates whether it is more likely to become a part of the future placenta or fetus.

“It seems that an embryo begins to push itself towards one lineage or another at this very early stage,” says John Marioni of the European Bioinformatics Institute in Cambridge, UK, who led the work with Magdalena Zernicka-Goetz of the University of Cambridge.

A vital turning point

How cells become different from one another for the very first time has been controversial, says Zernicka-Goetz. “We now know it happens much earlier than has been previously believed and it’s an important new insight into how these first decisions about cell fate are made.”

Marioini and Zernicka-Goetz’s team made this discovery by studying 2-day-old mouse embryos. They found that Sox21 – a gene involved in maintaining a stem cell-like state – was the most variable in the four cells. When they inhibited this gene in specific cells, they found that those cells were more likely to become part of the placenta.

But what actually initiates cell differentiation is still a mystery. The differences observed by Marioni and Zernicka-Goetz only bias cells towards the embryo or placenta, and don’t definitively determine a cell’s future specific function, says Janet Rossant of the University of Toronto, Canada.

However, the finding could help identify the most important players involved in determining cell fate. These would be a useful tool for directing the fate of stem cells used to make tissues and organs for regenerative medicine.

Zernicka-Goetz says the work might also aid fertility treatments, since in IVF these first few cell divisions happen in the lab. “It may help our ability to recognise which embryos have the highest viability,” she says.

“This is an important addition to our growing understanding of how to make a mouse blastocyst,” says Rossant. “The next question is how to make a human blastocyst. There is much less known about human early development and this is an important frontier.”

Journal reference: Cell, DOI: 10.1016/j.cell.2016.01.047