In the early stages of human embryonic development, a zygote divides into two identical totipotent cells that eventually become eight cells.1 Cell fate decisions begin to differentiate this totipotent population into specific lineages, giving rise to the blastocyst.2 At least, this has been the working model. Now, a new study published in Cell suggests this may not be the full story.3

They are not identical, said Magdalena Zernicka-Goetz, a developmental and stem cell biologist at the California Institute of Technology and the University of Cambridge and study coauthor. 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. The findings help elucidate what happens during the earliest periods in development.

I was always interested in how cells decide their fate, Zernicka-Goetz said. In the mouse developing embryo, she previously demonstrated a bias at the two-cell stage: one cell contributed more to fetal tissue and the other to the placenta.4

We know so little about the very early stages of human development, said Nicolas Plachta, a developmental biologist at the University of Pennsylvania who was not involved with the study.

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To understand this process better, Zernicka-Goetz set out to investigate if human embryonic development resembled that of mice. She and her team first tracked cell lineage from the two-cell stage; they injected mRNA for green fluorescent protein (GFP) fused to a membrane trafficking sequence into one of the two cells of the zygote. Thus, they could determine the contribution of each cell to the development of two early structures: the trophectoderm (TE) that becomes the placenta and the inner cell mass (ICM) that eventually produces the epiblast, or fetal tissue, and the hypoblast, or the yolk sac.

When they tracked GFP expression, the team found that one population of cells dominated in either the ICM or the TE, but that this imbalance was greatest in the ICM. Within the ICM, progeny from one clone at the two-cell stage dominated the population of the epiblast, while the composition of the hypoblast was split between cells of the two originating clones. This means that at the two-cell stage we have a cell fate bias of these two cells, but it's not a deterministic process, said Zernicka-Goetz.

To further investigate the cell contribution to the ICM, the researchers labeled DNA and actin and, starting at the eight-cell stage, tracked cellular positions after division using live cell imaging. Asymmetric cell divisions (ACD) involve cells that intrude into the growing cell mass rather than remain on the surface, and these interior cells contribute to the ICM. The team observed that while ACD were less common overall, their composition resembled that of the ICM.

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In mice, the two-cell stage clone that contributed more to the ICM divided faster than the second cell, so the team studied whether or not this pattern applied to human embryonic development.5 The team studied movies of actively dividing embryos and determined that in most of the embryos, one cell at the two-cell stage divided faster, and its progeny also inherited this feature. The team also noticed that the first cell to undergo ACD was one of these fast-dividing cells.

This is the first study to do some nice cell tracking in a human embryo at those early stages, said Platcha. However, he noted that the inherent variability in human embryos compared to established mouse models makes it difficult to draw conclusions in this research area. This is further complicated by the limited number of zygotes available for research because clinics typically preserve embryos at later developmental stages.

Next, Zernicka-Goetz aims to investigate the features and origins of the differences between clones at the two-cell stage.

Zernicka-Goetzs workwas nominated throughThe ScientistsPeer Profile Program submissions.

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The First Two Cells in a Human Embryo Contribute Disproportionately to Fetal Development - The Scientist