Unveiling the Secrets of Early Human Development: Totipotency and Cell Fate Bias in Embryos
IVF.net News,
01 June 2024

In the early stages of human embryonic development, a zygote divides into two seemingly identical totipotent cells, which eventually grow into eight cells. Totipotent cells have the potential to develop into any cell type, forming both the embryo and the extraembryonic tissues such as the placenta. Initially, it was believed that all these cells were identical and equally capable of developing into any cell type. However, recent research published in Cell has challenged this view, revealing a more nuanced understanding of early cell fate decisions.

Magdalena Zernicka-Goetz, a developmental and stem cell biologist at the California Institute of Technology and the University of Cambridge, and her team discovered that only one of the two initial cells is truly totipotent, capable of developing into both the body and the placenta. The other cell mainly contributes to the placenta. This groundbreaking finding sheds light on the critical early stages of development and the initial cell fate decisions that determine the embryo's future.

In previous research on mouse embryos, Zernicka-Goetz demonstrated that there is already a bias at the two-cell stage, with one cell more likely to contribute to fetal tissues and the other to the placenta. This new study aimed to explore if similar biases occur in human embryos. To investigate this, Zernicka-Goetz and her team used a sophisticated technique to track 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. This allowed them to visualize and determine the contribution of each cell to the development of the trophectoderm (TE) and the inner cell mass (ICM). The TE develops into the placenta, while the ICM eventually produces the epiblast, which forms fetal tissues, and the hypoblast, which forms the yolk sac.

When they tracked GFP expression, the researchers found that one population of cells predominantly contributed to either the ICM or the TE. The imbalance was most pronounced in the ICM, where progeny from one clone at the two-cell stage dominated the population of the epiblast. In contrast, the hypoblast's composition was more evenly split between the cells of the two originating clones. This observation suggests that at the two-cell stage, there is already a bias in cell fate, although it is not a deterministic process.

To further investigate the cell contribution to the ICM, the researchers labeled DNA and actin and tracked cellular positions after division using live cell imaging starting at the eight-cell stage. They observed that asymmetric cell divisions (ACDs) were crucial for forming the ICM. In ACDs, cells that intrude into the growing cell mass become part of the ICM, while those that remain on the surface contribute to the TE. Although ACDs were less common, their composition closely resembled that of the ICM.

In mice, the two-cell stage clone that contributed more to the ICM divided faster than the other cell. The team studied whether this pattern applied to human embryonic development by analyzing movies of actively dividing embryos. They found that in most embryos, one cell at the two-cell stage divided faster, and its progeny also inherited this characteristic. Additionally, the first cell to undergo ACD was usually one of these fast-dividing cells.

"This is the first study to perform detailed cell tracking in a human embryo at such early stages," noted Nicolas Plachta, a developmental biologist at the University of Pennsylvania who was not involved with the study. However, he mentioned that inherent variability in human embryos compared to established mouse models complicates drawing definitive conclusions. This complexity is further exacerbated by the limited availability of zygotes for research, as 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. The study suggests that early cell fate decisions in human embryos are influenced by the dynamics of cell division and the position within the growing embryo, rather than being entirely deterministic.

The research has broader implications for understanding human development and potential applications in reproductive medicine and stem cell therapy. By elucidating the mechanisms of early cell fate decisions, scientists can better understand congenital abnormalities and improve techniques for in vitro fertilization (IVF).

Moreover, this study opens new avenues for exploring how early embryonic cells establish their developmental trajectories. Understanding the interplay between cell division dynamics and fate specification could lead to breakthroughs in regenerative medicine, where controlling cell fate is crucial for developing therapies for various diseases.

In summary, this research highlights the complexity of early human development and provides new insights into how initial cell divisions can influence the entire developmental trajectory of an embryo. The findings challenge the traditional view of totipotency and underscore the importance of studying early cell fate decisions to unlock the mysteries of human development.


13 May 2024. Cell

13 May 2024. The Scientist

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