Researchers Identify Stem Cells for Modeling 8-Cell Embryonic Stage

Researchers from the U.K.’s Babraham Institute have described a new subset of human embryonic stem cells that closely resemble those present at the 8-cell embryo stage of human development. This stage is particularly significant because it is when the embryo’s genome “wakes up” and takes over cell differentiation and development from the maternal genome, a process called zygotic genome activation (ZGA).

The new stem cell model will allow researchers to map out the key genomic changes that occur during early development, and help move towards a better understanding of the implications of genome activation errors in developmental disorders and embryo loss.

Existing human stem cell models represented the embryo only at later stages of the developmental process, so researching human ZGA could only be done in human embryos. While not illegal in the UK, use of human embryos is highly regulated and much early development research has relied on non-human models. “Studying mouse embryonic stem cells [ESC] has allowed researchers to learn about the general process of genome activation, but we could learn even more about this important step in human development thanks to our discovery of a human stem cell counterpart,” says Dr. Jasmin Taubenschmid-Stowers, lead author and Research Fellow in the lab of Babraham Institute group leader, Professor Wolf Reik. 

In this study, published recently in Cell Stem Cell, researchers used existing human data sets and information from mouse ESC studies to identify characteristic transcriptome marks that could be linked to genome activation. Using single cell techniques, they started the search for similar cells in their population of human ESCs.  The team found a subset of human ESCs with the right transcriptome marks to be a potential match for the 8-cell stage. They called these cells “8-cell like cells” (8CLCs) and used the published human data to further validate and confirm that these cells shared the same molecular outputs indicative of genome activation and could be pursued as a reliable model for future studies.

To further explore the extent of the similarities between their 8CLCs and 8-cell stage in human embryos, the team worked with Professor Jennifer Nichols from the Wellcome - MRC Cambridge Stem Cell Institute. Together they were able to select and search for proteins present in both sets of cells that were indicative of ZGA. Their results showed that the ZGA-associated proteins of 8CLCs closely matched those seen in human 8-cell embryos.   

 “The collaboration with Professor Nichols and her team was vital as we could identify selected proteins and really look at those in real, fixed human 8-cell stage embryo cells compared to our new stem cell counterparts,” says Dr. Taubenschmid-Stowers.  “This work confirmed that our 8C-like cells matched at the protein level too, in additional to the transcriptomics data, providing validation that the 8-cell like cells matched embryo cells across multiple molecular layers.”

Dr. Reik says the focus is now on characterizing the cells and understanding their unique properties, “so that we can use 8-cell like cells as a tool to ask questions about the molecular changes that may cause developmental issues at this early stage.”