Researchers at the Reik lab have today published their latest book describing a new subset of human embryonic stem cells that closely resemble the cells present in the genomic “awakening” of the 8-cell embryonic stage in humans. This novel stem cell model will allow researchers to map major genomic changes during early development and contribute to a better understanding of the implications of genome activation errors in developmental disorders and embryo loss.
In all mammals, the early embryo undergoes a number of molecular events just after fertilization that set the stage for further development. During this key ‘wake-up’, the embryo’s genome takes control of the cell’s activities from the maternal genome. In humans, this occurs at the 8-cell stage and is called zygotic genome activation (ZGA).
Prior to the results of this study, study of the details of human ZGA could only be performed on human embryos; existing human stem cell models only represented the embryo at later stages of the development process. In the UK, experiments using embryos are permitted but highly regulated, which meant that early development research relied in part on alternative non-human models.
In 2012, cells representing the developmental stage of genome activation were found in mouse embryonic stem cells (ESCs), allowing researchers to learn more about mammalian ZGA. Nearly a decade later, the Reik lab has found a human equivalent. The discovery from the Reik lab opens the way to advancing our knowledge of the early events of preimplantation development.
Dr Jasmin Taubenschmid-Stowers, researcher at Reik Laboratory and lead author, commented, “Studying mouse embryonic stem cells has allowed researchers to learn more about the general process of genome activation, but we could learn even more about this important step in human development. through our discovery of a human stem cell counterpart.
Images showing human 8C-like cells among naïve embryonic stem cells (left) and human 8-cell embryos (right) fluorescently labeled for TPRX1 (green), H3.Y (red), and DNA (blue). The image shows that the ZGA marker proteins TPRX1 and H3.Y are present in both cell populations. Credit: Dr Jasmin Taubenschmid-Stowers Babraham Institute, Dr Fátima Santos Babraham Institute, Dr Jennifer Nichols, University of Cambridge.
To function, cells take copies of the genome in the form of an RNA code that is translated into proteins. The output of the RNA code is called the transcriptome and can be used to identify different populations of cells. In this study, the researchers used existing human datasets and information from mouse ESC studies to identify characteristic transcriptomic marks that may be linked to genome activation. Using single cell techniques, they began searching for similar cells in their population of human ESCs.
The team found that a subset of human ESCs with the correct transcriptome marks were a potential match for the 8-cell stage, when the major wave of genome activation occurs. They called these cells “8-cell like cells” or 8CLCs and used published human data to validate and further confirm that these cells shared the same molecular outputs indicative of genome activation and could be pursued as a reliable model for further development. future studies.
To further explore the extent of similarities between their 8CLCs and the 8-cell stage in human embryos, the team worked with Professor Jennifer Nichols of 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.
As Jasmin explains, “The collaboration with Dr. Nichols and his team was essential, because we could identify select proteins and really compare them to those of real, fixed human embryonic cells at the 8-cell stage compared to our new stem cells. counterparts. This work confirmed that our 8C-like cells also matched at the protein level, in addition to transcriptomic data, confirming that 8-cell-like cells matched embryonic cells through multiple molecular layers.
“Our goal now is to characterize these cells and understand their unique properties so that we can use 8-cell cells as a tool to ask questions about molecular changes that may cause developmental problems at this early stage.” said Professor Reik, group leader of the Babraham Institute.
Reference: Taubenschmid-Stowers J, Rostovskaya M, Santos F, et al. Type 8C cells capture the activation program of the human zygotic genome in vitro. Cell Stem Cell. 2022. do: 10.1016/j.stem.2022.01.014.
This article was republished from the following materials. Note: Material may have been edited for length and content. For more information, please contact the quoted source.