The ability of cells in early human embryos to become more specialised does not depend on a process previously thought necessary from work in stem cell models
Presented here is recently published work from A. Sophie Brumm, former PhD student in the group of Kathy Niakan, director of the Loke Centre for Trophoblast Research, and Professor of Reproductive Physiology at Cambridge University along with colleagues from the Babraham and Francis Crick Institutes.
The Niakan group has a long-standing interest in the early development of human embryos, from fertilization of the egg through to implantation into the uterus.
At 5 days post fertilisation, the human embryo forms a structure called the blastocyst, containing three types of cells which perform distinct functions to support further development of the embryo. One cell type is called the ‘epiblast’, which eventually generates all cell types in the adult body and is therefore considered pluripotent.
The authors assessed if a particular cell-to-cell communication was necessary to generate or maintain the human epiblast.
Why study cell specification in early human embryos?
Basic research on early human development is highly regulated and faces many technical challenges. Therefore, our understanding of early human development rests primarily on the study of other mammalian embryos, such as mouse, or cow, which serve as model. Moreover, pluripotent stem cells derived from the human embryo serve as models in a dish, which have been used extensively to study the mechanisms underlying human pluripotency.
However, no model could ever fully recapitulate the actual human embryo. To understand why human embryos fail to develop or to implant in the uterus, which are major causes of infertility, we need to study the human embryo development directly.
Copyright 2025 under CC BY 4.0
Copyright 2025 under CC BY 4.0
How do you analyse cell-to-cell communication?
Cells communicate with one another other by so-called signalling pathways. In this case, one cell secrets a signal protein (Nodal), which is recognised by a second protein (Receptor) on the surface of another cell. Binding of Nodal to the Receptor causes changes in the receiving cells that can be detected. In this case, a chemical modification of a third protein (Effector), which accumulates in the nucleus of the receiving cell.
To analyse signalling events caused by Nodal, the authors used antibodies, which are proteins produced by the immune system to stick to a specific protein. Antibodies are chemically connected to a fluorophore, which can be used to visualise the modification and location of the Effector.
Is Nodal signalling active in the human epiblast?
The authors optimised a method to detect the Effector specific to Nodal signalling in the early human embryo. This method was used to characterise the dynamic of Nodal signalling throughout early human development.
At first, we analysed when Nodal signalling becomes active in the course of human development. Using our method of Nodal signalling detection, we found signs of Nodal signalling activity at 6 and 7 days post fertilisation, but not earlier. Interestingly, we were able to detect the emergence of the pluripotent epiblast already at 5 days post fertilisation, suggesting that Nodal signalling was not required for this process.
Copyright 2025 under CC BY 4.0
Is Nodal signalling required in the human epiblast?
We then systematically explored the efficacy of different small-molecule inhibitors, designed to prevent Nodal signalling activity. In contrast to stem cell in a dish or mouse embryos, inhibition of Nodal signalling in human embryos proved challenging.
Once we identified a functional Nodal signalling inhibitor, we observed that treated human embryos developed normally, without signs of cell death, and generated all three cell types of the embryo as expected. We therefore concluded that Nodal signalling activity was not required for the specification or maintenance of the human pluripotent epiblast, or blastocyst formation as a whole.
Copyright 2025 under CC BY 4.0
What embryos were imaged and where did they come from?
The donation of human embryos to basic research is carefully regulated by the Human Fertilisation and Embryo Authority (HFEA) and local ethics committees, such as the Cambridge Central Research Ethics Committee. Within this framework, patients of IVF clinics donate embryos surplus to their family building to research and provide informed consent for their usage in specific projects and applications.
You can find out more about the process of embryo donation on this website and about HDBI research tissue and ethics on our page and in our FAQ.
New insights
We were able to visualise Nodal signalling activity in human embryos for the first time. Through small-molecule treatment, we found that inhibition of Nodal signalling did not impair the formation of the pluripotent epiblast.
This is in contrast to current stem cell models of human pluripotency, which requires Nodal signalling activity to preserve pluripotency.
These results indicate a difference in the basic regulation of human pluripotency in the embryo as compared to a model in a dish. Our study therefore suggests a need for better models and highlights the value and importance of basic research on the human embryo itself.
Copyright 2025 under CC BY 4.0
Where Can I Learn More?
You can read the full paper here
Find out more about the Niakan group and their latest work at their website
For more on early human development checkout their page on this site
Lay Summary by A. Sophie Brumm, Edited by Richard Acton & Kathy K. Niakan