Early embryonic development stage finally mapped in humans

Scientists have shed light on an important stage of early embryonic development that has never been fully mapped out in humans before — a milestone that should contribute to the improvement of experimental stem cell models.

Due to more readily available samples, studies so far have focused on the first week after conception and at later stages beyond a month into pregnancy, during which organs form and mature. However, there is currently very little understanding of events that take place in the intervening days, which includes the crucial gastrulation stage that occurs shortly after the embryo implants in the womb. Analysis of a unique sample by researchers from the University of Oxford and Helmholtz Zentrum München, published in the journal Nature, helps fill this gap in our knowledge of early human embryogenesis.

Taking place roughly between days 14 and 21 after fertilisation, gastrulation is one of the most critical steps of development, in which a single-layered embryo is transformed into a multilayered structure known as the gastrula. During this stage, the three main cell layers that will later give rise to the human body’s tissues, organs and systems are formed.

“Our body is made up of hundreds of types of cells,” said Oxford Professor Shankar Srinivas, principal investigator on the new study. “It is at this stage that the foundation is laid for generating the huge variety of cells in our body — it’s like an explosion of diversity of cell types.”

The acquisition of ethically obtained human samples at these early stages is exceptionally rare, but the research team managed to obtain a sample through the Human Developmental Biology Resource, from an anonymous donor who generously provided informed consent for the research use of embryonic material arising from the termination of her pregnancy. The sample is estimated to be from around 16–19 days after fertilisation.

“This is such an early stage of development that many people would not have known they were pregnant,” said lead researcher Dr Richard Tyser, also from Oxford. “It is the first time an embryo at this stage of development has been characterised in such detail using modern technology.”

Researchers can only legally culture human embryos up to the equivalent of 14 days of development, which is just before the start of gastrulation, so it is not currently possible to study this stage in cultured human embryos. Consequently, our knowledge of events beyond 14 days after fertilisation is largely based on studies in animal models such as mouse and chicken. The study thus offers a unique glimpse into a central but typically inaccessible stage of our development.

“Our new sample is the bridge that links the very early stage of development with the later stages when organs begin to form,” Dr Tyser said. “This link in the human had previously been a black box, so we had to rely on other model organisms such as the mouse. Reassuringly, we have now been able to show that the mouse does model how a human develops at the molecular level. Such models were already providing valuable insights, but now this research can be further enriched by the fact we’re able to cast light into that black box and more closely see how it works in humans.”

Using single-cell sequencing to closely profile the embryo’s individual cells, researchers were able to identify 11 distinct cell types. While most of these cells were still immature, they discovered the presence of both blood cells and the primordial germ cells that give rise to gametes (ovum and sperm cells). Notably, the team did not find any evidence of mature neuronal cells or other cell types associated with the central nervous system.

As part of the University of Oxford’s commitment to open research, the team made the raw data available to researchers around the world prior to publication. Prof Srinivas noted, “Many people have already requested our molecular data and used it in their own analyses. The images of the embryo are also really valuable and have attracted a lot of interest because they are amongst the clearest images of this particular stage of development.”

To further make this valuable information accessible, the team created an interactive website — www.human-gastrula.net — for both the science community and general public. Dr Tyser said, “We’ve made it very easy for people to access this data, so anybody can go and look at a gene of interest and see where it’s expressed in the human embryo at this stage.”

Image credit: ©Tatiana Shepeleva/Dollar Photo Club

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