How does the human embryo develop shortly after it has implanted in the uterus? Researchers have not yet been able to answer this question in detail. A human embryo donated to science, which originated from an abortion between the 16th and 19th day after fertilization, has now provided unique insights into an important phase of early human development, gastrulation. For the first time, researchers were able to describe in detail which cell types occur in this phase and which genes they express. The findings help to be able to use and interpret model systems better in the future.
Gastrulation is a crucial step in human embryonic development. In the third week after fertilization, the so-called three-leaved germinal disc is formed from which the various parts of the embryo’s body later develop. This phase is considered to be the beginning of human individuality. For this very reason it is internationally forbidden to examine embryos in test tubes longer than 14 days after fertilization. Most of the knowledge about gastrulation in humans therefore comes from animal or cellular model systems. But without a natural role model, the informative value of these models was limited.
Analysis of cell types and gene expression
A team led by Richard Tyser from the University of Oxford now had the extraordinary opportunity to examine a real human embryo between the ages of 16 and 19 days. The embryo came from an unwanted pregnancy and was made available for research after the abortion. “The sample was completely intact and morphologically normal,” write the researchers. “Our analyzes indicate that this sample is representative of normal human gastrulation.” However, they emphasize that generalizations can only be made to a limited extent as the findings are based on only a single sample.
Tyser and his colleagues mapped 1,195 individual cells of the embryo and assigned them to eleven different cell types, including the endoderm, from which the digestive tract, among other things, and various types of mesoderm, from which bones, muscles and various internal organs later develop . In addition, they analyzed for all cell types which genes were active in the respective cells. They recorded around 4,000 genes per cell. Since the embryo was a boy, activity on the Y chromosome could be detected in all cells, so that the researchers were able to rule out contamination by maternal cells.
Similarities and differences to model systems
In order to classify the results and make them comparable, the researchers compared the data obtained from the human embryo with previous model systems, including gastrulation in mice and macaques and an in vitro model in which gastrulation is simulated in a test tube with the help of embryonic stem cells will. “The analysis of the gene expression in the three species revealed great similarities, but also some specific differences,” the researchers report. Many genes were activated similarly during gastrulation in both humans and mice. “This suggests that the mouse is a good model for human gastrulation,” conclude Tyser and his colleagues.
On the other hand, they discovered serious differences in some important aspects. Red blood cell precursors were already found in the human embryo, which was barely more than two weeks old. The corresponding globin genes were also active. “This was unexpected, since pigmented blood cells in the appropriate stage are missing in mouse embryos,” said the researchers. “The presence of cells with hemoglobin and several hematopoietic precursor populations suggests that the formation of blood cells in humans is more advanced than in mouse embryos at the same stage.” In addition, the researchers discovered so-called primordial germ cells in the embryo which later develop eggs or sperm. The differentiation of cells of the nervous system, however, had not yet started at this stage.
Resource for future research
“These human-specific details of differentiation will be a valuable resource when it comes to refining approaches for the targeted differentiation of human embryonic stem cells,” the researchers write. “In addition, they will help to interpret experimental results on the gastrulation of model organisms such as the mouse or in vitro gastrula systems.”
Alexander Goedel and Fredrik Lanner from the Karolinska Institute in Stockholm, who were not involved in the study, see it similarly an accompanying commentary that was also published in the journal Nature. Accordingly, it is also important to clarify the transferability of the in vitro models currently being developed for gastrulation. “A careful assessment of their correspondence with the corresponding cell types in vivo is necessary in order to determine whether such models keep the promise of opening this black box of embryology and providing mechanistic insights into this stage of human development,” said Goedel and Lanner.
Source: Richard Tyser (University of Oxford, UK) et al., Nature, doi: 10.1038 / s41586-021-04158-y