Blastocyst model
Artificial human embryo was able to start implantation in a test tube
Polina Loseva, N+1
A group of embryologists has taken another step in modeling early human development: they managed not only to create an embryo from stem cells, but also to simulate its implantation into the uterine wall. However, this happened only in a test tube — that's why they used an endometrial organoid instead of a uterus, and the implanted embryo could not develop normally. Nevertheless, it shows that the artificial embryo possessed many properties of real embryos, and it can be used as a model, for example, in the development of contraceptives. The work was published in the journal Nature (Kagawa et al., Human blastoids model blastocyst development and implantation).
It is very difficult to study the early stages of human development — two problems prevent this. Firstly, there are no available embryos: in the first weeks, women often do not know that they are pregnant, and even if they want to, they do not have time to have an abortion. And working with "extra" embryos that remain, for example, after IVF, is not allowed in all countries.
Secondly, such embryos are difficult to grow: at the end of the first week they must be implanted into the uterine wall in order to develop normally further. This stage has not yet been learned to reproduce in vitro, so researchers have to simulate it using different substrates and signaling substances. As a result, even if the embryo continues to develop, it still turns out not to look like a real embryo — at least in its geometry.
A group of scientists led by Nicolas Rivron from the Institute of Molecular Biotechnology of the Austrian Academy of Sciences was lucky not to encounter the first problem: they worked with a culture of stem cells from a donor embryo left after IVF (parents donated it for research). Armed with these cells, they tried to solve the second problem and create an embryo that would look like a real one and could be implanted into a model uterus in vitro.
To do this, the researchers placed the cells in wells of hydrogel, where they formed compact spheres. After that, they were affected by inhibitors of three signaling pathways, Hippo, TGF-β and ERK. As a result, the cells that were on the surface of the spheres turned into a trophectoderm — a dense layer of cells from which extraterrestrial tissues are subsequently formed. They started pumping water into the sphere and turned it into a cellular ball with a cavity inside. This is what the embryo looks like by the end of the first week of development, this stage is called blastocyst.
Blastoids in gel wells. Drawings from the article by Kagawa et al.
At the same time, inside all the blastoids (as the researchers called their result), two groups of cells spontaneously stood out, resembling a primitive endoderm (another future extra-germ tissue) and an epiblast (the embryo itself, from which all body tissues are then formed). The authors of the work disassembled the blastoids by individual cells and checked that these three types of cells, according to the set of working genes, are really similar to their counterparts from ordinary embryos. No other types were found in the blastoids — with the exception of analogues of the amnion, later extra-germ tissue, but they were counted no more than 3 percent.
After that, the scientists checked whether their blastoids retained the main property of the blastocyst — the ability to implant. To do this, they planted blastoids to endometrial organoids — groups of cells that mimic the structure of the uterine wall. It turned out that blastoids can successfully attach to the endometrium. At the same time, the blastoids, from which the epiblast was removed, leaving only extra-germ tissues, could not be implanted. Similarly, they did not attach to the endometrium, which was not activated by female sex hormones. Thus, they reproduced all the main implantation mechanisms quite accurately.
A real blastocyst (top) and a blastoid (bottom) after implantation. All cells of the embryo are colored blue, the germinal part itself is yellow, the extra—embryonic tissues are gray (they form an analog of the amniotic cavity).
The researchers left the attached embryos to grow on the endometrium for several more days. Their extra—germ tissues have grown and even started producing chorionic gonadotropin, a hormone whose concentration in a woman's blood determines pregnancy in the early stages. But the actual germ part, although it remained alive, did not look like real embryos, and on the 13th day the experiment was stopped.
This is not the first study whose authors managed to collect blastoids from stem cells. Moreover, previously they could be created even from non-embryonic stem cells. But until now, no one has tested them for their ability to implant. The next step should be to improve the model, which will allow the embryonic part of the blastoids to develop further. In the meantime, the authors promise that their model could be useful in developing environments for embryo cultivation (they are used, for example, in IVF) — and checking for contraceptive drugs that block the attachment of the blastocyst to the uterus.
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