Synthetic embryos

Artificial mouse embryos developed before the eighth day outside the uterus

Polina Loseva, N+1

Israeli scientists have created mouse embryos from stem cells and grown them up to the eighth day of development — at this stage they have a body plan, symmetry and the heart begins to contract. Then they stopped growing, and the next day there were already anomalies of development. All this time, the embryos existed outside the uterus, it was replaced first by a static die, and then by a rotating drum. Next, the researchers plan to test this technique on humans, and if it works, use artificial embryos as a source of organs and cells for transplantation. The work of Tarazi et al. Post-gastrulation synthetic embryos generated ex utero from mouse naive ESCs is published in the journal Cell, and a story about new plans is published in MIT Technology Reviews.

In the spring of 2021, biologists from the Weizmann Institute under the leadership of Jacob Hanna they reported on their experience of using an "artificial uterus" for growing mouse embryos. Scientists, however, did not try to recreate the uterus itself as a structure, they were only interested in whether it was possible to reproduce the conditions in which embryos develop. Therefore, instead of the uterus, they first used a die with compartments filled with liquid, and then test tubes with liquid in a rotating drum.

This was not the first experience in the history of growing embryos outside the mother, but it turned out to be the most successful — mouse embryos grew to 11 days, they began to form internal organs and limbs. However, their development was not completely autonomous: the first six days the embryos were carried out in the mother's body, and only then they were removed from the uterus and transferred to ex utero culture.

Now Hannah's group has shown the results of their next experiment. Biologists continued to work with mice, but this time they tried to do without a mother at all, and even without a sperm with an egg.

The first task that the scientists had to solve was to assemble the embryo itself. Since they did not want to use eggs, they had only embryonic stem cells at hand — a culture that looks like part of the cells of an early embryo, but from which extra-embryonic tissues do not develop. Therefore, the researchers divided this culture into three groups. One was treated with signaling substances so that it turned into a trophectoderm (one of the extra-germ layers), the other was turned into a visceral endoderm (another extra-germ tissue), and the third was left unchanged. Then all three types of cells were put together and a structure similar to a germ cylinder was obtained — this stage of development is usually reached by the mouse embryo on the fourth day.

On the fifth day, the embryos were transferred to a rotating drum — the same one in which Hanna and his colleagues had previously grown real mouse embryos. There the embryos continued to develop: they have the necessary outlines, a longitudinal axis of symmetry, new germ membranes (yolk sac and allantois) have grown, precursors of the nervous system and intestines have appeared, muscles in the developing heart have begun to contract. But by the ninth day, they had anomalies: the heart had grown too much, and development stopped.

Researchers have verified that artificial embryos are similar to real ones in terms of gene expression. They found in them characteristic markers of extra-germ tissues, different layers of the future embryo and even germ cell precursors.

In conclusion to their article, Hanna and colleagues reported that they plan to repeat the technique further, but with artificial human embryos. But not in order to learn how to grow full-fledged people in vitro. Synthetic embryos, the researchers note, still cannot be considered identical to natural ones - the expression of genes and characteristic markers in their tissues, although quite close, still do not completely coincide. Nevertheless, according to the authors of the work, it will help to simulate human embryogenesis in vitro and understand how individual organ systems develop and where pathologies appear in them.

However, in an interview with MIT Technology Reviews, Hanna talked about bolder plans. He expects that synthetic human embryos grown ex utero can be used as a source of stem cells or even spare tissues and organs — not everything today can be grown in vitro. "We consider the embryo as the best 3D bioprinter," Hanna said. For these studies, he has already founded a new startup, Renewal Bio, together with his employees.

The startup has not yet disclosed detailed information about the planned experiments (except that the donor of cells for the first sample will be Hannah himself). But it is already clear that a fully working "printer" is still far away. One of the problems on the way of scientists will be the low efficiency of the procedure. At least in the case of mice, only two percent of the embryonic cylinders transplanted into a rotating culture survived without abnormalities until the eighth day. This is 0.1–0.5 percent of all cellular aggregates that scientists collected at the initial stage of work.

In addition, it may be difficult to obtain ethical approval for experiments. In many countries, it is prohibited to grow human embryos longer than 14 days of development or to use parts of them for therapeutic purposes. But in order to create a "printer", the embryos will have to grow to a stage similar to 40-50 days of pregnancy. In Israel, however, the legislation is not so strict: only cloning is prohibited, the remaining restrictions are advisory in nature.

Portal "Eternal youth" http://vechnayamolodost.ru