China: Three monkeys became pregnant with artificial embryos made with stem cells

(Jie Li https://go.nature.com/43kMUT2)

Chinese embryologists from the Institute of Neurosciences in Shanghai have harvested macaque embryos from stem cells and grown them up to day 17 of development.

So far, no one had obtained such results on monkeys; most artificial embryos were grown from mouse cells.

Scientists transplanted several collected embryos into surrogate mothers, and three of them even took root, but could not grow further and stopped developing.

This means they may not have turned out to be completely identical to ordinary embryos.

If it were possible to collect a full-fledged embryo without the participation of a sperm and an egg, this would solve many problems, both scientific and practical.

For example, one could investigate where developmental anomalies come from in the early stages.

Or testing drugs for teratogenicity.

But no one has yet created artificial embryos that would develop in exactly the same way as ordinary ones.

Israeli and British scientists, who are training to grow mouse embryos outside the uterus, have advanced the furthest in this direction.

Their embryos lasted eight days in culture, to the stage at which limbs begin to form.

This has not yet happened with human embryos - artificial embryos grow only to the stage of a blastocyst, which is about a week after fertilization.

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THE EXPERIMENT
Now, Chinese scientists led by Zhen Liu have decided to do a similar experiment on cynomolgus monkeys, a model that is much closer to humans than mice.

They collected the artificial embryos themselves according to the same principle as their Israeli and British colleagues.

As a source, they used a culture of macaque embryonic stem cells: those that can give rise to any tissue of the embryo.

Then the cells were divided into two groups, and one of them was affected by signaling substances, which turned it into an extra-embryonic tissue (trophoblast).

After that, the two groups were connected back, the trophoblast formed a layer of cells around the embryonic stem cells - and a blastoid, an analogue of the blastocyst, was obtained.

To make sure that the artificial embryo is similar in cellular composition to the real one, the scientists kept it in vitro for several days and disassembled it back into cells.

They checked whether the cells contained key marker proteins that distinguish between cell layers in early embryos.

And then RNA was sequenced in six thousand artificial embryo cells.

In the end, the researchers did not find significant differences between their artificial embryos and normal macaque embryos.

Nevertheless, there were some cells in the blastoids that were not fully analogous in the usual blastocyst.

After that, the scientists selected the most successful embryos and continued to grow them in vitro, comparing them with ordinary macaque blastocysts along the way.

Blastoids, like blastocysts, matured up to 15 days, and they had embryonic membranes.

After that, the blastocysts stopped developing, while the artificial blastoids continued to grow.

And by the 17th day they showed signs of gastrulation: the embryonic cells began to form the outer, inner and middle layers of the cells of the future body.

And the embryo formed an anterior-posterior axis.

(Cell Stem Cell/Li et al. https://bit.ly/3meY2jF)

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PREGNANT MONKEYS
Finally, the researchers decided to test how viable their blastoids would be in a real uterus.

They selected eight surrogate monkey mothers and implanted 8–10 blastoids each.

Three monkeys became pregnant.

Each of them had an outgrowth on the surface of the endometrium on ultrasound (apparently, it was an attached embryo).

Also, the concentration of gonadotropin (which determines the early stages of pregnancy) in the blood increased.

However, the signs of pregnancy disappeared in the second week.

Thus, the authors have created a valuable model for research.

The artificial embryos they collected have grown to the stage after which a body plan is formed - which means that developmental anomalies can be studied.

And this is the stage that has not yet been able to reproduce on human embryos, since in many countries experiments with them are limited to the 14th day after fertilization.

In addition, scientists expect they will be able to grow embryos even longer if they use more sophisticated cultivation technology.

Also, the researchers were convinced that their model is not a complete analogue of natural embryos, since they could not develop in the body of a surrogate mother.

Now scientists will have to find out what is the matter: either some properties of the original cells that prevent them from forming a full-fledged embryo, or some cultivation conditions are not optimally selected.

(Li et al. / Cell Stem Cell, 2023 https://bit.ly/40WX22A)

Sources:

• Cell Stem Cell: https://www.cell.com/cell-stem-cell/fulltext/S1934-5909(23)00080-2?
• ScienceAlert: https://www.sciencealert.com/world-first-monkeys-fall-pregnant-with-engineered-embryo-structures
• Nature: https://www.nature.com/articles/d41586-023-00996-0

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