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The early embryo is in the driver’s seat

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It is often thought that the early embryo is fragile and in need of support. However, in the early stages of development, it has the power to nourish the future placenta and instruct the uterus so that it can nest. Using “blastoids”, in vitro models of embryos formed with stem cells, Nicolas Rivron’s laboratory at IMBA has shown that the first molecular signals that induce placental development and prepare the uterus come from the embryo itself. The findings, now published in Cell Stem Cell, could contribute to a better understanding of human fertility.

Who takes care of whom early in life? The placenta and uterus nourish and harbor the fetus. But the situation at the beginning of development, when the blastocyst still floats in the uterus, was unclear until now. Now Nicolas Rivron’s research team at IMBA (Institute of Molecular Biotechnology of the Austrian Academy of Sciences) has discovered the basic principles of early development using blastoids.

Blastoids are in vitro models of the blastocyst, the mammalian embryo in the first few days after fertilization. These embryo models were first developed by the Rivron laboratory from mouse stem cells (Nature, 2018) and then from human stem cells (Nature, 2021). Blastoids offer an ethical alternative to using embryos for research and, above all, allow for multiple discoveries.

Now the blastoids have solved a “chicken or egg” dilemma. Using mouse blastoids, the researchers found that the early embryonic part (~ 10 cells) instructed the future placental part (~ 100 cells) to form and the uterine tissues to change. “By doing so, the embryo invests in its future: it favors the formation of tissues that will soon take charge of its development. The embryo is responsible, ordering the creation of a supportive environment ”, specifies Nicolas Rivron.

Indeed, the team discovered several molecules secreted by the few cells from which the fetus develops, the epiblasts. They observed that these molecules tell other cells, the trophoblasts that will later form the placenta, to self-renew and proliferate, two properties of stem cells essential for placental growth.

The team also found that these molecules cause trophoblasts to secrete two more molecules, WNT6 and WNT7B. WNT6 and WNT7B signal the uterus to wrap around the blastocyst. “Other researchers had already seen that WNT molecules are involved in the uterine reaction. We now show that these signals are WNT6 / 7B and are produced by the trophoblasts in the blastocyst to notify the uterus to respond. The relevance could be high because we have verified that these two molecules are also expressed by the trophoblasts of the human blastocyst ”, points out Nicolas Rivron.

The team made their findings in part by examining the extent of implantation of mouse blastoids in an in vivo implantation mouse model. “I was very surprised at how efficiently our blastoids implanted into the uterus. And by altering the properties of trophoblasts in blastoids, including secretion levels of WNT6 / 7B, we were clearly able to alter the size of the uterine cocoon, “says co-first author Jinwoo Seong, a postdoctoral fellow at the lab. Rivron, who carried out these experiments.

Since implantation is the bottleneck of human pregnancies – about 50% of pregnancies fail at this point – and WNT6 and WNT7B are also present in human blastocysts, these findings could explain why things sometimes go wrong. “We are now repeating these experiments with human blastoids and uterine cells, all in one dish, to estimate the conservation of these basic principles of development. These discoveries could eventually contribute to the improvement of IVF procedures, the development of fertility drugs and contraceptives, “says Nicolas Rivron.

The teamwork was also led by two other co-first authors: Javier Frías Aldeguer, a former PhD student, and Viktoria Holzmann, a current PhD student. student. “Understanding these fundamental principles of embryonic development will ultimately help women have greater control over their fertility, which would not only improve family planning, but would also impact gender equality in society,” says Viktoria Holzmann. .

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