Early life: Early embryo is in the driver's seat - Azi News

People often think that early embryos are fragile and need support. However, in the early stages of development, it has the power to feed the future placenta and command the uterus for nesting. Using the ‘blastoid’, an in vitro embryo model formed with stem cells, Nicolas Rivron’s Lab at IMBA demonstrated that the earliest 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 took care of whom in early life? The placenta and uterus nourish and protect the fetus. But the situation at an early stage of development, when the blastocyst is still afloat in the uterus, is so far unclear. Now, Nicolas Rivron’s group of researchers at IMBA (Institute of Molecular Biotechnology of the Austrian Academy of Sciences) discovered the basic principles of early development using blastoids.

The blastoid is an in vitro model of the blastocyst, the mammalian embryo in the first few days after fertilization. This embryonic model was first developed by Rivron’s lab from mouse stem cells (Alam, 2018) and later from human stem cells (Alam, 2021). Blastoids provide an ethical alternative to the use of embryos for research and, importantly, enable many discoveries.

Now, the blastoid solves the “chicken or egg” dilemma. Using mouse blastoids, the researchers found that the early embryonic portion (~10 cells) instructed the future placental portion (~100 cells) to form, and uterine tissue changed. “By doing this, the embryo is investing in its own future: promoting the formation of a network that will immediately take care of its development. The embryo is in control, instructing the creation of a supportive environment,” says Nicolas Rivron.

Indeed, the team found several molecules secreted by some of the cells from which the fetus develops, namely the epiblast. They observed that these molecules tell other cells, the trophoblast which then forms the placenta, to renew themselves and proliferate, two stem cell properties that are important for the placenta to grow.

The team also found that these molecules induce the trophoblast to secrete two other molecules, WNT6 and WNT7B. WNT6 and WNT7B tell the uterus to enclose the blastocyst. “Other researchers have previously seen that the WNT molecule is involved in the uterine reaction. We now show that these signals are WNT6/7B and they are produced by the blastocyst’s trophoblast to tell the uterus to react. The relevance could be high because we have verified that these two molecules are also expressed by the trophoblast of the human blastocyst,” said Nicolas Rivron.

The team made their findings in part by examining the extent of mouse blastoid implantation in a mouse model of implantation in vivo. “I was very surprised by the efficiency with which our blastoids were implanted into the uterus. And by changing the trophoblast properties in the blastoid, including the level of WNT6/7B secretion, we were able to clearly change the size of the uterine cocoon,” said co-first author Jinwoo Seong, a postdoctoral fellow in Rivron’s lab, who conducted the experiment.

Since implantation is a bottleneck in human pregnancies – about 50 percent of pregnancies fail at that – and WNT6 and WNT7B are also present in human blastocysts, these findings may explain why, sometimes, things go wrong. “We are currently repeating this experiment with human blastoids and uterine cells, all in a crucible, to estimate the conservation of this basic principle of development. This discovery could ultimately contribute to improving IVF procedures, developing fertility drugs, and contraception,” said Nicolas Rivron.

Teamwork was also encouraged by the other two first authors: Javier Frías Aldeguer, a former Ph.D. student, and Viktoria Holzmann, Ph.D. student. “Understanding the basic principles of embryonic development will ultimately contribute to empowering women to have a better grip on their fertility, which will not only improve family planning but also have an impact on gender equality in society,” says Viktoria Holzmann.

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