The early embryo is in charge at the start of life.

 One frequently believes that the early embryo is fragile and requires assistance. However, during the early stages of development, it has the ability to feed the future placenta and instruct the uterus on how to nest. The Lab of Nicolas Rivron at IMBA demonstrated, using 'blastoids,' in vitro embryo models formed with stem cells, that the earliest molecular signals that induce placental development and prepare the uterus to come from the embryo itself. The findings, which have just been published in Cell Stem Cell, could help us better understand human fertility.

A fluorescently stained mouse blastoid for various cellular components
A fluorescently stained mouse blastoid for various cellular components. ©Rivron/CellStemCell/IMBA.

Who looks after whom at the start of life? The placenta and uterus nourish and protect the fetus. However, the situation at the very early stage of development, when the blastocyst is still floating in the uterus, has been unknown thus far. Using blastoids, Nicolas Rivron's research group at IMBA (Institute of Molecular Biotechnology of the Austrian Academy of Sciences) has now discovered fundamental principles of early development.

Blastoids are in vitro replicas of the blastocyst, the first few days of a mammalian embryo after fertilization. The Rivron lab-created these embryo models first with mouse stem cells (Nature, 2018) and then with human stem cells (Nature, 2021). Blastoids offer an ethical alternative to using embryos for research and, more importantly, allow for multiple discoveries.

Now, blastoids have solved a "chicken or egg" problem. The researchers discovered that the early embryonic part (ten cells) instructs the future placental part (100 cells) to form and the uterine tissues to change using mouse blastoids. "By doing so, the embryo invests in its own future by encouraging the formation of tissues that will soon care for its development. The embryo is in command, instructing the formation of a supporting environment "Nicolas Rivron says

A protein expression axis in a mouse blastoid.
A protein expression axis in a mouse blastoid. ©Rivron/CellStemCell/IMBA.

Indeed, the team discovered several molecules secreted by the epiblasts, the few cells from which the fetus develops. They discovered that these molecules instruct other cells, the trophoblasts that eventually form the placenta, to self-renew and proliferate, which are two stem cell properties required for the placenta to grow.

The researchers also discovered that these molecules cause trophoblasts to secrete two other molecules, WNT6 and WNT7B. The WNT6 and WNT7B genes instruct the uterus to wrap around the blastocyst. "WNT molecules have previously been shown to be involved in the uterine reaction by other researchers. We now show that these signals are WNT6/7B and are produced by blastocyst trophoblasts to alert the uterus to act. We know that these two molecules are expressed by the trophoblasts of human blastocysts, so the significance could be significant "Nicolas Rivron says

The researchers arrived at their conclusions in part by examining the extent of implantation of mouse blastoids in an in vivo implantation mouse model. "I was astounded by how quickly our blastoids implanted into the uterus. And we could clearly change the size of the uterine cocoon by changing the properties of the trophoblasts within blastoids, including WNT6/7B secretion levels "says Jinwoo Seong, a postdoctoral fellow in the Rivron lab who carried out the experiments.

Because implantation is the bottleneck in human pregnancies (around 50% of pregnancies fail at this stage), and WNT6 and WNT7B are also present in human blastocysts, these findings could help explain why things go wrong sometimes. "We are currently repeating these experiments in a dish with human blastoids and uterine cells to estimate the conservation of such fundamental principles of development. These discoveries could eventually help to improve IVF procedures, fertility drugs, and contraception "Nicolas Rivron says

Two other co-first authors contributed to the collaboration: Javier Fras Aldeguer, a former Ph.D. student, and Viktoria Holzmann, a current Ph.D. student. "Understanding these fundamental principles of embryonic development will eventually 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.

Source: Materials provided by IMBA- Institute of Molecular Biotechnology of the Austrian Academy of Sciences.

DOI: 10.1016/j.stem.2022.06.002


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