One often thinks that the early embryo is fragile and needs support. In the earliest stages of development, however, it has the power to feed the future placenta and instructs the uterus to nest. Using ‘blastoids’, in vitro embryo models formed with stem cells, Nicolas Rivron’s Lab at IMBA showed 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, may contribute to a better understanding of human fertility.
Who cares for whom at the beginning of life? The placenta and the uterus feed and protect the fetus. But the situation in the very early stage of development, when the blastocyst was still floating in the uterus, was so far unclear. Now the research group of Nicolas Rivron at IMBA (Institute for Molecular Biotechnology of the Austrian Academy of Sciences) has uncovered basic principles of early development using blastoids.
Blastoid is 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 (Earth2018) and then of human stem cells (Earth, 2021). Blastoids provide an ethical alternative to the use of embryos for research and, more importantly, enable multiple discoveries.
Now blastoids have solved a “chicken or egg” dilemma. Using mouse blastoids, the researchers found that the early embryonic part (~ 10 cells) instructs the future placental part (~ 100 cells) to form, and the uterine tissues to change. “By doing so, the embryo invests in its own future: it promotes the formation of the tissues that will soon take care of its development. The embryo is in charge and commands the creation of a supportive environment,“says Nicolas Rivron.
The team has indeed discovered several molecules secreted by the pair of cells from which the fetus develops, the epiblasts. They observed that these molecules tell other cells, the trophoblasts that later form the placenta, to renew and proliferate on their own, two stem cell properties that are essential for the placenta to grow.
The team also found that these molecules cause the trophoblasts to secrete two other molecules, WNT6 and WNT7B. WNT6 and WNT7B tell the uterus to wrap around the blastocyst. “Other researchers have previously seen that WNT molecules are involved in the uterine reaction. Now we show that these signals are WNT6 / 7B and that they are produced by the blastocyst trophoblasts to notify the uterus to respond. The relevance may be high because we have verified that these two molecules are also expressed by the trophoblasts of the human blastocyst,“says Nicolas Rivron.
The team made their findings in part by the extent of the implantation of the mouse blastoids in a in vivo implant mouse model. “I was very surprised by the effectiveness with which our blastoids were implanted in the uterus. And by changing the properties of the trophoblasts within blastoids, including the secretion levels of WNT6 / 7B, we can clearly change the size of the uterine cocoon,“says co-first author Jinwoo Seong, a postdoctoral fellow in the Rivron Laboratory, who conducted these experiments.
Because implantation is the bottleneck in human pregnancies – about 50 percent of pregnancies fail at that time – and WNT6 and WNT7B also occur in human blastocysts, these findings may explain why things sometimes go wrong. “We are currently repeating these experiments with human blastoids and uterine cells, all in one dish, to estimate the preservation of such basic principles of development. These discoveries may ultimately contribute to the improvement of IVF procedures, the development of fertility drugs and contraceptives“says Nicolas Rivron.
The teamwork was also driven by two other co-first authors: Javier Frías Aldeguer, a former Ph.D. student, and Viktoria Holzmann, a current Ph.D. student. “Understanding these fundamental principles of embryonic development will ultimately help empower women to have a better grasp on their fertility, which will not only improve family planning but also influence gender equality in society.“says Viktoria Holzmann.
Institute of Molecular Biotechnology of the Austrian Academy of Sciences
Seong, J., et al. (2022) Epiblast inducers capture mouse trophectoderm stem cells in vitro and pattern blastoids for implantation in utero. Selstamsel. doi.org/10.1016/j.stem.2022.06.002.