The early embryo is often thought to be fragile and in need of support. However, in the earliest stages of development, it has the power to nourish the future placenta and instructs the uterus so that it can 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 takes care of whom at the beginning of life? The placenta and uterus nourish and protect the fetus. But the situation at the very early stage of development, when the blastocyst is still floating in the uterus, has been unclear until now. Now Nicolas Rivron’s research group at IMBA (Institute of Molecular Biotechnology of the Austrian Academy of Sciences) has uncovered basic principles of early development using blastoids.
Blastoids are in vitro models of the blastocyst, the mammalian embryo in the first days after fertilization. These embryo models were first developed by the Rivron lab from mouse stem cells (Nature, 2018) and then from human stem cells (Nature, 2021). Blastoids provide an ethical alternative to using embryos for research and, most 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. “In this way, the embryo invests in its own future: it promotes the formation of the tissues that will later ensure its development. The embryo is in control and instructs the creation of a supportive environment,” says Nicolas Rivron.
Indeed, the team discovered several molecules secreted by the few cells from which the fetus develops, the epiblasts. They noted that these molecules tell other cells, the trophoblasts that later form the placenta, to self-renew and proliferate, two stem cell properties essential for placental growth.
The team also found that these molecules prompt the trophoblasts to secrete two other molecules, WNT6 and WNT7B. WNT6 and WNT7B tell the uterus to wrap around the blastocyst. “Other researchers had previously seen that WNT molecules are involved in the uterine response. Now we show that these signals are WNT6/7B and that they are produced by the blastocyst trophoblasts to warn 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,” says Nicolas Rivron.
The team made their findings in part by examining the degree of implantation of the mouse blastoids in an in vivo implantation mouse model. “I was very surprised by the efficiency with which our blastoids were implanted in the uterus. And by changing the properties of the trophoblasts in blastoids, including WNT6/7B secretion levels, we could clearly change the size of the uterine cocoon,” said co-first author Jinwoo Seong, a postdoctoral researcher in the Rivron lab, who did these experiments.
Because implantation is the sticking point in human pregnancies — about 50 percent of pregnancies fail at that point — and WNT6 and WNT7B are also present 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 a dish, to estimate the conservation of such basic principles of development. These discoveries could ultimately help improve IVF procedures, develop 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. pupil. “Understanding these fundamental principles of embryonic development will ultimately help women gain more control over their fertility, which would not only improve family planning but also influence gender equality in society,” says Viktoria Holzmann.
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