Researchers Grow Synthetic Mouse Embryo

Researchers from the University of Cambridge and Caltech have created model mouse embryos from stem cells that have beating hearts and the foundations for a brain and all other organs. The culmination of more than a decade of research, the breakthrough could help researchers understand why some embryos fail while others go on to develop into a fetus as part of a healthy pregnancy. Additionally, the results could be used to guide repair and development of synthetic human organs for transplantation.

"This opens new possibilities to study the mechanisms of neurodevelopment in an experimental model," says Magdalena Zernicka-Goetz, Bren Professor of Biology and Biological Engineering at Caltech and a professor of mammalian development and stem cell biology in Cambridge’s Department of Physiology, Development and Neuroscience. "In fact, we demonstrate the proof of this principle in the paper by knocking out a gene already known to be essential for formation of the neural tube, precursor of the nervous system, and for brain and eye development. In the absence of this gene, the synthetic embryos show exactly the known defects in brain development as in an animal carrying this mutation. This means we can begin to apply this kind of approach to the many genes with unknown function in brain development."

For a human embryo to develop successfully, there needs to be a "dialogue" between the tissues that will become the embryo and the tissues that will connect the embryo to the mother. In the first week after fertilization, three types of stem cells develop: one will eventually become the tissues of the body, and the other two will support the embryo's development. One of these latter two types, known as extraembryonic stem cells, will become the placenta, which connects the fetus to the mother and provides oxygen and nutrients. The other will become the yolk sac, where the embryo grows and from which it receives nutrients in early development.

Many pregnancies fail at the point when the three types of stem cells begin to send mechanical and chemical signals to each other, which tell the embryo how to develop properly.

The synthetic mouse embryo model, described in a recent issue of the journal Nature, was developed by guiding the three types of stem cells found in early mammalian development to the point where they start interacting. By inducing the expression of a particular set of genes and establishing a unique environment for their interactions, the researchers were able to get the stem cells to "talk" to each other. The stem cells self-organized into structures that progressed through the successive developmental stages until the synthetic embryos had beating hearts and the foundations for a brain, as well as the yolk sac where the embryo develops and from which it receives nutrients in its first weeks. This is the most advanced stage of development achieved to date in a stem cell-derived model.

A major advance in this study is the ability to generate the entire brain, in particular the anterior region, which has been a "holy grail" in the development of synthetic embryos.  "Our mouse embryo model not only develops a brain, but also a beating heart, all the components that go on to make up the body," Zernicka-Goetz says.

Over the past decade, Zernicka-Goetz's team has been studying these earliest stages of pregnancy to understand why some pregnancies fail and some succeed.  "The stem cell embryo model is important because it gives us accessibility to the developing structure at a stage that is normally hidden from us due to the implantation of the tiny embryo into the mother's womb," Zernicka-Goetz says. "This accessibility allows us to manipulate genes to understand their developmental roles in a model experimental system."

While the current research was carried out in mouse models, the researchers are developing an analogous model for human embryo development to understand mechanisms behind crucial processes that would be otherwise impossible to study in real embryos. If these methods are shown to be successful with human stem cells in future, they could also be used to guide development of synthetic organs for patients awaiting transplants.