Scientists from the University of Cambridge have created models of embryos from mouse stem cells that form a brain, a beating heart and the foundations of all the body’s other organs. It represents a new avenue for recreating the early stages of life. The team of researchers, led by Professor Magdalena Zernicka-Goetz, developed the embryo model without eggs or sperm. Instead, they used stem cells – the body’s master cells, which can develop into almost any type of cell in the body. “It’s incredible that we’ve come this far. This has been the dream of our community for years, and the main focus of our work for a decade, and we finally did it.” — Magdalena Zernicka-Goetz By directing the three types of stem cells found in early mammalian development to the point where they begin to interact, the researchers mimicked natural processes in the laboratory. Scientists have managed to make stem cells “talk” to each other by causing the expression of a specific set of genes and creating a unique environment for their interactions. The stem cells self-organized into structures that progressed through the successive developmental stages until they hit the hearts and foundations of the brain. They also had the yolk sac where the embryo develops and receives nutrients from its first weeks. Unlike other synthetic embryos, the models developed at Cambridge reached the point where the entire brain, including the forebrain, began to develop. This is a further development point than has been achieved in any other stem cell-derived model. According to the team, their results could help researchers understand why some embryos fail while others develop into a healthy pregnancy. In addition, the results could be used to guide the repair and development of synthetic human organs for transplantation. The study, which is the result of more than a decade of research that has gradually led to increasingly complex embryo-like structures, was reported on August 25, 2022 in the journal Nature. Natural and synthetic embryos side by side show comparable brain and heart formation. Credit: Amadei and Handford “Our mouse embryo model not only develops a brain, but also a beating heart, all the components that make up the body,” said Zernicka-Goetz, Professor of Mammalian Development and Stem Cell Biology in Cambridge’s Department of Physiology, Development. and Neuroscience. “It’s incredible that we’ve come this far. This has been the dream of our community for years, and the main focus of our work for a decade, and we finally did it.” A “dialogue” between the tissues that will form the fetus and the tissues that will connect the fetus to the mother is necessary for the healthy development of a human fetus. Three different types of stem cells begin to form in the first week after fertilization. one of these will eventually develop into body tissues, while the other two support the development of the embryo. One of these extraembryonic stem cell types will become the placenta, which connects the fetus to the mother and provides oxygen and nutrients. The second is the yolk sac, where the embryo develops and from where it gets its nutrients in early development. Many pregnancies fail at the point where the three types of stem cells begin to send mechanical and chemical signals to each other that instruct the embryo how to develop properly. “So many pregnancies fail right now, before most women even realize they’re pregnant,” said Zernicka-Goetz, who is also a professor of biology and biological engineering at Caltech. “This period is the foundation for everything else that follows in pregnancy. If it goes wrong, the pregnancy will fail.” Professor Zernicka-Goetz in the laboratory. Credit: University of Cambridge Professor Zernicka-Goetz’s team at Cambridge has been studying these early stages of pregnancy for the past decade in order to understand why some pregnancies fail and some succeed. “The stem cell embryo model is important because it gives us access to the developing structure at a stage that is normally hidden from us due to the implantation of the tiny embryo in the mother’s uterus,” said Zernicka-Goetz. “This accessibility allows us to manipulate genes to understand their developmental roles in a model experimental system.” To guide the development of their synthetic embryo, the scientists assembled cultured stem cells representing each of the three tissue types in the right proportions and environment to promote their growth and communication with each other, eventually self-assembling into an embryo. The research team discovered that the extraembryonic cells signal to the embryonic cells with chemical signals as well as mechanically or through touch, guiding the development of the embryo. “This period of human life is so mysterious, to be able to see how it happens in a dish – to have access to these individual stem cells, to understand why so many pregnancies fail and how we can prevent that from happening – is very special,” Zernicka-Goetz said. “We looked at the dialogue that needs to take place between the different types of stem cells at that time – we showed how it occurs and how it can go wrong.” A major advance in the study is the ability to create the entire brain, particularly the anterior part, which has been a major target in the development of synthetic embryos. This works in the Zernicka-Goetz system because that part of the brain requires signals from one of the extraembryonic tissues to be able to develop. The team thought this might be taking place from their 2018 and 2021 studies, which used the same constituent cells to develop into embryos at a slightly earlier stage. Now, pushing development just one day further, they can say definitively that their model is the first to signal the development of the forebrain, and indeed the entire brain. “This opens up new possibilities for studying the mechanisms of neurodevelopment in an experimental model,” said Zernicka-Goetz. “In fact, we demonstrate proof of principle in the paper by knocking out a gene already known to be necessary for the formation of the neural tube, a precursor to the nervous system, and for brain and eye development. In the absence of this gene, synthetic embryos show exactly the same known defects in brain development as an animal carrying this mutation. This means we can start to apply this kind of approach to the many genes with unknown function in brain development.” While the current research was conducted in mouse models, researchers are developing similar human models with the potential to target the creation of specific types of organs to understand mechanisms behind critical processes that would otherwise be impossible to study in real embryos. Currently, UK law only allows human embryos to be studied in the laboratory up to day 14 of development. If the methods developed by Zernicka-Goetz’s team prove successful with human stem cells in the future, they could also be used to guide the development of synthetic organs for patients awaiting transplants. “There are so many people around the world who wait years for organ transplants,” Zernicka-Goetz said. “What makes our work so exciting is that the knowledge that comes from it could be used to develop correct synthetic human organs to save lives that are currently lost. It should also be possible to affect and heal adult organs using the knowledge we have of how they are made. “This is an incredible step forward and has taken 10 years of hard work from many of my team members – I never thought we would get to this place. You never think your dreams will come true, but they have.” Professor Magdalena Zernicka-Goetz made an incredible scientific discovery. Creating synthetic test-tube mouse embryos that develop brains and beating hearts, starting with just embryonic stem cells, is the culmination of a decade’s worth of work. Magda explains: I am fascinated by the mystery of how embryos work. Every embryo follows a similar journey: one cell becomes many, then they communicate with each other and arrange themselves to form a structure that will provide a blueprint for all parts of the adult body. But how do embryonic cells decide their fate, how do they know where to go and what to do? How do they form the right parts in the right place at the right time? The construction of the first “synthetic embryo” models was a step-by-step process. To begin with, we knew that embryonic stem cells could be grown indefinitely in the lab and that when injected into an embryo they could potentially contribute to any tissue in the adult body. The challenge was to guide them to develop into a full embryo. In addition to embryonic stem cells, we used two types of extraembryonic tissue: one forms the placenta and the other a sac in which the embryo develops. These tissues are very important as they send signals to the embryo to develop all its parts at the right time and in the right place. The combination of stem cells that represent each of these three tissue types is easier said than done. We had to find an environment where all three different types of cells could grow and communicate with each other. And we had to find the right proportions of each cell type and add them in the right order. Once we established these basics, the stem cells did the rest: they organized themselves to proceed through successive developmental stages until they had beating hearts and the foundation for a brain. The key to our success was thinking outside the conventional box. The majority of embryonic model studies focus on embryonic stem cells, but do not consider the important role of extraembryonic cells. We…
