Cambridge University researchers have created model embryos from mouse stem cells that form a brain, a beating heart and the foundations of all the body’s other organs, a new way to recreate the early stages of life .
The team, led by Professor Magdalena Zernicka-Goetz, developed the embryo model without eggs or sperm and instead used stem cells, the body’s master cells, which can become almost any type of cell in the body.
The researchers mimicked natural processes in the lab by guiding the three types of stem cells found in early mammalian development to the point where they begin to interact. 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.
Stem cells self-organize into structures that progress through successive stages of development to have beating hearts and the foundations of the brain, as well as the yolk sac where the embryo develops and obtains nutrients in its early stages. weeks. Unlike other synthetic embryos, the models developed by Cambridge reached the point where the entire brain, including the anterior part, began to develop. This is a step further in development than has been achieved in any other stem cell-derived model.
The team says their findings, the result of more than a decade of research that progressively led to increasingly complex embryo-like structures and reported in the journal Nature, could help researchers understand why that 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.
“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, a professor of mammalian development and stem cell biology at the Department of Physiology, Cambridge Development. and Neuroscience. “It’s amazing that we’ve come this far. This has been the dream of our community for years and the main goal of our work for a decade and we’ve finally achieved it.”
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 support the development of the embryo. One of these types of extraembryonic stem cells will become the placenta, which connects the fetus to the mother and provides oxygen and nutrients; and the second is the yolk sac, where the embryo grows and where it gets its nutrients in the early stages of development.
Many pregnancies fail at the point when the three types of stem cells start sending mechanical and chemical signals to each other, telling the embryo how to develop properly.
“So many pregnancies fail around this time, 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 the pregnancy. If it goes wrong, the pregnancy will fail.”
For the past decade, Professor Zernicka-Goetz’s group in Cambridge has been studying these early stages of pregnancy, in order to understand why some pregnancies fail and others 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,” he said. 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 researchers 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, and eventually self- group in an embryo.
The researchers found that the extraembryonic cells signal the embryonic cells through chemical signals, but also mechanically, or through touch, guiding the development of the embryo.
“This period of human life is so mysterious, so to be able to see it happen in a dish, to have access to these individual stem cells, to understand why so many pregnancies fail and how we might prevent that from happening – is pretty special.” , said Zernicka-Goetz. “We looked at the dialogue that has to happen between the different types of stem cells at that time; we showed how it happens and how it can go wrong.”
An important advance in the study is the ability to generate the entire brain, particularly the anterior part, which has been an important goal in the development of synthetic embryos. This works in the Zernicka-Goetz system because this part of the brain requires signals from one of the extraembryonic tissues in order to develop. The team thought this might be the case based on their 2018 and 2021 studies, which used the same component cells to develop into embryos at a slightly earlier stage. Now, by pushing the development just one day further, they can say definitively that their model is the first to point to the development of the forebrain, and indeed the entire brain.
“This opens up new possibilities for studying neurodevelopmental mechanisms in an experimental model,” said Zernicka-Goetz. “In fact, we demonstrate proof of this principle in the paper by knocking out a gene that is already known to be essential for the formation of the neural tube, the precursor to the nervous system, and for the development of the brain and eyes. In the absence of this gene, synthetic embryos show exactly the same defects known 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.”
Although the current research was conducted in mouse models, researchers are developing similar human models with the potential to target the generation of specific organ types to understand the mechanisms behind crucial processes that otherwise it would be impossible to study in real embryos. UK law currently allows human embryos to be studied in the laboratory only 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 resulting knowledge could be used to grow correct synthetic human organs to save lives that are currently lost. It should also be possible to affect and heal organs adults using the knowledge we have about how they are made.
“This is an incredible step forward and it took 10 years of hard work from many of my team – I never thought we would get to this place. You never think your dreams will come true, but they have.”
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