‘Synthetic’ embryo with brain and beating heart grown from multiple stem cells by Cambridge scientists

1. Natural and synthetic embryos

image: Natural and synthetic embryos side by side show comparable brain and heart formation.
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Credit: Amadei and Handford

Cambridge University researchers have created model embryos from mouse stem cells that form a brain, a beating heart and the foundations of all other organs in the body – a new way to recreate the earliest stages of life .

The team, led by Professor Magdalena Zernicka-Goetz, developed the embryo model without an egg or sperm, and instead used stem cells – the body’s master cells, which can develop into almost any type of cells in the body.

The researchers mimicked natural processes in the lab by guiding the three types of stem cells found early in mammalian development to the point where they begin to interact. By inducing the expression of a particular set of genes and creating a unique environment for their interactions, the researchers succeeded in making the stem cells “talk” to each other.

Stem cells self-organized into structures that progressed through successive stages of development until they had beating hearts and the foundations of the brain, as well as the yolk sac where the embryo grows and draws its nutrients in its first weeks. Unlike other synthetic embryos, the models developed by Cambridge have reached the point where the entire brain, including the front part, has begun to develop. This is a higher stage of development than that achieved in any other stem cell-derived model.

The team say their findings, the result of more than a decade of research that has gradually led to increasingly complex embryonic structures reported in the journal Nature, could help researchers understand why some embryos fail while others continue to develop into a healthy pregnancy. Additionally, 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, professor of mammalian development and stem cell biology in the Department of Cambridge Developmental Physiology. and Neuroscience. “It’s just incredible that we’ve come this far. It’s been our community’s dream for years, and the main focus of our work for a decade and finally we’ve done it.

For a human embryo to develop successfully, there must be a “dialogue” between the tissues that will become the embryo and the tissues that will connect the embryo to the mother. During 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 development of the embryo. One of these types of extra-embryonic 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 develops and from which it gets its nutrients during early development.

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

“So many pregnancies fail around this time, before most women realize they’re pregnant,” said Zernicka-Goetz, who is also a professor of biology and bioengineering at Caltech. “This period is the basis for everything that follows during pregnancy. If it goes wrong, the pregnancy will fail.

Over the past decade, Professor Zernicka-Goetz’s group at Cambridge has been studying these early stages of pregnancy, 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 small embryo in the mother’s womb,” Zernicka said. -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 support their growth and communication with each other, ultimately self-sustaining. -assemble into an embryo.

The researchers found that extra-embryonic cells send signals to embryonic cells through chemical signals but also mechanistically, or through touch, guiding the development of the embryo.

“This period of human life is so mysterious, so 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 might be able to prevent this from happening . — is pretty special,” Zernicka-Goetz said. “We looked at the dialogue that needs to happen between different types of stem cells at that time – we showed how it happens and how it can go wrong.”

A major advance in the study is the ability to generate the whole brain, especially the anterior part, which has been a major goal in the development of synthetic embryos. It works in the Zernicka-Goetz system because this part of the brain needs signals from one of the extra-embryonic tissues in order to develop. The team thought this might happen from their 2018 and 2021 studies, which used the same constituent cells to develop into embryos at a slightly earlier stage. Now, taking the development one day further, they can definitely say that their model is the very first to report the development of the forebrain, and indeed the whole brain.

“This opens up new possibilities for studying the mechanisms of neurodevelopment in an experimental model,” Zernicka-Goetz said. “In fact, we demonstrate the proof of this principle in the article by deleting a gene already known to be essential for the formation of the neural tube, precursor of the nervous system, and for the development of the brain and the eyes. In the absence of this gene, synthetic embryos exhibit exactly the known defects in brain development as in an animal carrying this mutation. This means that we can begin to apply this type of approach to the many genes whose function is unknown in brain development.

While current research has been conducted in mouse models, researchers are developing similar human models with the potential to be directed towards generating specific organ types to understand the mechanisms behind crucial processes that would otherwise be impossible to study in real embryos. At present, UK law only allows human embryos to be studied in the laboratory until the 14the development day.

If the methods developed by Zernicka-Goetz’s team prove effective 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 waiting years for organ transplants,” Zernicka-Goetz said. “What makes our work so exciting is that the knowledge derived from it could be used to develop correct synthetic human organs to save lives that are currently being lost. It should also be possible to affect and cure adult organs using the knowledge we have of how they are made.

“This is an incredible step forward that took 10 years of hard work from several members of my team. I never thought we would come to this. You never think your dreams will come true, but they did.

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