Summary: Researchers have created model embryos from mouse stem cells that form a heart, a brain, and the basis for other organs. The new model offers future researchers a new way to create and investigate the early stages of development.
Source: University of Cambridge
Researchers at the University of Cambridge have created models of embryos from mouse stem cells that form a brain, a beating heart, and the building blocks of all other organs in the body – a new way of recreating 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 cell in the body.
The researchers mimicked natural processes in the lab by guiding the three types of stem cells found in the earliest stages of 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 made the stem cells “talk to each other.”
The stem cells self-organized into structures that progressed through successive stages of development until they had beating hearts and the building blocks of the brain, as well as the yolk sac where the embryo grows and draws its nutrients in its first few weeks. Unlike other synthetic embryos, the models developed by Cambridge have reached the point where the entire brain, including the frontal part, has begun to develop.
This is a stage of development superior to that reached in any other model derived from stem cells.
The team says their findings, the result of more than a decade of research that has gradually led to increasingly complex embryonic structures and is reported today in the journal Nature, could help researchers understand why some embryos fail while others do. others continue to develop into a healthy pregnancy. Furthermore, 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 in the department of physiology at Cambridge development. and neuroscience, adding:
“It’s amazing that we’ve come this far. It’s been the dream of our community for years and a major focus of our work for a decade, and we’ve finally made 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 body’s tissues, 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 it with 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 begin to send mechanical and chemical signals to each other, telling the embryo how to develop properly.
“Many pregnancies fail around this time before most women realize they are 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.
For the last 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 tiny embryo in the mother’s womb.”
Zernicka-Goetz added: “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 correct proportions and environment to support their ultimately self-sustaining growth and communication with one another.
The researchers found that extra-embryonic cells signal 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 on a plate, to have access to these individual stem cells, to understand why so many pregnancies fail and how we might prevent this from happening. . – is quite special,” said Zernicka-Goetz.
“We look at the dialogue that needs to happen between the different types of stem cells at that time, we show how it happens and how it can go wrong.”
A major advance in the study is the ability to generate the entire 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 first to report the development of the forebrain and indeed the whole 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 deleting a gene already known to be essential for the formation of the neural tube, a precursor to the nervous system, and for the development of the brain and eyes. In the absence of this gene, the synthetic embryos exhibit exactly the known defects in brain development as in an animal carrying this mutation.
“This means we can start to apply this kind of approach to the many genes whose function is unknown in brain development.”
While current research has been done 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 would otherwise be impossible to study in actual 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 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 an organ transplant,” Zernicka-Goetz said. “What makes our work so exciting is that the insights gained 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 done.
Professor Magdalena Zernicka-Goetz has made an incredible scientific breakthrough.
Creating synthetic mouse embryos in a test tube that develop brains and beating hearts, starting with only embryonic stem cells, is the culmination of a decade of work.
Magda explains: “I am fascinated by the mystery of how embryos work. Each embryo follows a similar course: one cell becomes multiple, then they communicate with each other and organize themselves to form a structure that will provide a blueprint for all the 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?
“Building the first ‘synthetic embryo’ models was a step-by-step process. Initially, we knew that embryonic stem cells could be grown indefinitely in the laboratory 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 become complete embryos.
“In addition to embryonic stem cells, we use two types of extra-embryonic tissue: one forms the placenta and the other a sac in which the embryo develops. These tissues are very important because they send signals to the embryo so that all its parts develop 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 in which the three different types of cells could grow and communicate with each other. And we had to find the correct proportions of each cell type and add them in the correct order.