Cambridge University researchers have generated model embryos from mouse stem cells that form a brain, a beating heart, and the foundations of all the other organs of the body: a new path for replicating the initial stages of life.
Author: Sara Maria Majernikova
Artist: Sylvia Tsai
Editor: Charlotte Chevrie
Amadei et al. have built an embryo model without using eggs nor sperm, relying instead on stem cells, which are master cells of the body that can differentiate into virtually any other cell type. In the laboratory, Zernicka-Goetz and colleagues emulated natural processes by taking three types of stem cells widespread in early mammalian development and coaxing them to interact. By stimulating the production of a specific set of genes and providing a unique environment for their interactions, the researchers were able to cause these stem cells to ‘speak’ to one another.
The stem cells self-organised into structures, which progressed through the developmental stages until they created beating hearts and brain foundations, as well as the rest of the body’s components, including the yolk sac from which the embryo receives nutrients during its first few weeks of development. In contrast to other synthetic embryos, the Cambridge-made models produced a whole brain, including the anterior region. This stem cell-derived model has reached a more advanced level of development than any prior model. According to the researchers, their results, which are the culmination of more than a decade of research that has gradually led to increasingly complex structures resembling embryos, may help them understand why some embryos fail while others develop into healthy pregnancies. Additionally, these discoveries may potentially be applied to the production and repair of synthetic human organs for transplantation.
A healthy human embryo requires a ‘conversation’ between the tissues that will become the embryo, and the tissues connecting the embryo to the mother. In the first week following fertilisation, three types of stem cells emerge: one will eventually become body tissues, while the other two aid the embryo to expand. One of these extraembryonic stem cell types will grow into the yolk sac, where the embryo develops and obtains nutrients throughout early development; the other will develop into the placenta, which later provides oxygen and nourishment to the foetus. Numerous pregnancies end when the three types of stem cells begin exchanging mechanical and chemical messages directing the embryo on how to grow properly. This phase is the foundation for everything else that occurs throughout pregnancy: in the event of any complication, the pregnancy will terminate in failure, in other words a miscarriage, even before most women realise they are pregnant. Over the past decade, the Zernicka-group has studied these early moments of pregnancy, notably by investigating into the discussion between the various stem cell types, in order to determine why some pregnancies fail, while others succeed. Because this moment is so mysterious, it is pretty thrilling to be able to observe it in a laboratory, to have access to these particular stem cells, and to learn why so many pregnancies fail—and how we may be able to avoid such failures.
The researchers combined grown stem cells representing each of the three types of tissue in the correct quantities, and the environment needed to promote their development and communication with one another, which resulted in the formation of an embryo via self-assembly. Researchers revealed that extra-embryonic cells communicate with embryonic cells not only chemically, but also mechanically or by touch—thus regulating embryonic development. This is consistent with Zernicka-Goetz’s theory, since development of this brain region requires input from extraembryonic tissues. Studies made in 2018 and 2021, in which the researchers used these same component cells to produce embryos at a relatively earlier stage, had already suggested that this exchange was occurring. By extending the development by a single day, the researchers can now confidently assert that their model is the very first to demonstrate the development of the anterior and the entire brain. This ability to fabricate the entire brain, especially the anterior area (which has been a primary goal in the production of synthetic embryos), is a particularly significant advance in the study.
The stem cell embryo model is crucial because it enables us to observe the developing structure at a stage that is normally hidden by the small embryo’s implantation into the mother’s womb. This accessibility allows us to change different genes in an experimental model in order to better comprehend their developmental roles, opening up new experimental possibilities for the research of neurodevelopmental processes. In fact, they demonstrated this concept in the study by silencing a gene previously believed to be essential for neural tube formation, the precursor to the nervous system, as well as brain and eye development. Without this gene, synthetic embryos demonstrated the same brain development defects as animals usually found with the corresponding mutation. This suggests that we could apply a similar strategy to the countless genes whose functions in brain development are still unclear. While the current study was conducted on mouse models, the researchers are developing similar human models that have the potential to be directed toward the generation of specific organ types. This would allow them to comprehend the mechanisms underlying critical processes which would be impossible to study in real embryos, since UK law currently permits research on human embryos only up to the fourteenth day of development in the laboratory.
This research is particularly exciting because the knowledge collected may be used to create realistic synthetic human organs, perhaps saving lives that are currently being lost. Indeed, if the Zernicka-Goetz team’s project later proves successful with human stem cells, it may be applied to the production of synthetic organs for patients awaiting transplants. Currently, numerous patients throughout the world are on years-long waiting lists for organ transplants. Using the knowledge we now have on mouse organ development, it should be possible to start altering and treating adult organs as well.
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