Natural and synthetic embryos side by side with heart and head folds stained in color. Credit: M. Zernicka-Goetz
In vitro embryo models grown from stem cells could provide scientists with unprecedented access to study the earliest stages in the development of an organism. A major hurdle in this area of research has been sustaining embryonic stem cells to the point where structures such as the brain and heart are able to form. Recently, researchers from the University of Cambridge and Caltech have overcome this hurdle and generated a “synthetic” mouse model embryo from stem cells that contains both a beating heart and the foundations of a brain and all other organs in the mouse body.
One of the keys to growing an embryo with these important structures, without using eggs or sperm, was enabling interaction between three types of stem cells – embryonic stem cells, trophoblast stem cells and inducible extraembryonic endoderm stem cells. This includes the exchange of both chemical and mechanical signals between the tissues that will form the embryo and those that will connect the embryo to the mother. The researchers found that embryonic stem cells alone cannot form an entire brain without signaling with extraembryonic tissues. To foster and guide the self-organization of these stem cell tissues, the researchers needed to both design an optimal growth environment and determine the correct proportions of each cell type to incorporate and in what sequence to incorporate them.
The resulting embryo model produced by the researchers closely resembles a whole natural mouse embryo at 8.5 days in utero. The model includes a beating heart-like structure, a yolk sac and the foundations of multiple organs, most notably defined forebrain and midbrain regions that have never been produced in an in vitro embryo model before. The researchers additionally demonstrated the value of their model in studying early neurodevelopment, by knocking out the Pax6 gene, which is essential for neural tube formation. They found that the Pax6 knockout embryos showed exactly the known defects in brain development as animals carrying the mutation, said corresponding author Magdalena Zernicka-Goetz, Bren Professor of Biology and Biological Engineering at Caltech and professor of mammalian development and stem cell biology at Cambridge’s Department of Physiology, Development and Neuroscience. This research was published in Nature.
“The stem cell embryo model is important because it gives us accessibility to the developing structure at a stage that is normally hidden from us due to the implantation of the tiny embryo into the mother’s womb,” said Zernicka-Goetz. “This accessibility allows us to manipulate genes to understand their developmental roles in a model experimental system.”
The researchers are currently working to develop an analogous model for human embryo development, which could one day help scientists understand why some pregnancies fail, as well as advance the development of synthetic transplant organs grown from human stem cells.