Stem cells organize themselves to form embryoidDecember 17, 2021
New insights into stem cell development in mice could enable an alternative to animal experiments in the future
Researchers of the Cluster of Excellence in cooperation with an international team have developed a method to generate embryo-like cell complexes from the stem cells of mice. The method provides new insights into embryonic development. In the medium term, it might also be suitable for developing tests for substances that could be harmful to fertility. The study has recently been published in Nature Communications.
It is still not fully understood how entire organisms develop from one single cell. Every type of tissue in the organism, whether it is bone, skin, muscle or the brain, is derived from one fertilized oocyte. This omnipotent cell subsequently develops into the blastocyst, which is implanted into the uterus, where it develops into an embryo. "Embryo development is largely based on self-organization," explains Prof. Dr. Hubert Schorle of the Institute of Pathology at the University of Bonn. "Each cell releases messenger substances into its environment and thereby helps determine the fate of its neighbors." The current study allows new insights into these precisely coordinated processes.
In vitro, three different stem cell lineages may be derived from the blastocyst and propagated in cell culture indefinitely: Trophoblast stem cells (TSCs), embryonic stem cells (ESCs) and extraembryonic endoderm (XEN) stem cells. The researchers around Prof. Schorle succeeded in maturing ESCs from mice into a so-called embryoid. Unlike the omnipotent oocyte, ESCs are pluripotent cells, exhibiting already restricted developmental abilities. "In addition to the actual embryo, the membrane that surrounds it and parts of the placenta also emerge from the egg," Schorle explains. "ESCs, on the other hand, cannot form these tissue structures outside the embryo."
However, ESCs play a decisive role in embryonic development: If ES cells are stimulated to divide, they merely turn into an undifferentiated cluster of cells. "We have now genetically modified some of the ES cells in our study," explains Schorle's colleague Jan Langkabel. He performed the main experiments in the study together with Arik Horne from Cluster Member Prof. Dr. Joachim Schultze's research group at the German Center for Neurodegenerative Diseases (DZNE) and the LIMES Institute at the University of Bonn. "Some ES cells were then able to form the membrane and others the embryonic portion of the placenta."
When the researchers brought these two modified cell lines together with the original ES cells, they observed something astonishing: The mouse cells differentiated in a finely balanced manner, eventually producing an embryo-like complex - an embryoid. "This resembled a 5-day-old mouse embryo," Arik Horne says. "The disordered mixture of the three cell types had therefore evolved into a strictly ordered structure, much like the one that normally emerges from a fertilized egg." Studies of their gene activity confirmed this finding: Each individual cell of the embryoid behaved very similarly to its counterpart in a real embryo.
Embryoids could help replace animal testing
It was already possible to create such embryoids before. However, this required the use of three completely different cell lines, which were grown separately in a strictly coordinated manner. This approach is very complex and error-prone - unlike the new method: "We work with a single culture," stresses Prof. Schorle, who, like Prof. Schultze, is a member of the Transdisciplinary Research Area (TRA) "Life and Health" at the University of Bonn. "We then switch on the placenta program after a certain time in one part of the cells and the membrane program in another part. The rest then happens, as it were, by itself through self-organization."
Prof. Schorle is now planning to create such embryoids from ES cells of monkeys in a very similar way. These could then be used for toxicity tests, he says - for example, to determine whether certain substances cause malformations in the womb. Toxicity studies like this currently still rely on animal testing. "The use of such embryoids could replace at least some of these," notes the researcher. He is already planning a corresponding cooperation project with researchers at the University of Göttingen.
The study was funded by the German Research Foundation (DFG).
Jan Langkabel et. al. (2021), Induction of Rosette-to-Lumen stage embryoids using reprogramming paradigms in ESCs; Nature Communications, DOI: 10.1038/s41467-021-27586-w
Prof. Dr. Hubert Schorle
Institute of Pathology at the University of Bonn
Phone +49 228/28716342
Prof. Dr. Joachim Schultze
German Center for Neurodegenerative Diseases (DZNE)
& the LIMES Institute at the University of Bonn
Phone +49 228/43302410