Evolutionarily ancient stem-cell-related genes used to create chimeric mouse

Functional mouse induced pluripotent stem (iPS) cells were generated using genes originating in an evolutionarily ancient unicellular organism and injected into a mouse embryo to create chimeric mice.

Specific genes from choanoflagellates, eukaryotes that are the closest living unicellular relative to animals, can induce pluripotency in mammalian cells. The Sox2 gene is important for determining pluripotency, where stem cells can become many different cell types, and versions can be found across different species. The research, published in Nature Communications, shows that functional mouse iPS cells can be generated by replacing the mouse Sox2 gene with a choanoflagellate version.

'The study implies that key genes involved in stem cell formation might have originated far earlier than the stem cells themselves, perhaps helping pave the way for the multicellular life we see today,' said Dr Alex de Mendoza of Queen Mary University of London, a lead author of the study.

In multicellular organisms, including animals, pluripotent stem cells are responsible for generating all the different cell types required for the body to function, however they are not present in unicellular organisms. However, different transcription factors, such as the SOX factors, control pluripotency in vertebrates. Although choanoflagellates do not have stem cells, the researchers discovered that they do have a version of the Sox2 gene and so hypothesised that it could fulfil the same function in mice.

'Choanoflagellates don't have stem cells, they're single-celled organisms, but they have these genes, likely to control basic cellular processes that multicellular animals probably later repurposed for building complex bodies,' explained Dr de Mendoza.

Using the Sox2 gene from choanoflagellates, the researchers reprogrammed mouse cells into iPS cells. These were then injected into a mouse embryo resulting in chimeric mice, meaning the mice had traits from both the donor embryo and the lab generated iPS cells. This research shows the choanoflagellate Sox2 gene can fulfil the function of the mouse Sox2 gene.

As the common ancestor of choanoflagellate and animals is evolutionarily ancient, the role of the Sox2 gene could have begun early in animal evolution and been important for the emergence of stem cells and multicellular animals.

'Studying the ancient roots of these genetic tools lets us innovate with a clearer view of how pluripotency mechanisms can be tweaked or optimised. Advancements could arise from experimenting with synthetic versions of these genes that might perform even better than native animal genes in certain contexts,' said Professor Ralf Jauch from the Centre for Translational Stem Cell Biology at the University of Hong Kong, who was also a lead author in the study.

Understanding the ancient role of these genes is important outside of evolutionary biology, as it could help to inform research in regenerative medicine. The deeper understanding of the determination of stem cells throughout evolution may help researchers to generate new methods for making iPS cells, which could be used to treat diseases or repair damaged tissue.