Genes of ancient animal relatives used to grow a mouse: Study reveals hidden history of stem cells

15 Nov 2024, 18:10 by Queen Mary, University of London

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The mouse on the left is a chimeric with dark eyes and patches of black fur, a result of stem cells derived from a choanoflagellate Sox gene. The wildtype mouse on the right has red eyes and all white fur. The colour difference is due to genetic markers used to distinguish the stem cells, not a direct effect of the gene itself. Credit: Gao Ya and Alvin Kin Shing Lee, with thanks to the Centre for Comparative Medicine Research (CCMR) for their support.

An international team of researchers has achieved an unprecedented milestone: the creation of mouse stem cells capable of generating a fully developed mouse using genetic tools from a unicellular organism, with which we share a common ancestor that predates animals.

This breakthrough reshapes our understanding of the genetic origins of stem cells, offering a new perspective on the evolutionary ties between animals and their ancient single-celled relatives. The research is published in the journal Nature Communications.

In an experiment that sounds like science fiction, Dr. Alex de Mendoza of Queen Mary University of London collaborated with researchers from The University of Hong Kong to use a gene found in choanoflagellates, a single-celled organism related to animals, to create stem cells which they then used to give rise to a living, breathing mouse.

Choanoflagellates are the closest living relatives of animals, and their genomes contain versions of the genes Sox and POU, known for driving pluripotency—the cellular potential to develop into any cell type—within mammalian stem cells. This unexpected discovery challenges a longstanding belief that these genes evolved exclusively within animals.

"By successfully creating a mouse using molecular tools derived from our single-celled relatives, we're witnessing an extraordinary continuity of function across nearly a billion years of evolution," said Dr. de Mendoza. "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."

The 2012 Nobel prize to Shinya Yamanaka demonstrated that it is possible to obtain stem cells from "differentiated" cells just by expressing four factors, including a Sox (Sox2) and a POU (Oct4) gene. In this new research, through a set of experiments conducted in collaboration with Dr. Ralf Jauch's lab in The University of Hong Kong / Center for Translational Stem Cell Biology, the team introduced choanoflagellate Sox genes into mouse cells, replacing the native Sox2 gene achieving reprogramming towards the pluripotent stem cell state.

To validate the efficacy of these reprogrammed cells, they were injected into a developing mouse embryo. The resulting chimeric mouse displayed physical traits from both the donor embryo and the lab induced stem cells, such as black fur patches and dark eyes, confirming that these ancient genes played a crucial role in making stem cells compatible with the animal's development.

The study traces how early versions of Sox and POU proteins, which bind DNA and regulate other genes, were used by unicellular ancestors for functions that would later become integral to stem cell formation and animal development. "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.

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This novel insight emphasizes the evolutionary versatility of genetic tools and offers a glimpse into how early life forms might have harnessed similar mechanisms to drive cellular specialization, long before true multicellular organisms came into being, and into the importance of recycling in evolution.

This discovery has implications beyond evolutionary biology, potentially informing new advances in regenerative medicine. By deepening our understanding of how stem cell machinery evolved, scientists may identify new ways to optimize stem cell therapies and improve cell reprogramming techniques for treating diseases or repairing damaged tissue.

"Studying the ancient roots of these genetic tools lets us innovate with a clearer view of how pluripotency mechanisms can be tweaked or optimized," Dr. Jauch said, noting that advancements could arise from experimenting with synthetic versions of these genes that might perform even better than native animal genes in certain contexts.

More information: Ya Gao et al, The emergence of Sox and POU transcription factors predates the origins of animal stem cells, Nature Communications (2024). DOI: 10.1038/s41467-024-54152-x

Journal information: Nature Communications

Provided by Queen Mary, University of London