The support of pluripotent cells over time is an essential feature of development. Pluripotent cells are stem cells that can develop into all other cells. Understanding how pluripotent stem cells develop into a heart could help replicate this process in the lab.

An ancient fish dubbed a “living fossil” has helped scientists understand the basics of stem cells. Scientists at the University of Copenhagen have discovered that the coelacanth fish contains the master gene that regulates stem cells and maintains pluripotency. This gene, known as OCT4 in humans and mice, was found to be replaceable by a coelacanth variant in mouse stem cells.

The coelacanth is referred to as a “living fossil” and is classified separately from mammals due to the fact that it evolved into its current form about 400 million years ago. It mimics the first animals that went from the sea to land, as it has fins that resemble limbs.

Assistant Professor Molly Lowndes said: “By studying his cells, you can, as it were, go back in evolution.”

OCT4 protein
3D model of the OCT4 protein. Illustration: Woranop Sukparangsi.

Assistant Professor Woranop Sukparangsi continues: “The central factor that regulates the gene network in stem cells is in the coelacanth. This shows that the network existed early in evolution, possibly as far back as 400 million years ago.”

Ph.D. student Elena Morganti said: “The beauty of going back in evolution is that the organisms become simpler. For example, they only have one copy of some essential genes instead of many versions. This way you can separate what is important for stem cells and thus improve how you grow stem cells in a dish.”

Scientists discovered that the stem cell network is much older than previously believed and can be found in extinct species. They also discovered how evolution changed the gene network to allow for pluripotent stem cells.

stem cell genes from more than 40 animals
Scientists looked at the stem cell genes of more than 40 animals. For example sharks, mice and kangaroos. Illustration: Woranop Sukparangsi.

More than 40 animal stem cell genes were examined: kangaroos, mice and sharks. The animals were chosen to represent a good cross-section of key evolutionary turning points.

The study used artificial intelligence to create three-dimensional models of the different OCT4 proteins. According to the experts, the overall structure of the protein has been preserved during evolution. While the parts of these proteins known to be critical to stem cells do not change, species-specific variations in these proteins that appear unrelated to each other change their orientation, which may affect how well they retain their pluripotency.

Joshua Mark Brickman said: “This is a fascinating finding about evolution that would not have been possible before the advent of new technologies. You can see it as evolution if you think smartly, we don’t tinker with the ‘engine in the car’, but we can move the engine and improve the powertrain to see if that makes the car go faster.”

Magazine reference:

  1. Sukparangsi, W., Morganti, E., Lowndes, M. et al. Evolutionary origin of vertebrate OCT4/POU5 functions supporting pluripotency. Nat Commun 13, 5537 (2022). DOI: 10.1038/s41467-022-32481-z