Ancient Fish Holds Key to Understanding Pluripotent Stem Cells

Researchers have made a step forward in creating artificial organs by using a "living fossil" to understand the basics of stem cells. Professor Joshua Mark Brickman at the Novo Nordisk Foundation Center for Stem Cell Medicine (reNEW) has identified the evolutionary origins of a master gene that acts on a network of genes instructing stem cells. This discovery, published in the journal Nature Communications, brings researchers one step closer to designing artificial organs, which could save the lives of people whose own organs have failed.

Pluripotent stem cells are stem cells that can develop into all other cells, including heart cells. If scientists understand how pluripotent stem cells develop into a heart, they may be able to replicate this process in a laboratory. Brickman and his colleagues discovered that the master gene that controls stem cells and supports pluripotency exists in a coelacanth fish. In humans and mice, this gene is called OCT4, and researchers found that the coelacanth version could replace the mammalian one in mouse stem cells.

The coelacanth is in a different class from mammals and has been called a "living fossil" due to the fact that it has remained essentially unchanged for ~400 million years. By studying the coelacanth's cells, the researchers can "go back in evolution, so to speak," according to Assistant Professor Molly Lowndes. The researchers can also distill the basic concepts that support a stem cell by studying the network of genes in other species, such as the coelacanth.

The researchers looked at the evolution of the Pou5 gene family, which is primarily involved in maintaining pluripotent cells during development. The team used a combination of evolutionary analysis and functional studies in mice to understand how the ability of Pou5 proteins to support pluripotency originated.

They found that this ability originated in a group of animals called gnathostomes and that subsequent gene duplication led to the evolution of two paralogues (genes with similar functions) that differ in their ability to support different stages of pluripotency. This specialization allowed for the diversification of function in pluripotent cells. The researchers also identified specific regions of the OCT4 protein (a central pluripotency factor) that are important for maintaining pluripotency and how these regions have changed over evolutionary time.

In addition to the coelacanth, the researchers also studied the stem cell genes of over 40 other animals (including sharks, mice, and kangaroos) to provide a broad sampling of the main branch points in evolution. By using artificial intelligence to build three-dimensional models of the different OCT4 proteins, they were able to see that the general structure of the protein is maintained across evolution, but species-specific differences in other regions of the protein can alter its orientation and affect how well it supports pluripotency.

"This a very exciting finding about evolution that would not have been possible prior to the advent of new technologies. You can see it as evolution cleverly thinking, we do not tinker with the 'engine in the car,' but we can move the engine around and improve the drive train to see if it makes the car go faster," says Brickman, senior author of the paper.