HKUMed Discovery Points to Ancient Origins of Animal Stem Cell Proteins
HKUMed researchers have traced the origins of proteins crucial for the function of animal stem cells to 700-million-year-old single-cell organisms.
The findings by Dr Ya Gao and Dr Daisylyn Senna Tan overturn the prevailing theory that proteins essential for regulating stem cells — a type of cell that can renew itself and develop into different types of cells — were an animal invention.
These proteins were thought to have first developed in animals as only multicellular organisms require the capacity to create different cells for different functions.
“The tools that make stem cells possible already existed in these organisms,” said Dr Tan. “The implication is that when we evolved into multicellular beings, we didn’t really reinvent the wheel, we repurposed what we already had and used it to regulate these stem cell characteristics.”
The pair’s findings offer scientists greater insight into the origins of these cell functions and could help illuminate new areas of research for stem cell therapies.
Their article, based on research carried out during their PhD studies at HKUMed, was published in November in Nature Communications.
Working with international collaborators, the scientists identified two types of proteins vital to modern stem cells in choanoflagellates, unicellular organisms that have existed for 700 million years.
Taking these Sox and POU genes from our ancient cousins, Dr Tan first worked to purify the proteins. She then ran tests to see if they would bind in a similar way to their modern equivalents. She was surprised to find that Sox performed in the same way biochemically as Sox2 found in mammals.
“Daisy showed that this Sox factor mechanistically can bind with the modern Sox DNA motif in the same way as the mammalian Sox,” said Dr Gao. “In parallel I tested this unicellular Sox factor biologically, we surprisingly found it can also replace mammalian Sox2 to induce pluripotency and even replace Sox2 to generate stem cells that can contribute to create a viable and healthy mouse.”
Pluripotency refers to the ability of pluripotent stem cells to become any type of cell.
The scientists repeated their experiments multiple times to confirm their discoveries before attempting to create a mouse with the ancestor Sox.
In the next stage of the study, they replaced the mammalian Sox2 for stem cell inductions from a black mouse with the choanoflagellate Sox. These were then injected into a blastocyst, a fertilised egg, from a white mouse. The resulting healthy mice had black patches and black eyes, showing the ancient Sox gene was able to induce pluripotent stem cells in a mammal cell.
While their study found the ancient Sox factor was able to bind in a similar way to its modern counterpart, the POU gene did not.
Dr Gao and Dr Tan both completed their PhDs as members of Professor Ralf Jauch’s laboratory in the School of Biomedical Sciences.
Before joining HKUMed, Dr Gao completed a medical degree followed by a Master of Science in cell biology in mainland China, specialising in cancer biology. She joined HKUMed in 2019 for her PhD.
Dr Tan, who is from the Philippines, has a background in biochemistry and first enrolled at HKUMed in 2018 for an MPhil, later completing a doctorate.
The duo combined their diverse skill sets to forge a complementary pairing that has produced a handful of papers and co-first authors.
To bring in expertise in evolutionary biology for this study, Dr Gao and Dr Tan turned to collaborators in Europe. They worked with Mathias Girbig, who specialises in reconstructing ancestral sequences at the Max Planck Institute for Terrestrial Microbiology, and Dr Alex De Mendoza, an evolutionary biologist at Queen Mary University of London.
Following their work on a yet-to-be published study examining the role of Sox in other species like jellyfish, the group was inspired to reach back further in evolutionary time to single-cell organisms.
They trained their focus on choanoflagellates, the closest single-celled ancestors to animals.
Scientists have sketched a family tree tracing the evolution from single-celled organisms to multicellular animals, but are yet to pinpoint the first animals.
In recent years, researchers have sequenced choanoflagellates’ genome, allowing the team to scour public datasets where they were surprised to find the Sox and POU genes. Sox and POU are seen as biomarkers for stem cells and have an important role in regulating the cells.
“We’re talking about hundreds of millions of [years of] evolutionary time apart that these sequences existed,” Dr Tan said. “That’s the part that’s very fascinating, the preservation of function and the likelihood that these Sox sequences were in a sense repurposed in animals.”
The team’s findings not only offer a piece of the puzzle in exploring how multicellular organisms came to be, but also further scientists’ understanding of these crucial cells.
“As we learn more about how stem cells work and how they evolved, it can help us to understand the basic principles of cell biology,” said Dr Gao. “And later on, may have some practical applications to improve stem cell therapies.”
The former labmates plan to focus their careers on developing and bringing these therapies to market.
Dr Gao is now working as a postdoctoral researcher in Professor Jauch’s lab. She is looking to deepen her knowledge of stem cell biology and how stem cell technologies can be used to treat conditions like cancers and autoimmune diseases. In the longer term, she hopes to develop products to advance precision medicine and bring benefit to patients.
Dr Tan took a different route after completing her PhD. She is now working in business development for the Centre for Translational Stem Cell Biology, one of HKUMed’s Innovation Hubs, to help bring innovations from the laboratory bench to the bedside.
“I love discussing science and spreading science,” said Dr Tan. “I wanted to be at the intersection of academia and industry and wanted to learn more about the commercial side of science.”
