Creative image of embryonic stem cells, cellular therapy. 3d illustration. (Image by pinkeyes on Shutterstock)
In a nutshell
- Scientists discovered that changing stem cells’ energy source from glucose to galactose creates “super stem cells” with enhanced abilities and developmental potential.
- This metabolic switch activates sirtuin proteins that improve how cells regulate gene expression, creating better “signal-to-noise ratio” in cellular DNA—similar to mechanisms involved in aging.
- The research has promising applications for fertility treatments and regenerative medicine, potentially improving IVF success rates and developing treatments for conditions like Parkinson’s disease.
COPENHAGEN — A remarkable study from University of Copenhagen researchers reveals how changing what cells use for energy dramatically transforms their identity and abilities—findings that could revolutionize our the future of cellular development and aging processes.
By forcing embryonic stem cells to switch energy sources, researchers transformed them into a more versatile and robust cell type. The metabolic shift triggered a cascade of molecular changes that fundamentally rewired the cells.
“We show that by changing their diet, the stem cells can rejuvenate and turn into ‘super stem cells’. It forces them to metabolize their energy in a different way than they normally would, and that process essentially reprograms the stem cells,” says first author Robert Bone, an assistant professor at the Novo Nordisk Foundation Center for Stem Cell Medicine, also known as reNEW.
The Copenhagen team made this discovery by replacing glucose (sugar) with galactose in the growth medium of mouse embryonic stem cells. This simple substitution forced the cells to rely more heavily on oxidative phosphorylation instead of glycolysis for energy production.
“What is really striking is that they’re not just better at differentiating, but they stay fit and keep healthy much better over time compared to stem cells in standard culture conditions. And it is done with a relatively simple method,” says corresponding author Joshua Brickman, a professor at reNEW.
The Metabolic Key to Cellular Identity
This metabolic shift activated proteins called sirtuins that remove chemical tags from both histones (proteins that DNA wraps around) and transcription factors (proteins that control gene activity). The result was what researchers called “Enhanced Metabolic Embryonic Stem Cells” (EMESCs) that outperformed regular embryonic stem cells.
When injected into developing mouse embryos, these metabolically enhanced cells contributed more effectively to various tissues and showed greater ability to develop into both embryonic and extra-embryonic tissues—demonstrating their increased developmental potential.
A protein called SOX2, critical for maintaining stem cell properties, worked much more efficiently in these metabolically altered cells. The activated sirtuins removed chemical tags from specific sites in SOX2, allowing it to bind more strongly to DNA and activate genes essential for maintaining the enhanced stem cell state.
How Will ‘Super Stem Cells’ Be Used In The Future?
The metabolic process created by this dietary change improves what researchers call the “signal-to-noise ratio” in cell DNA. The change causes DNA to be more densely packed in areas with redundant genetic information while making important instructions more accessible.
The researchers liken it to being in a noisy restaurant with our grandparents, who struggle to hear what we’re saying not only because we’re not speaking loud enough, but also because the background noise is too overpowering. Aging stem cells experience a similar struggle listening to their own genomes.
One particularly promising application may be in fertility treatments. “One of the things that the ‘super stem cells’ seem to be better at making is a cell lineage that becomes something called the yolk sac. Previous research has found that the formation of yolk sac in embryos cultured in a dish is very important for their ability to implant and become successful pregnancies,” explains Bone.
Brickman adds, “We hope to improve IVF technology by developing a culture for IVF that uses the same metabolic process. Hopefully, it can be used as part of the embryo culture regime that they use in the clinic to improve success rates of implantation.”
Beyond fertility treatment, the researchers see potential applications in regenerative medicine. “Given that we now have a simple means to rejuvenate cells, we want to investigate how this trick could work on a variety of cell types. For example, can we use this diet to revitalize liver or heart cells and use them to treat patients with congestive heart failure or liver cirrhosis? Perhaps we could use this trick to regenerate aging cells and treat diseases such as Parkinson’s disease, osteoporosis or diabetes,” Brickman suggests.
The paper is published in The EMBO Journal.
Paper Summary
Methodology
Researchers manipulated the metabolism of mouse embryonic stem cells (ESCs) by replacing glucose and pyruvate in their culture medium with galactose, creating what they called Enhanced Metabolic Media (EMM). This forced the cells to rely more on oxidative phosphorylation rather than glycolysis for energy production. They extensively characterized these metabolically altered cells (called EMESCs) using techniques including RNA sequencing, ATAC sequencing (to assess chromatin accessibility), mass spectrometry to analyze protein acetylation, and CUT&Tag to examine protein binding to DNA. They also tested the developmental potential of these cells by injecting them into mouse embryos and assessing their contribution to various tissues.
Results
The switch to galactose-based media rapidly changed the cells’ metabolism within hours, activating NAD+-dependent sirtuin deacetylases. These enzymes removed acetyl groups from both histones and important transcription factors like SOX2, resulting in an “improved” embryonic stem cell with characteristics closer to cells in the inner cell mass (ICM) of early embryos. These EMESCs showed enhanced contribution to chimeric mice, including better ability to form both embryonic and extra-embryonic tissues. Detailed molecular analysis revealed that sirtuin-dependent deacetylation of SOX2 was particularly important for this enhanced cellular state.
Limitations
The study was conducted in mouse embryonic stem cells, so the findings may not directly translate to human cells. The researchers note that cell growth was slower in the galactose medium, with EMESCs having approximately double the cell cycle length compared to standard ESCs. While the researchers identified the sirtuin pathway as critical, there could be additional molecular mechanisms involved that weren’t fully characterized in this study.
Funding/Disclosures
The research was supported by several foundations including the Lundbeck Foundation, the Independent Research Fund Denmark, the European Union, and the Danish National Research Foundation. Two of the authors (Robert A. Bone and Joshua M. Brickman) have filed a patent on the use of Enhanced Metabolic Media (EMM) for stem cell culture.
Publication Information
The study titled “Altering metabolism programs cell identity via NAD+-dependent deacetylation” was published in The EMBO Journal on April 25, 2025. The lead author is Robert A. Bone, and the corresponding author is Joshua M. Brickman from the Novo Nordisk Foundation Center for Stem Cell Medicine at the University of Copenhagen, Denmark.
