A small shift in nutrient supply has led to the development of a new method to rejuvenate stem cells. Scientists at the University of Copenhagen found that these “super stem cells” remain healthier in culture and demonstrate an improved ability to differentiate into various specialized cell types. This small but impactful change to stem cell culture could advance both fertility treatment and regenerative medicine.
Led by Robert Bone, PhD, assistant professor at the Novo Nordisk Foundation Center for Stem Cell Medicine (reNEW), the research team identified that a small modification to the standard stem cell culture media—replacing glucose with galactose—resulted in the cells switching their primary energy source from glycolysis to oxidative phosphorylation.
“We show that by changing their diet, the stem cells can rejuvenate and turn into ‘super stem cells’,” said Bone. “It forces them to metabolize their energy in a different way than they normally would, and that process essentially reprograms the stem cells.”
Their study was published in The EMBO Journal under the title, “Altering metabolism programs cell identity via NAD+-dependent deacetylation.”
Using embryonic stem cells (ESCs) from mice, the team replaced glucose with galactose in culture media. By changing their nutrient source, the ESCs are reprogrammed into an earlier stage of development, more similar to the inner cell mass (ICM) of the early mammalian blastocyst.
“The net result is that they behave like they are from an earlier stage of development, which enhances their ability to develop, or differentiate, into other types of cells,” said Bone.
The reprogramming of these cells activates NAD⁺-dependent sirtuin deacetylases—enzymes that play a central role in regulating aging and gene expression—resulting in deacetylation of histone and key transcription factors that enhance their identity and function.
Transcriptional noise is also reduced, as the chromatin is more densely packed in areas with redundant or irrelevant genetic information and more accessible in areas encoding developmental instructions.
“What’s 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,” said senior author Joshua Brickman, PhD, professor at reNEW. “And it is done with a relatively simple method.”
IVF and regenerative applications
Among the most immediate translational prospects is in vitro fertilization (IVF). The researchers observed that their metabolically reprogrammed stem cells had enhanced capacity to form extraembryonic tissue.
“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,” said Bone. “Previous research has found that the formation of the yolk sac in embryos cultured in a dish is very important for their ability to implant and become successful pregnancies.”
The team looks forward to the use of this strategy in clinical applications. “We hope to improve IVF technology by developing a culture for IVF that uses the same metabolic process,” added Brickman. “Hopefully, it can be used as part of the embryo culture regime that they use in the clinic to improve success rates of implantation.”
Additionally, this study has broader implications on aging and age-related disease studies. As they are more similar to ICMs, the rejuvenated ESCs may generate tissues such as liver, skin, and neural lineages in culture more efficiently. The implications span a wide range of therapeutic applications, from tissue regeneration to neurodegenerative disease. The team aims to further study the possibility of using this strategy on other cell types.
“Perhaps we could use this trick to regenerate aging cells and treat diseases such as Parkinson’s disease, osteoporosis, or diabetes,” supposed Brickman. “Can we use this diet to revitalize liver or heart cells and use them to treat patients with congestive heart failure or liver cirrhosis?”
The study provides fresh insight into how environmental changes—such as nutrient availability—can influence cellular identity and fate. The findings lay important groundwork for developing robust and therapeutically useful stem cell populations through metabolic reprogramming.