Researchers at Stanford Medicine have uncovered a surprising role for glucose in the body’s regenerative processes. The sugar, which serves as the primary energy source for cells, has now been revealed as a key regulator of tissue differentiation by directly influencing gene expression and protein function essential for tissue development and tissue regeneration.
The study’s findings, published in Cell Stem Cell, emerged unexpectedly. Researchers Paul Khavari, MD, PhD, and Vanessa Lopez-Pajares, PhD, were initially investigating molecules that drive cellular differentiation in human skin stem cells. Through mass spectrometry and high-throughput screening methods, the researchers tracked biomolecular changes as stem cells in the epidermis differentiated into mature keratinocytes. To their surprise, glucose was one of the most elevated molecules during this process.
“At first, we just didn’t believe it. But the results of extensive follow-up experiments were clear: glucose interacts with hundreds of proteins throughout the cell and modulates their function to promote differentiation,” said Kavari, senior author of the study and a professor of dermatology at the Stanford School of Medicine. “We had expected glucose levels to decrease during differentiation because the cells begin to divide less rapidly, and their energy requirements are less. Yet glucose levels in the cells increase significantly as they move from epidermal stem cells to differentiated keratinocytes.”
This new understanding of glucose’s role has significant implications for clinical care, particularly in the treatment of diabetes and cancer. Diabetes, which often involves elevated blood sugar levels, can impair wound healing and tissue regeneration. The study suggests that understanding glucose’s role in tissue differentiation could lead to targeted therapies to address these issues. Similarly, in cancer, where cells often fail to differentiate properly, glucose’s potential to promote differentiation could provide a new avenue for treatment.
To confirm the initial findings, the investigators used fluorescent and radioactive glucose analogs and sensors to track glucose levels in cells. These experiments showed that glucose levels rose as cells differentiated into various tissue types, including bone, fat, and white blood cells. This discovery suggested that glucose plays a broader role in tissue regeneration beyond just energy supply.
Further experiments showed that the glucose increase was not related to its breakdown into energy. Instead, it acted as a signaling molecule, binding to proteins that regulate gene expression. One of these proteins, IRF6, plays a crucial role in tissue differentiation. When glucose binds to IRF6, it causes a conformational change that enhances its ability to regulate genes essential for differentiation.
“This finding is a springboard for research on dysregulation of glucose levels, which affects hundreds of millions of people,” Khavari said. “But it’s also likely to be important in cancer development because cancer is a disease of failed differentiation.”
The research also has potential applications in regenerative medicine, where controlled differentiation of stem cells is critical. By manipulating glucose levels, it might be possible to enhance tissue regeneration for patients with burns, injuries, or degenerative diseases.
The team is already planning the next phase of their research to explore the precise mechanisms by which glucose influences gene expression and protein function. They hope to better understand how glucose interacts with various proteins to drive differentiation in different tissue types. Future studies will also delve into how glucose metabolism is altered in diseases such as cancer and diabetes.
“We’re seeing glucose acting like a broadcast signal in the cell,” Khavari said. “When glucose levels rise in a cell, they rise everywhere, all at once. It’s like a fire alarm going off in a firehouse. Everyone in the firehouse activates in response.”
