Scientists Discover Key Differences Between Men’s and Women’s Skin

The discovery was made by researchers from the Free University of Bruxelles (ULB), the University of Cambridge and several collaborating institutions. Their findings suggest that biological sex influences skin regeneration and repair, even though skin is not part of the reproductive system.

For decades, research into biological differences between males and females has focused largely on reproductive organs. However, sex can also influence other tissues and organs. Understanding these differences may help improve the prevention and treatment of inflammatory diseases and cancer, although their importance has often been overlooked.

The study, published in Nature, was led by Cédric Blancpain, MD/PhD, a researcher at the WEL Institute, director of the Stem Cell Cancer Research Institute and professor at the Vrije Universiteit Bruxelles. The research was conducted with Professor Benjamin Simmons and his team at the University of Cambridge, along with scientists from several other institutions.

Researchers tracked skin stem cells for five months

Using advanced microscopy, the researchers recorded individual cells through the skin of living mice. This allowed them to track the same stem cells and their descendants for five months, an unprecedented period of observation.

The team’s original goal was to understand how skin regenerates. During the research, however, they unexpectedly discovered significant differences between male and female mice. Further experiments showed that sex hormones were responsible for much of this variation.

How skin stem cells regenerate the skin

The outermost layer of skin is constantly replaced. The process begins with stem cells at the bottom of the layer. These cells divide to produce new cells, some of which retain stem cell capabilities while others begin developing into specialized skin cells.

The specialized cells eventually form the protective barrier that shields the body from its surroundings. As they mature, they lose the ability to divide, a process known as differentiation. They then move toward the surface of the skin and eventually fall away.

Scientists have debated the precise organization of this regeneration process for decades. By repeatedly examining the same areas of skin over five months, the researchers found that stem cells do not immediately become fully mature skin cells.

Instead, they pass through an intermediate stage in which they can divide a limited number of times before completing their development into specialized cells. This finding helps clarify long-standing questions about how skin is maintained.

Female skin cells work together more synchronously

One of the study’s most unexpected findings involved the behavior of newly formed cells.

In female mice, two “sister” cells produced when a single parent cell divides frequently made the same developmental decisions at the same time. Both cells might divide again, or both might begin specializing into mature skin cells.

The researchers compared this behavior to two rowers moving their oars in unison. In male mice, sister cells were less synchronized and tended to follow more independent patterns.

“We first sought to understand how skin regenerates and whether there is a hierarchy with stem cells at the top. We were surprised to discover that there were significant differences in the way stem cells regenerated skin in women and men,” explains Dr. Dan Engelman, lead author of the study.

Sex hormones control skin stem cell behavior

To identify the cause of these differences, the scientists investigated the effects of male and female hormones.

They first examined what happened when male mice were castrated, removing their primary source of testosterone. Without this hormone, the mice’s skin cells began behaving more like cells in female mice. When researchers administered dihydrotestosterone (DHT), the active form of testosterone, the cells returned to a typical male pattern.

These experiments showed that male hormones help regulate the rate at which skin cells mature and move away from the stem cell layer.

The researchers also examined the role of female hormones. Removing the ovaries through oophorectomy reduced the rate of stem cell proliferation and almost completely eliminated the characteristic synchrony between sister cells.

Treatment with estradiol, a form of estrogen, reversed the reduction in stem cell proliferation.

Together, the findings indicate that testosterone influences the rate of skin cell maturation, while estrogen helps stimulate stem cell proliferation and regulate the behavior of newly formed cells.

The team also tested testosterone in reconstructed human skin grown in the laboratory. The hormone promoted stem cell differentiation, suggesting that at least some mechanisms observed in mice may also operate in human skin.

Why do female mice heal skin wounds faster?

The differences in stem cell behavior were accompanied by another important finding: female mice recovered from skin injuries faster than male mice.

When the researchers examined wounds on the animals’ backs, they found that female wounds closed significantly faster, particularly during the first few days after injury.

This early advantage was partly associated with faster activation of skin stem cells and more coordinated cell activity. As healing progressed, the differences between male and female mice gradually narrowed.

The results suggest that hormonal regulation of skin stem cells may help explain why skin repair differs between males and females.

What the findings could mean for wound healing and skin cancer

Doctors have long observed differences between males and females in wound healing, the severity of certain inflammatory conditions and the frequency of some skin cancers. However, the biological mechanisms behind these differences remain incompletely understood.

By showing how sex hormones affect skin stem cell activity, the study offers a possible explanation for some of these clinical observations.

The findings could eventually contribute to medical care that takes biological sex into account. Potential applications include improving recovery from burns and surgery and developing treatments for chronic wounds in people with diabetes, which affects millions of people worldwide.

Understanding these differences could also help researchers develop new strategies for preventing skin cancer, one of the most common types of cancer.

So far, faster wound healing and coordinated stem cell behavior have been demonstrated in mice. Further research is needed to determine how closely these processes match those in human skin and whether they can be used to improve patient care.

Beyond their potential clinical importance, the findings provide new insight into the fundamental biology of skin regeneration and help address questions that have puzzled scientists for decades.

“This study is a masterpiece of technology, and the discovery of differences between male and female skin stem cells was both fascinating and completely unexpected. It sheds light on a series of clinical observations that previously lacked a biological explanation. It raises a wide range of new questions, from the basic biology of stem cells to clinical issues such as wound healing, cancer development, and autoimmune diseases. Gender is an all too often overlooked parameter in biology and medicine. We will now investigate the differences between men and women in the formation and progression of skin cancer, and elucidate the molecular mechanisms responsible for these differences,” said Professor Cédric Blancpain, who led the study.

Research collaboration and funding

The project brought together Professor Blancpain’s team at ULB in Belgium and Professor Simmons’ group at the University of Cambridge in the United Kingdom. It also included research teams led by Michele De Luca of the University of Modena-Reggio Emilia in Italy, Julia Schwartz of the University of Southern California, Los Angeles, and the Broad CIRM Center, and Esther Hoste of VIB Ghent University in Belgium.

Funding came from FNRS, including a FRIA fellowship, TELEVIE, the WEL Research Institute, Fondation contre le Cancer, Fondation ULB, the Fonds Erasme, The Fondation Julie et Françoise Drion, the Fonds Yvonne Boël, the FNRS/FWO joint EOS (Excellence of Science) program and the European Research Council (ERC).