Study Finds Sex Hormones Shape Skin Stem Cell Behavior and Wound Healing

Skin stem cells appear to follow different patterns in female and male mice, and sex hormones help explain why. A five-month study tracking individual cells found that female cells coordinate their next steps more often, while testosterone speeds the maturation of skin cells. Females also closed wounds faster in the first days after injury. The findings point to biological sex as a factor in skin renewal and repair, while leaving open how much of the mechanism applies to people.

Published in Nature, the research was led by Prof. Cédric Blanpain of the Université libre de Bruxelles (ULB) and the WEL Research Institute, in collaboration with Prof. Benjamin Simons and colleagues at the University of Cambridge. Teams from several other institutions also contributed. The researchers set out to study how skin renews itself; long-term imaging exposed differences between the sexes that they then traced to hormones.

Five months of watching skin renew

The team used advanced microscopy to follow individual stem cells and their descendants in living mice over five months. This extended view let researchers observe the same areas repeatedly, rather than infer the renewal process from isolated snapshots.

Skin’s outer layer replaces itself continuously. Stem cells near the bottom divide, producing daughter cells. Some retain stem cell function; others move toward specialization, eventually forming the protective outer barrier. As those cells mature, they stop dividing, travel toward the surface and are shed.

The observations also help resolve a question about how cells move from stem cell status to mature skin. The researchers found an intermediate phase: newly formed cells can divide a limited number of times before completing differentiation. That staged progression offers a clearer account of how the skin replenishes its surface.

“We initially set out to understand how the skin renews itself, and whether there is a hierarchy with stem cells at the top. We were surprised to discover strong differences in the way stem cells renew the skin in females and males,” said first author Doctor Dan Engelman.

Female sister cells often make the same choice

A particularly clear difference emerged when the researchers compared pairs of “sister” cells, produced by the same parent cell. In female mice, sisters often chose the same course at the same time: both divided again, or both began specializing. In males, those paired cells were less synchronized and more likely to act independently.

The distinction is about coordination, not simply the number of cells. A more synchronized pattern could help explain how female skin maintains its stem cell population and responds to injury, though the study does not establish that coordination alone causes faster healing.

Hormone experiments helped identify what drives these patterns. After castration reduced the main source of testosterone in male mice, their skin cells began behaving more like female cells. Giving the animals dihydrotestosterone (DHT), an active form of testosterone, restored the typical male pattern. The results link male hormones to faster maturation and movement of skin cells out of the stem cell layer.

The researchers also removed the ovaries of female mice. Stem cell multiplication slowed, and the characteristic synchronization between sister cells nearly disappeared. Estradiol, a form of estrogen, reversed the decline in proliferation. Taken together, the experiments suggest that estrogen supports stem cell growth and coordinated behavior, while testosterone influences the pace of cell maturation.

Wound closure was faster in female mice

The cellular patterns had a visible counterpart: wounds on the backs of female mice closed substantially faster, especially in the first few days after injury. Female stem cells appeared to activate sooner and work in a more coordinated way during this early period. As healing continued, the difference between male and female mice narrowed.

That timing matters. The study links hormone-regulated stem cell behavior to an early advantage in wound closure, but it does not show that the same size or timing of effect occurs in people. The researchers did test testosterone on human skin reconstructed in the laboratory, where it accelerated stem cell differentiation. That result supports the possibility that part of the mechanism carries over to human skin, but reconstructed tissue and living patients are different settings.

Clinical questions remain open

Differences in wound healing, inflammatory conditions and some skin cancers have been observed between men and women. The study offers a possible biological explanation for some of those patterns by showing how sex hormones can shape stem cell activity. It does not establish a treatment or show that changing hormone levels would improve healing.

If follow-up work confirms the mechanisms in human skin, accounting for sex could inform research into recovery after burns or surgery and chronic wounds, including those associated with diabetes. The findings may also guide investigations of skin cancer, a research direction Blanpain’s team says it will pursue. For now, these are potential applications rather than demonstrated clinical benefits.

Blanpain described the discovery as unexpected and said it raises questions spanning stem cell biology, wound healing, cancer development and autoimmune disease. His team plans to examine how male and female biology affects the formation and progression of skin cancers, as well as the molecular mechanisms behind those differences.

The project joined Blanpain’s group at ULB in Belgium with Simons’ team at Cambridge in the UK, and research groups led by Michele De Luca at the University of Modena and Reggio Emilia, Yulia Shwartz at the Broad CIRM Center at the University of Southern California in Los Angeles, and Esther Hoste at VIB-Ghent University.

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

The strongest takeaway is that skin renewal is not governed by a single shared pattern across the sexes: hormones can change both the pace and coordination of stem cell behavior. Whether that biology can explain differences in human healing—and eventually improve care—will depend on studies that test the mechanism directly in people.