Male hormones speed skin cell turnover while female skin heals faster, study finds

The outermost layer of our skin is in a constant state of renewal. Every day, thousands of cells in the epidermis divide, specialize and eventually flake away, replaced by fresh recruits from a pool of proliferating basal cells. For decades, biologists have argued about how this assembly line is organized: is it run by a single, uniform population of progenitors, or by a hierarchy in which long-lived stem cells feed a short-lived workforce of transit-amplifying cells? A new study published in Nature offers a strikingly detailed answer, and along the way uncovers something nobody expected: the entire choreography differs between males and females, tuned by sex hormones.

A team led by Cédric Blanpain at the Université Libre de Bruxelles and Benjamin Simons at the University of Cambridge set out to settle the long-running debate over epidermal architecture. The skin’s interfollicular epidermis, the flat expanse of tissue between hair follicles, is a stratified epithelium with a proliferative basal layer and several layers of differentiated cells above it. When a basal cell commits to differentiation, it detaches from the underlying membrane and moves upward, eventually shedding from the surface. Earlier lineage-tracing work had suggested that a single equipotent population maintains this tissue, with roughly 80 percent of divisions producing one renewing and one differentiating daughter. But other studies hinted at hidden heterogeneity, including evidence of progenitors with strictly limited proliferative capacity and single-cell RNA sequencing data revealing multiple transcriptional states within the basal layer.

The decisive step was watching the process unfold in living animals. The researchers used mice engineered so that a low dose of tamoxifen stochastically switches on one of three fluorescent nuclear markers in basal cells, allowing individual clones to be tracked unambiguously. With intravital microscopy of the ear skin, they followed 1,171 clones in ten mice, five female and five male, over 140 days, imaging at intervals ranging from weekly to monthly. This long time course, rare in the field, made it possible to distinguish clones that died out after a division or two from those that expanded substantially before being lost.

The pooled data showed the expected signatures of tissue homeostasis: average clone size grew steadily while the probability that a clone survived fell to about 27 percent by day 84, and the overall density of labelled cells converged to a constant. But when the team split the data by sex, the picture changed. Female mice had consistently larger basal clones, and both their basal and suprabasal clone sizes showed a marked enrichment for even numbers of cells, a bias that persisted across the full five months and even among the largest clones. An independent EdU pulse-chase experiment, which labels dividing cells and follows their progeny, confirmed the same even-numbered signature within just six days. A similar pattern appeared in back and tail skin, indicating that this is a general feature of the epidermis rather than a quirk of the ear.

That even-odd signature proved to be the key to the architecture question. The team built spatial models of the basal layer in a two-dimensional Voronoi framework, placing cells in a solid-like, jammed regime where neighbor exchange is suppressed and stem cell fate is governed by mechanical feedback on local cell density. A one-compartment model, in which all proliferative cells are equivalent, could fit the average clone sizes but failed spectacularly at reproducing the even-odd correlations, especially in females. Only a two-compartment model, in which stem cell differentiation proceeds through an intermediate transit-amplifying state with limited proliferative potential, could capture the full richness of the clonal data. In this hierarchy, most stem cell divisions are asymmetric, while most transit-amplifying divisions are terminal, and crucially, the timing of sister cell divisions and delaminations is correlated, so that stem cell and transit-amplifying partners turn over in coordinated pairs.

Short-term imaging every twelve hours validated those predictions directly. Sister cells in both sexes showed strong temporal correlations in their lifetimes, with correlation coefficients well above zero for dividing sisters, delaminating sisters and mixed pairs. Within a single twelve-hour window, 84 percent of delaminations in male clones and 98 percent in female clones involved sister cells. The model also quantified the sex differences: terminally differentiated basal cells lingered about 5.1 days in females but only about 3.0 days in males, and more than 95 percent of transit-amplifying divisions in females were terminal, compared with roughly 70 percent in males. Sister cell delamination was also more tightly synchronized in females.

Why should males and females differ? The answer turned out to be testosterone. Castrating male mice dropped their basal cell delamination rate from 47 percent to 14 percent, matching females, and restoring the androgen dihydrotestosterone reversed the effect. Using the four-core-genotype mouse model, which separates chromosomal sex from gonadal sex, the team showed that the Sry gene, and hence testicular hormones rather than the Y chromosome itself, drove the faster delamination and higher rate of asymmetric division. Ovariectomy in females, by contrast, did not alter delamination but did reduce basal cell proliferation, and oestradiol replacement restored it. Long-term lineage tracing in castrated males revealed a female-like enrichment of even-sized clones, confirming that androgens reshape the clonal dynamics of the entire stem and transit-amplifying hierarchy.

The consequences extend beyond steady-state maintenance. When the researchers inflicted six-millimeter punch wounds on the back skin, female mice closed their wounds significantly faster than males. Two days after injury, the proliferative ring of dividing keratinocytes surrounding the wound was thicker in females, 800 versus 590 micrometers, and denser, with 4,330 versus 2,860 EdU-positive cells per square millimeter. Lineage tracing showed larger basal clones and a stronger even-size enrichment in females during early repair. The findings echo decades of clinical observations that estrogen accelerates wound healing while androgens slow it, but here the mechanism is traced directly to the keratinocytes themselves rather than only to inflammation or the extracellular matrix.

Single-cell RNA sequencing of sorted basal cells added a molecular layer to the story. Unsupervised clustering identified three non-cell-cycle populations that mapped neatly onto the stem cell, transit-amplifying and differentiated compartments defined by clonal analysis. The stem cell cluster expressed markers such as Lgr6, Trp73, Sox6 and Jag2; the transit-amplifying cluster was defined by basal keratins, Wnt4 and S100a6; and the differentiated cluster expressed Krt10, Grhl1 and Notch1. RNA velocity pointed to a progression from stem cell to transit-amplifying state followed by cell cycle exit. Lineage tracing with Lgr6- and Notch1-driven reporters confirmed the functional split: Lgr6-targeted clones persisted far longer and grew more, while Notch1-targeted cells mostly divided briefly or not at all. Sex-specific transcriptomes revealed that males upregulated differentiation-associated genes including Klf4 targets, while females showed elevated expression of stem markers and immune-related genes, with many of the male-biased genes suppressed after castration.

The team also tested whether the hormonal effect is conserved in humans. In three-dimensional skin equivalents built from primary human keratinocytes, treatment with 100 nanomolar dihydrotestosterone did not change proliferation but increased the fraction of EdU-labelled cells that had delaminated into suprabasal layers after 72 hours, from about 25 to 37 percent. In human skin epithelioids, DHT upregulated differentiation genes including EVPL, IVL, KRTDAP, OVOL1 and TGM1 in two of three donors. Together with the mouse data, these results establish that male sex hormones directly promote epidermal differentiation and stratification, even in the absence of stroma or immune cells. The broader implications are considerable: epidermal stem cells are central to skin cancer initiation, and inflammatory skin diseases such as atopic dermatitis show well-known sex biases in prevalence and severity. A hormonally tuned, sexually dimorphic control system operating on the stem cell and transit-amplifying compartments offers a new framework for understanding those disparities, and potentially for designing sex-aware therapies for wound care and skin disease.

Subject of Research: Sexual dimorphism in epidermal stem cell and transit-amplifying cell dynamics regulated by sex hormones

Article Title: Sexual dimorphism in epidermal stem cell dynamics

Article References: Sexual dimorphism in epidermal stem cell dynamics. (n.d.). https://doi.org/10.1038/s41586-026-11159-2

Image Credits: AI Generated

DOI: 10.1038/s41586-026-11159-2

Keywords: epidermal stem cells, transit-amplifying cells, sexual dimorphism, sex hormones, testosterone, oestrogen, wound healing, intravital imaging, lineage tracing, single-cell RNA sequencing, skin homeostasis, keratinocytes