Abstract: All-trans retinoic acid (ATRA), the active form of retinoids, is an effective anti-aging molecule with pleiotropic effects on skin pathologies. The interfollicular epidermis is composed of anatomically distinct structures, known as the interscale and scale, which are replenished by slow- and fast-cycling epidermal stem cell populations, respectively. In hematopoietic stem cells, the level of retinoic acid signaling controls the balance between dormancy and activation; however, the effect of ATRA on epidermal stem cell heterogeneity and behavior remains unknown. Here, we show that ATRA treatment in the mouse tail skin reduces the scale compartment while the interscale compartment expands. Notably, we discovered ATRA triggered both epidermal stem cell populations in differentiation, and the remaining Slc1a3+ clones in the basal layers switched their fate to the slow-cycling lineage. Similar changes in epidermal stem cell balance are also observed in human primary culture in vitro. Transcriptome analysis shows that the ERK/MAPK signaling pathway is down-regulated by ATRA treatment, and forskolin, an activator of cAMP/PKA, partially rescues the loss of the fast-cycling compartment. These findings provide insight into the existence of a universal mechanism by which RA signaling regulates the proper balance of tissue stem cell heterogeneity.
Funding Source: Grant-in-Aid for Scientific Research (B) (24K02035, 20H03266) Grant-in-Aid for Challenging Research (Exploratory) (24K21973) Takeda Science Foundation Scholarship supported by Rajamangala University of Technology Thanyaburi
