Retinoic Acid Signaling Alters the Balance of Epidermal Stem Cell Populations in the Skin

Thisakorn Dumrongphuttidecha; Mizuho Ishikawa; Nina Cabezas-Wallscheid; Aiko Sada

doi:10.1016/j.jid.2025.09.008

Retinoic Acid Signaling Alters the Balance of Epidermal Stem Cell Populations in the Skin

J Invest Dermatol. 2025 Sep 18:S0022-202X(25)02433-9. doi: 10.1016/j.jid.2025.09.008. Online ahead of print.

Authors

Thisakorn Dumrongphuttidecha¹, Mizuho Ishikawa², Nina Cabezas-Wallscheid³, Aiko Sada⁴

Affiliations

¹ International Research Center for Medical Sciences (IRCMS), Kumamoto University, Kumamoto, Japan; Division of Skin Regeneration and Aging, Medical Institute of Bioregulation, Kyushu University, Fukuoka, Japan; Faculty of Integrative Medicine, Rajamangala University of Technology Thanyaburi (RMUTT), Thanyaburi, Thailand.
² International Research Center for Medical Sciences (IRCMS), Kumamoto University, Kumamoto, Japan; Division of Skin Regeneration and Aging, Medical Institute of Bioregulation, Kyushu University, Fukuoka, Japan.
³ International Research Center for Medical Sciences (IRCMS), Kumamoto University, Kumamoto, Japan; Laboratory of Stem Cell Biology and Ageing, Department of Health Sciences and Technology, Swiss Federal Institute of Technology (ETH Zürich), Zürich, Switzerland.
⁴ International Research Center for Medical Sciences (IRCMS), Kumamoto University, Kumamoto, Japan; Division of Skin Regeneration and Aging, Medical Institute of Bioregulation, Kyushu University, Fukuoka, Japan. Electronic address: aiko.sada@bioreg.kyushu-u.ac.jp.

PMID: 40975211
DOI: 10.1016/j.jid.2025.09.008

Abstract

All-trans retinoic acid, the active form of retinoid, is a potent antiaging and anti-inflammatory agent with pleiotropic effects on various skin conditions. In the interfollicular epidermis, tissue turnover is maintained by heterogeneous epidermal stem cell populations located at the basal layer. Mouse tail skin contains slow- and fast-cycling epidermal stem cell populations. The reduction of fast-cycling epidermal regions after all-trans retinoic acid application was first documented in 1987; however, stem cell-level changes have remained largely unexplored. This study demonstrates that all-trans retinoic acid treatment leads to reversible changes that decrease the fast-cycling epidermal compartment while expanding the slow-cycling one. All-trans retinoic acid biases both slow- and fast-cycling epidermal stem cell populations toward differentiation, with the remaining Slc1a3-CreER+ fast-cycling clones in the basal layers biasing to the slow-cycling lineage. Similar changes in slow- and fast-cycling epidermal stem cell populations are also evident in human primary cultures in vitro. These findings shed light on the role of retinoic acid signaling in regulating the balance of epidermal stem cell heterogeneity and lineages.

Keywords: All-trans retinoic acid; Epidermal stem cells; Retinoic acid signaling; Skin; Slow-cycling cells.