Aryl hydrocarbon receptor controls skin homeostasis, regeneration, and hair follicle cycling by adjusting epidermal stem cell function

Abstract

Skin integrity requires constant maintenance of a quiescent, yet responsive, populationof stem cells. While interfollicular epidermal progenitors control normal homeostasis,hair follicle stem cells residing within the bulge provide regenerative potential duringhair cycle and in response to wounding. The aryl hydrocarbon receptor (AhR) modulatescell plasticity and differentiation and its overactivation results in severe skin lesions inhumans. However, its physiological role in skin homeostasis and hair growth isunknown. Reconstitution assays grafting primary keratinocytes and dermal fibroblastsinto nude mice and 3-D epidermal equivalents revealed a positive role for AhR in skinregeneration, epidermal differentiation, and stem cell maintenance. Furthermore, lackof receptor expression inAhR / mice delayed morphogenesis and impaired hairregrowth with a phenotype closely correlating with a reduction in suprabasal bulgestem cells (α6lowCD34+). Moreover, RNA-microarray and RT-qPCR analyses of fluores-cence-activated cell sorting (FACS)-isolated bulge stem cells revealed that AhR deple-tion impaired transcriptional signatures typical of both epidermal progenitors and bulgestem cells but upregulated differentiation markers likely compromising theirundifferentiated phenotype. Altogether, our findings support that AhR controls skinregeneration and homeostasis by ensuring epidermal stem cell identity and highlightsthis receptor as potential target for the treatment of cutaneous pathologies.