Regulation of epidermal proliferation and hair follicle cycling by synthetic photostable retinoid EC23.

Abstract

Retinoid signaling is an important regulator of the epidermis and skin appendages. Therefore, synthetic retinoids have been developed for therapeutic use for skin disorders such as psoriasis and acne. In previous studies, we showed how the photostable retinoid EC23 induces neuronal differentiation in stem cell-like cell populations, and here, we aim to investigate its ability to influence epidermal and hair follicle growth. EC23 influence on skin biology was investigated initially in cultures of monolayer keratinocytes and three-dimentional in vitro models of skin, and finally in in vivo studies of mice back skin. EC23 induces keratinocyte hyperproliferation in vitro and in vivo, and when applied to mouse skin increases the number of involucrin-positive suprabasal cell layers. These phenotypic changes are similar in skin treated with the natural retinoid all-trans retinoic acid (ATRA); however, EC23 is more potent; a tenfold lower dose of EC23 is sufficient to induce epidermal thickening, and resulting hyperproliferation is sustained for a longer time period after first dose. EC23 treatment resulted in a disorganized stratum corneum, reduced cell surface lipids and compromised barrier, similar to ATRA treatment. However, EC23 induces a rapid telogen to anagen transition and hair re-growth in 6-week-old mice with synchronously resting back skin follicles. The impact of EC23 on the hair cycle was surprising as similar results have not been seen with ATRA. These data suggest that synthetic retinoid EC23 is a useful tool in exploring the turnover and differentiation of cells and has a potent effect on skin physiology.