Abstract
Olfactory receptors are expressed by different cell types throughout the body and regulate physiological cell functions beyond olfaction. In particular, the olfactory receptor OR2AT4 has been shown to stimulate keratinocyte proliferation in the skin. Here, we show that the epithelium of human hair follicles, particularly the outer root sheath, expresses OR2AT4, and that specific stimulation of OR2AT4 by a synthetic sandalwood odorant (Sandalore®) prolongs human hair growth ex vivo by decreasing apoptosis and increasing production of the anagen-prolonging growth factor IGF-1. In contrast, co-administration of the specific OR2AT4 antagonist Phenirat® and silencing of OR2AT4 inhibit hair growth. Together, our study identifies that human hair follicles can engage in olfactory receptor-dependent chemosensation and require OR2AT4-mediated signaling to sustain their growth, suggesting that olfactory receptors may serve as a target in hair loss therapy.
Highlights
Olfactory receptors are expressed by different cell types throughout the body and regulate physiological cell functions beyond olfaction
OR2AT4 protein was predominantly expressed by suprabulbar keratinocytes of the proximal outer root sheath (ORS) (Figs. 1a, 2c), while hair matrix keratinocytes expressed low-level OR2AT4 protein (Figs. 1a, 2b), both in healthy scalp skin in situ[27] (Fig. 2a–c) and in amputated microdissected anagen hair follicles (HFs) ex vivo[25,26] (Fig. 1a)
OR2AT4 expression was downregulated during spontaneous, apoptosisdriven HF regression[26,27] (Fig. 2d–g)
Summary
Olfactory receptors are expressed by different cell types throughout the body and regulate physiological cell functions beyond olfaction. We show that the epithelium of human hair follicles, the outer root sheath, expresses OR2AT4, and that specific stimulation of OR2AT4 by a synthetic sandalwood odorant (Sandalore®) prolongs human hair growth ex vivo by decreasing apoptosis and increasing production of the anagen-prolonging growth factor IGF-1. The present study shows that human HFs express a specific OR, namely, OR2AT4 The activation of this OR by its specific agonist, Sandalore®, prolongs anagen maintenance ex vivo by decreasing hair matrix keratinocytes apoptosis and increasing the production of IGF-1 in the outer root sheath (ORS). The anagenprolonging effect mediated by Sandalore® is OR2AT4 dependent, as confirmed by co-administration of Sandalore® with the OR2AT4 competitive antagonist, Phenirat®, as well as the specific knock-down of OR2AT4 in human HFs. Taken together, we show that human HFs can engage in chemosensation and that the specific activation of OR2AT4 is required to sustain HF growth. Alone, Phenirat® tended to be weakly hair growth inhibitory (Supplementary Fig. 2a, b and Supplementary Note 2 for extended discussion)
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