Human scalp hair follicles can “taste”: Chemosensory signalling via the bitter taste receptor, TAS2R4, inhibits hair growth ex vivo

Abstract Background Taste receptors (TRs) exert many ‘non-gustatory’ chemosensory functions beyond the sensation of taste. Recently, human keratinocytes were found to express some bitter TRs, whose physiological functions remain unknown. Since we had discovered that human scalp hair follicles (HFs) use olfactory receptors to regulate their growth, we hypothesized that some bitter TRs may exert a similar function. Objectives To explore whether human scalp HFs express the bitter TR, TAS2R4, whether its stimulation with cognate agonists or its selective knockdown impacts key human HF functions and, if yes, how. Methods TAS2R4 mRNA and protein expression were assessed in situ, and organ-cultured scalp HFs were stimulated with the TAS2R4-agonistic natural sweetener, rebaudioside A (Reb A), in the presence/absence of TAS2R4 siRNA. Subsequently, changes in hair growth, growth factor expression, and HF gene expression were assessed ex vivo. Results TAS2R4 mRNA and protein are mainly expressed in the outer root sheath and matrix of human anagen scalp HFs. Stimulating these with Reb-A ex vivo initially inhibits hair matrix keratinocyte proliferation, followed by enhanced intrafollicular production of catagen-promoting TGF-β2. This leads to TGF-β-driven premature catagen entry, which can be antagonized by TGF-β-neutralizing antibodies. Premature catagen induction is also seen with other known TAS2R4 agonists, while TAS2R4 knockdown in the presence of Reb-A promotes hair growth, thus documenting the TAS2R4-dependence of the observed HF effects of Reb-A. Gene expression profiling (RNA-seq) revealed differential transcriptional signatures consistent with TAS2R4-mediated changes in cell cycle control and TGF-β pathway signalling. Conclusion Our study uncovers that human scalp HFs engage in chemosensation via bitter TRs to regulate their growth, matrix keratinocyte proliferation, growth factor production, and overall gene expression. Specifically, we demonstrate that a simple tastant like Reb-A can promote the anagen-catagen switch of human scalp HFs, their TGF-β2 production, and modulate both HF keratinocyte proliferation and intrafollicular gene transcription in a TAS2R4-dependent manner. This expands our understanding of bitter TR-mediated chemosensation in human skin and invites a novel, drug-free strategy for inhibiting unwanted hair growth (hirsutism, hypertrichosis) by targeting TAS2R4, e.g. via topical Reb-A.