Human scalp hair follicles can ‘taste’: chemosensory signalling via the bitter taste receptor TAS2R4 inhibits hair growth ex vivo

BACKGROUND: Taste receptors (TRs) exert many 'nongustatory' chemosensory functions beyond the sensation of taste. Recently, human keratinocytes have been found to express some bitter TRs, whose physiological functions remain unknown. As it has been 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 and whether its stimulation with cognate agonists or its selective knockdown affects 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 or absence of TAS2R4 small interfering RNA. Subsequently, changes in hair growth, growth factor expression and HF gene expression were assessed ex vivo. RESULTS: TAS2R4 mRNA and protein were mainly expressed in the outer root sheath and matrix of human anagen VI scalp HFs. Stimulating these with Reb A ex vivo initially inhibited hair matrix keratinocyte proliferation, followed by enhanced intrafollicular production of catagen-promoting transforming growth factor (TGF)-β2. This led to TGF-β-driven premature catagen entry, which could be antagonized by TGF-β-neutralizing antibodies. Premature catagen induction was also seen with other known TAS2R4 agonists, while TAS2R4 knockdown in the -presence of Reb A promoted hair growth, documenting that the observed effects of Reb A on the HF depend on TAS2R4-mediated signalling. Gene expression profiling (RNA sequencing) revealed differential transcriptional signatures consistent with TAS2R4-mediated changes in cell cycle control and TGF-β pathway signalling. CONCLUSIONS: Our study found 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 demonstrated that a simple tastant like Reb A can promote the anagen-catagen switch of human scalp HFs and their production of TGF-β2, and modulate 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 suggests a novel, drug-free strategy to inhibiting unwanted hair growth (e.g. in hirsutism and hypertrichosis) by targeting TAS2R4 (e.g. via topical Reb A).