888 VGF: Key growth factor implicated simultaneously in hair growth, color, and loss

Abstract

and 4 Univ of Manchester, Manchester, United Kingdom Chemical signals acting on olfactory receptors (OR) regulate many cell functions beyond olfaction, e.g. OR2AT4-mediated keratinocyte (kerat) proliferation and migration in vitro.Here, we asked whether OR2AT4 also plays a role in human hair follicle (hHF) biology. Indeed, anagen scalp hHFs prominently express OR2AT4 protein (IF) in the central outer root sheath, and up-regulate OR2AT4 transcription (qRT-PCR) after stimulation with a specific OR2AT4 agonist, SandaloreÒ. SandaloreÒ significantly retarded spontaneous catagen development in anagen HFs ex vivo and decreased the number of apoptotic (TUNEL + or caspase-3 + ) hair matrix (HM) kerat compared to controls. These effects were partially counteracted by co-administering the specific OR2AT4 antagonist, PheniratÒ. Most importantly, catagen was induced prematurely and HM kerat apoptosis was enhanced in OR2AT4silenced hHFs, compared to vehicle HFs, even under SandaloreÒ stimulation. SandaloreÒ significantly decreased TGFb2 expression, but significantly increased IGF-1. OR2AT4 knockdown decreased IGF-1 expression while TGFb2 expression was unchanged, suggesting that OR2AT4 activation impacts on HF cycling via up-regulating IGF-1. Microarray analysis showed that SandaloreÒ significantly downregulated the transcription of pro-apoptotic and up-regulated anti-apoptotic genes. By phosphokinase assay, phosphorylation of kinases involved in the IGF-1 pathway was enhanced under SandaloreÒ stimulation. In summary, we show for the first time that hHFs engage in OR-mediated chemosensation and that OR2AT4 stimulation is required to maintain hHFs in anagen ex vivo. This suggests that OR2AT4 ligands like SandaloreÒ can be recruited for the management of hHF growth disorders.