Epiregulin promotes hair growth via EGFR-medicated epidermal and ErbB4-mediated dermal stimulation

Objectives: EREG (epiregulin), a member of the epidermal growth factor (EGF) family, plays a role in inflammation, wound healing, normal physiology and malignancies. However, little is known about its function on hair growth. Materials and Methods: Cell growth assay, QPCR and immunostaining were carried out. Telogen-to-anagen transition and organ culture were conducted. ROS level was monitored by staining DCFDA. Results: We investigated the hair inductive effect of EREG and the mechanism of stimulation on DPCs and ORS cells during hair cycling. Whereas EREG promoted hair growth, EREG knockdown inhibited hair growth as evidenced by telogen-to-anagen transition and organ culture models. EREG was expressed in epidermal cells including ORS cells in vivo. EREG activated phospho-ErbB4 in DPCs during hair cycling and stimulated DPCs via ErbB4 activation in vitro. In terms of the underlying mechanism, reactive oxygen species (ROS) played a key role in DPC stimulation. EREG also activated phospho-EGF receptor (EGFR) in epidermal cells including matrix and ORS cells in vivo and stimulated ORS cells via EGFR activation in vitro. Conclusions: EREG, which is released from ORS cells, activated EGFR and ErbB4 on epidermal cells and DPCs during hair cycling, respectively. As a result, EREG stimulated epidermal cells a positive feedback and DPCs via regulating ROS generation for hair growth. Therefore, EREG therapy may be a novel solution for hair loss treatment.