Identifying novel strategies for treating human hair loss disorders: Cyclosporine A suppresses the Wnt inhibitor, SFRP1, in the dermal papilla of human scalp hair follicles

摘要

Hair growth disorders often carry a major psychological burden. Therefore, more effective human hair growth–modulatory agents urgently need to be developed. Here, we used the hypertrichosis-inducing immunosuppressant, Cyclosporine A (CsA), as a lead compound to identify new hair growth–promoting molecular targets. Through microarray analysis we identified the Wnt inhibitor, secreted frizzled related protein 1 (SFRP1), as being down-regulated in the dermal papilla (DP) of CsA-treated human scalp hair follicles (HFs) ex vivo. Therefore, we further investigated the function of SFRP1 using a pharmacological approach and found that SFRP1 regulates intrafollicular canonical Wnt/β-catenin activity through inhibition of Wnt ligands in the human hair bulb. Conversely, inhibiting SFRP1 activity through the SFRP1 antagonist, WAY-316606, enhanced hair shaft production, hair shaft keratin expression, and inhibited spontaneous HF regression (catagen) ex vivo. Collectively, these data (a) identify Wnt signalling as a novel, non–immune-inhibitory CsA target; (b) introduce SFRP1 as a physiologically important regulator of canonical β-catenin activity in a human (mini-)organ; and (c) demonstrate WAY-316606 to be a promising new promoter of human hair growth. Since inhibiting SFRP1 only facilitates Wnt signalling through ligands that are already present, this ‘ligand-limited’ therapeutic strategy for promoting human hair growth may circumvent potential oncological risks associated with chronic Wnt over-activation. Author summary Hair loss is a common disorder and can lead to psychological distress. Cyclosporine A, a fungal metabolite commonly used as an immunosuppressant, can potently induce hair growth in humans. However, it cannot be effectively used to restore hair growth because of its toxic profile. In this study, we used Cyclosporine A as a lead compound to identify novel therapeutic targets that can aid the development of new hair growth–promoting agents. Through microarray analysis, we found that the level of the secreted Wnt inhibitor, SFRP1 , was significantly reduced by Cyclosporine A. This inspired us to design a new pharmacological approach that uses WAY-316606, a reportedly well-tolerated and specific antagonist of SFRP1, to prolong the growth phase of the hair cycle. We show that WAY-316606 enhances human hair growth ex vivo, suggesting that it is a more targeted hair growth promoter with the potential to treat human hair loss disorders.