Abstract
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.
Highlights
The current pharmacological treatment for hair loss disorders is unsatisfactory, with patients being limited to only two FDA-approved hair growth promoters, neither of which is robustly and universally efficacious [1]
We used Cyclosporine A as a lead compound to identify novel therapeutic targets that can aid the development of new hair growth–promoting agents
We found that the level of the secreted Wnt inhibitor, secreted frizzled related protein 1 (SFRP1), was significantly reduced by Cyclosporine A
Summary
The current pharmacological treatment for hair loss disorders is unsatisfactory, with patients being limited to only two FDA-approved hair growth promoters (minoxidil and finasteride), neither of which is robustly and universally efficacious [1]. There are relatively few known drugs that cause excessive hair growth (hypertrichosis) in patients. The immunosuppressive calcineurin inhibitor, Cyclosporine A (CsA), most frequently and characteristically induces hypertrichosis [2,3]. CsA prolongs active hair growth (anagen) in organ-cultured human scalp hair follicles (HFs) ex vivo [4,5]. The hair growth–stimulatory effects of CsA are independent of its T cell–inhibitory activity, because human HFs grafted onto immunocompromised nude mice treated with CsA show anagen prolongation in vivo [6]
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