Expression data from human hair follicles (ex vivo) incubated with cyclosporine A and vehicle control

Since hair growth disorders can carry a major psychological burden, more effective human hair growth-modulatory agents need to be urgently developed. Here, we used the hypertrichosis-inducing immunosuppressant, cyclosporine A (CsA), as a lead compound to identify new hair growth-promoting targets. Through microarray analysis we identified the Wnt inhibitor, SFRP1, as being downregulated 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/-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 signaling as a novel, non-immune-inhibitory CsA target; (b) introduce SFRP1 as a physiologically important regulator of canonical -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 signaling 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.

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Hawkshaw NJ, Hardman JA, Haslam IS, Shahmalak A, Gilhar A, Lim X, Paus R