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

PLoS Biol. 2018 May 8;16(5):e2003705. doi: 10.1371/journal.pbio.2003705. eCollection 2018 May.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alopecia / drug therapy*
  • Cyclosporine / pharmacology
  • Cyclosporine / therapeutic use*
  • Drug Evaluation, Preclinical
  • Hair Follicle / drug effects*
  • Humans
  • Intercellular Signaling Peptides and Proteins
  • Male
  • Membrane Proteins / antagonists & inhibitors*
  • Organ Culture Techniques
  • Wnt Signaling Pathway / drug effects*

Substances

  • Intercellular Signaling Peptides and Proteins
  • Membrane Proteins
  • SFRP1 protein, human
  • Cyclosporine

Grant support

Giuliani S.p.A. https://giulianipharma.com/en/ supported a PhD student fellowship to NJH. The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.