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

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.

Deciphering the molecular morphology of the human hair cycle: Wnt signalling during the telogen–anagen transformation

“…For negative controls, primary antibodies raised against SFRP1 and K15 were omitted. Congruence of the observed SFRP1 and K15 immunostaining patterns with the ones reported for human scalp HFs was used as positive control.…”

PPAR‐γ signalling as a key mediator of human hair follicle physiology and pathology

“…For this purpose, it is essential to have reliable models for the examination of the effects of PPAR‐γ modulators specifically in the HF. One such instructive model is the human healthy or lesional HF or scalp skin organ culture that allows examination of many HF parameters (eg, hair growth, pigmentation, hair cycle, mitochondria, stem cells) simultaneously and in a reproducible manner, as was already shown with PPAR‐γ modulators . Nevertheless, HF organ culture has several limitations (eg, lack of innervation and endocrine effects, inter‐ and intra‐individual differences of harvested HFs, short anagen time), the most prominent one being the inability to test the complete HF cycle .…”

“…[16] This gene encodes the alpha 1 chain of collagen VI, which is expressed in the bulge area of the HF and is involved in the development of the HF during embryogenesis, where it is postulated to inhibit Wnt/β-catenin signalling. [74][75][76][77][78] Wnt/β-catenin signalling is essential for normal human HF function [79][80][81] and for stem cell maintenance [82] ; however, it is Selective PPAR-γ receptor modulators may exert antagonistic or agonistic effects, according to the cell type they function in, and act by modulating the cofactor affinity resulting in changes in the transcriptional activation. This is in contrast to full PPAR-γ agonists that lead to the release of the co-repressor complex and co-activator binding, and PPAR-γ antagonists that result in inadequate conformational modulation of the receptor and preventing the connection with the co-activator.…”

Do hair follicles operate as primitive, multifocal kidney‐like excretory (mini‐) organs?

“…[7,9,26,71] In order to manipulate the excretory function of HFs, it could be useful to promote human catagen/telogen development. While anagen induction and prolongation by drugs and other agents are an exception in clinical medicine, [85,[87][88][89][90] drug-induced telogen effluvium is one of the most frequent adverse effects of pharmacological therapy: the vast majority of agents reported to impact on human hair growth actually promotes catagen and thus telogen development (eg Refs [59,76,[91][92][93] ). Luckily, therefore, we are actually quite proficient in the pharmacological induction of catagen/telogen in human HFs and already have a wide repertoire of agents at our disposal for therapeutic exogen induction, that is the promotion of excretory HS shedding.…”