P-Cadherin Regulates Human Hair Growth and Cycling via Canonical Wnt Signaling and Transforming Growth Factor-β2

Abstract

P-cadherin is a key component of epithelial adherens junctions, and it is prominently expressed in the hair follicle (HF) matrix. Loss-of-function mutations in CDH3, which encodes P-cadherin, result in hypotrichosis with juvenile macular dystrophy (HJMD), an autosomal recessive disorder featuring sparse and short hair. Here, we attempted to recapitulate some aspects of HJMD in vitro by transfecting normal, organ-cultured human scalp HFs with lipofectamine and CDH3-specific or scrambled control siRNAs. As in HJMD patients, P-cadherin silencing inhibited hair shaft growth, prematurely induced HF regression (catagen), and inhibited hair matrix keratinocyte proliferation. In situ, membrane β-catenin expression and transcription of the β-catenin target gene, axin2, were significantly reduced, whereas glycogen synthase kinase 3 β (GSK3β) and phospho-β-catenin immunoreactivity were increased. These effects were partially reversed by inhibiting GSK3β. P-cadherin silencing reduced the expression of the anagen-promoting growth factor, IGF-1, whereas that of transforming growth factor β 2 (TGFβ2; catagen promoter) was enhanced. Neutralizing TGFβ antagonized the catagen-promoting effects of P-cadherin silencing. In summary, we introduce human HFs as an attractive preclinical model for studying the functions of P-cadherin in human epithelial biology and pathology. This model demonstrates that cadherins can be successfully knocked down in an intact human organ in vitro, and shows that P-cadherin is needed for anagen maintenance by regulating canonical Wnt signaling and suppressing TGFβ2.

Promotion Effect of Apo-9′-fucoxanthinone from <i>Sargassum muticum</i> on Hair Growth <i>via</i> the Activation of Wnt/β-Catenin and VEGF-R2

“…TGF-β is known as an important factor in the regulation of cell proliferation, hair cycle and hair growth. 33,49) It has been reported that the repression of TGF-β delays the phase transition from angen to catagen, 32,34) which suggests that inhibition of TGF-β signaling may increase hair growth. However, apo-9′-fucoxanthinone had no effect on the nuclear translocation of Smad2/3.…”

“…To identify new hair-growing agents, cultures of hair fol- licles from several species such as human, 11,32) rat, 39) sheep 51) and mouse 40,52) were developed. The hair follicle culture method has several advantages in hair research, including the measure of hair-fiber elongation and maintenance of normal architecture.…”

“…32,33,49) Binding of TGF-β to receptors can increase the nuclear translocation of Smad2/3, a mediator of the TGF-β pathway. 50) To explore the TGF-β pathway related to apo-9′-fucoxanthinone-induced proliferation of DPCs, we evaluated the nuclear transition of Smad2/3 using an immunoblotting assay.…”

“…27,28) These studies suggest that the VEGF-R2 pathway may act as an activator in the proliferation of hair follicles cells. In addition, several growth factors, such as insulin-like growth factor-1, 29) fibroblast growth factor-5, 30) -7 31) and transforming growth factor-β (TGF-β) 32,33) have also been known to positively or negatively regulate hair growth. Especially, TGF-β is the most important regulator in hair growth and the hair cycle.…”

Hair Follicle Reconstruction and Stem Cells

“…As mentioned above, HF in mammals is the only organ which in normal physiological condition undergoes degeneration (catagen) to small aggregates of resting cells (telogen) with subsequent full regeneration leading to complete restoration of multicellular organ generating corneal shaft (anagen). Multiple mechanisms regulating organogenesis and physiological regeneration of HFs are found, the cellular structure of HF is studied in detail, properties and functions of cell subpopulations are elucidated [74][75][76][77][78].…”