Hawkshaw N J, Hardman J A, Alam M, Jimenez F, Paus R
Centre for Dermatology Research, The University of Manchester and NIHR Biomedical Research Centre, Manchester, U.K.
Mediteknia Skin and Hair Lab, Las Palmas de Gran Canaria, Spain.
Br J Dermatol. 2020 May;182(5):1184-1193. doi: 10.1111/bjd.18356. Epub 2019 Sep 29.
The signals that induce anagen (growth) in 'quiescent' human telogen hair follicles (HFs) are as yet unknown. Their identification promises better targeted therapeutic hair growth interventions.
Recognizing the central role of Wnt signalling in hair biology, the aim was to delineate the differential expression of key agonists, antagonists and target genes of this pathway during the telogen-to-anagen transformation of human scalp HFs.
This differential expression was studied by in situ hybridization in human telogen and early-anagen scalp HF sections.
On anagen induction, gene expression of the Wnt ligands WNT3, WNT4 and WNT10B, the Wnt ligand secretion regulator WLS, and the Wnt target genes AXIN2 and LEF1, is significantly increased within the secondary hair germ and the dermal papilla. Conversely, expression of the secreted Wnt inhibitor SFRP1 (secreted frizzled-related protein 1) is reduced. Human epithelial HF stem cells upregulate WNT4 and WNT10A expression, suggesting that these Wnt agonists are important for stem cell activation.
We provide the first evidence that key changes in Wnt signalling that drive murine anagen induction also occur in human scalp HFs, yet with notable differences. This provides a rational basis for Wnt-targeting therapeutic interventions to manipulate human hair growth disorders. What's already known about this topic? Upregulation of Wnt agonists and downregulation of Wnt antagonists in the secondary hair germ and/or dermal papilla drives hair growth (anagen) induction in mice. Autocrine Wnt signalling in murine epithelial hair follicle stem cells is required to maintain their stem cell function. Reduction of Wnt ligands or increased expression of Wnt antagonists induces dysregulation of the murine hair follicle cycle and causes alopecia. What does this study add? This study demonstrates for the first time that key Wnt pathway regulatory agonists, antagonists and target genes, are expressed in the human telogen-to-early-anagen transformation. On human anagen induction the Wnt ligands WNT3, WNT4 and WNT10B are increased in the regenerating epithelium, whereas the Wnt antagonist, SFRP1 (secreted frizzled-related protein 1), is reduced. Human anagen induction has fundamental differences in the expression of Wnt ligands compared with the murine system. What is the translational message? Regulation of these Wnt ligands permits targeted therapeutic interventions in human hair growth disorders and informs development of new drugs that promote or suppress anagen induction.
诱导“静止期”人类休止期毛囊进入生长期的信号目前尚不清楚。识别这些信号有望实现更有针对性的促进头发生长的治疗干预。
鉴于Wnt信号通路在毛发生物学中发挥核心作用，本研究旨在描绘该通路关键激动剂、拮抗剂和靶基因在人类头皮毛囊从休止期到生长期转变过程中的差异表达。
通过原位杂交技术研究人类休止期和早期生长期头皮毛囊切片中的这种差异表达。
在生长期诱导过程中，Wnt配体WNT3、WNT4和WNT10B、Wnt配体分泌调节因子WLS以及Wnt靶基因AXIN2和LEF1在次级毛芽和真皮乳头中的基因表达显著增加。相反，分泌型Wnt抑制剂SFRP1（分泌型卷曲相关蛋白1）的表达降低。人类上皮毛囊干细胞上调WNT4和WNT10A的表达，表明这些Wnt激动剂对干细胞激活很重要。
我们首次证明，驱动小鼠生长期诱导的Wnt信号通路关键变化也发生在人类头皮毛囊中，但存在显著差异。这为针对Wnt的治疗干预以治疗人类毛发生长紊乱提供了合理依据。关于该主题已知的信息有哪些？次级毛芽和/或真皮乳头中Wnt激动剂的上调和Wnt拮抗剂的下调驱动小鼠头发生长（生长期）诱导。小鼠上皮毛囊干细胞中的自分泌Wnt信号对于维持其干细胞功能是必需的。Wnt配体减少或Wnt拮抗剂表达增加会导致小鼠毛囊周期失调并引起脱发。本研究有何新发现？本研究首次证明关键的Wnt信号通路调节激动剂、拮抗剂和靶基因在人类从休止期到早期生长期的转变过程中表达。在人类生长期诱导过程中，再生上皮中Wnt配体WNT3、WNT4和WNT10B增加，而Wnt拮抗剂SFRP1（分泌型卷曲相关蛋白1）减少。与小鼠系统相比，人类生长期诱导在Wnt配体表达方面存在根本差异。该研究的转化意义是什么？对这些Wnt配体的调控有助于针对人类毛发生长紊乱进行有针对性的治疗干预，并为开发促进或抑制生长期诱导的新药提供信息。
