Hoxc-Dependent Mesenchymal Niche Heterogeneity Drives Regional Hair Follicle Regeneration

• Published in: Cell stem cell 2018-10, Vol.23 (4), p.487-500.e6
• Main Authors: Yu, Zhou, Jiang, Kaiju, Xu, Zijian, Huang, Huanwei, Qian, Nannan, Lu, Zhiwei, Chen, Daoming, Di, Ruonan, Yuan, Tianyi, Du, Zhenhai, Xie, Wei, Lu, Xiaoling, Li, Huawei, Chai, Renjie, Yang, Yong, Zhu, Bing, Kunieda, Tetsuo, Wang, Fengchao, Chen, Ting
• Format: Article
• Language: English
• Subjects: adult stem cell; Hox; niche; Polycomb; tissue regeneration; topologically associated domain; Wnt
• ISSN: 1934-5909; 1875-9777
• DOI: 10.1016/j.stem.2018.07.016

Mesenchymal niche cells instruct activity of tissue-resident stem and progenitor cell populations. Epithelial stem cells in hair follicles (HFs) have region-specific activity, which may arise from intrinsic cellular heterogeneity within mesenchymal dermal papilla (DP) cells. Here we show that expression of Hoxc genes is sufficient to reprogram mesenchymal DP cells and alter the regenerative potential of epithelial stem cells. Hoxc gene expression in adult skin dermis closely correlates with regional HF regeneration patterns. Disrupting the region-specific expression patterns of Hoxc genes, by either decreasing their epigenetic repression via Bmi1 loss or inducing ectopic interactions of the Hoxc locus with an active epigenetic region, leads to precocious HF regeneration. We further show that a single Hoxc gene is sufficient to activate dormant DP niches and promote regional HF regeneration through canonical Wnt signaling. Altogether, these results reveal that Hoxc genes bestow mesenchymal niches with tissue-level heterogeneity and plasticity. [Display omitted] •Distinct skin mesenchymal niches are uniquely marked by regional Hoxc expression•Epigenetic disruption of Hoxc expression leads to ectopic hair regeneration•Single Hoxc genes can reprogram a dormant mesenchymal niche into an active niche•Niche-expressed Hoxc genes activate epithelial SCs through Wnt signaling Yu et al. show that Hoxc gene expression in mesenchymal niches controls epithelial stem cell activation via Wnt signaling. Hoxc expression patterns vary at the tissue level, suggesting that the regenerative landscape of the skin is governed by mesenchymal niche plasticity.