Ma Xianghui, Tian Yuhua, Song Yongli, Shi Jianyun, Xu Jiuzhi, Xiong Kai, Li Jia, Xu Wenjie, Zhao Yiqiang, Shuai Jianwei, Chen Lei, Plikus Maksim V, Lengner Christopher J, Ren Fazheng, Xue Lixiang, Yu Zhengquan
Beijing Advanced Innovation Center for Food Nutrition and Human Health and State Key Laboratories for Agrobiotechnology, College of Biological Sciences, China Agricultural University, Beijing, China.
Medical Research Center, Department of Radiation Oncology, Peking University Third Hospital, Beijing, China.
J Invest Dermatol. 2017 May;137(5):1015-1024. doi: 10.1016/j.jid.2017.01.012. Epub 2017 Jan 29.
Hair follicles (HFs) undergo precisely regulated cycles of active regeneration (anagen), involution (catagen), and relative quiescence (telogen). Hair follicle stem cells (HFSCs) play important roles in regenerative cycling. Elucidating mechanisms that govern HFSC behavior can help uncover the underlying principles of hair development, hair growth disorders, and skin cancers. RNA-binding proteins of the Musashi (Msi) have been implicated in the biology of different stem cell types, yet they have not been studied in HFSCs. Here we utilized gain- and loss-of-function mouse models to demonstrate that forced MSI2 expression retards anagen entry and consequently delays hair growth, whereas loss of Msi2 enhances hair regrowth. Furthermore, our findings show that Msi2 maintains quiescent state of HFSCs in the process of the telogen-to-anagen transition. At the molecular level, our unbiased transcriptome profiling shows that Msi2 represses Hedgehog signaling activity and that Shh is its direct target in the hair follicle. Taken together, our findings reveal the importance of Msi2 in suppressing hair regeneration and maintaining HFSC quiescence. The previously unreported Msi2-Shh-Gli1 pathway adds to the growing understanding of the complex network governing cyclic hair growth.
毛囊(HFs)经历精确调控的活跃再生(生长期)、退化(退行期)和相对静止(休止期)循环。毛囊干细胞(HFSCs)在再生循环中发挥重要作用。阐明调控HFSC行为的机制有助于揭示毛发发育、毛发生长紊乱和皮肤癌的潜在原理。Musashi(Msi)的RNA结合蛋白与不同类型干细胞的生物学特性有关,但尚未在HFSCs中进行研究。在这里,我们利用功能获得和功能缺失小鼠模型证明,强制表达MSI2会延迟生长期的进入,从而延缓毛发生长,而缺失Msi2则会促进毛发再生。此外,我们的研究结果表明,Msi2在休止期到生长期的转变过程中维持HFSCs的静止状态。在分子水平上,我们的无偏向转录组分析表明,Msi2抑制Hedgehog信号活性,并且Shh是其在毛囊中的直接靶点。综上所述,我们的研究结果揭示了Msi2在抑制毛发再生和维持HFSC静止状态方面的重要性。先前未报道的Msi2-Shh-Gli1途径增加了对控制周期性毛发生长的复杂网络的理解。