研究人员发现在小鼠身体不同部位的皮肤中,Hoxc在干细胞微环境中的差异性表达引起下游Wnt信号通路的激活的差别,从而引起毛囊干细胞再生的位置性差异,揭示了干细胞微环境在身体水平的异质性与可塑性如何影响干细胞再生能力的分子机制。
为了研究区域特异性毛发再生能力的细胞和分子机制,研究人员以多毛突变体考拉鼠(Koa)作为切入点,研究人员利用FACS分离了野生型小鼠的耳部和背部以及Koa耳部的表皮细胞和真皮细胞,通过RNA高通量测序发现Koa断点附近的Hoxc基因在野生型小鼠的背部真皮和Koa耳部的真皮细胞内高表达,而在野生型小鼠的耳部不表达。研究人员通过RNAin situ的方法进一步证明了,Hoxc基因主要在真皮乳头细胞中表达。接下来,研究人员利用Crisper/Cas9技术在Koa染色体上敲除了9个Hoxc基因,发现伴随着Hoxc在真皮中表达量的下降,Koa的多毛表型消失了——这证明Hoxc 基因家族是导致Koa多毛的原因。如果只在Koa染色体上敲掉单个Hoxc基因,Koa的多毛表型无法或无法全部消失。
最终,研究人员发现Wnt信号通路位于Hoxc基因的下游,从而激活毛囊的再生。尤其有意思的是Hoxc下游刺激Wnt信号通路激活的基因Rspo2在人体突变会导致毛发缺失的疾病。因此,接下来的研究将是进一步探索人类毛发发育和进化的细胞与分子机制。
推荐阅读原文:
Hoxc-dependent mesenchymal niche heterogeneity drives regional hair follicle regeneration.
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.
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