β-cateinin activation in hair follicle dermal sheath induces ectopic hair outgrowth and skin fibrosis

Dermal sheath (DS) shows potent hair inducing capability and high plasticity without leading to immuno rejection. A recent study showed a subset of DS cells, identified as hair follicle (HF) dermal stem cells, can be mobilized to regenerate DS, maintain/supply the cell number of dermal papilla (DP) and modulate hair type. However, it is unclear how Wnt/β-catenin signaling regulates DS cells behaviors. Here we report that activation of β-catenin in DS, to some extent, endows it with hair inducing ability, reprogramming HF epidermal cells to generate new outgrowth. The new formed dermal condensates (DC)/DP lying adjacent the outgrowth derives from DS and/or its progeny, and homeostasis of pre-existing HFs is disturbed. Additionally, progressive skin fibrosis is prominent in hypodermis, where the excessive activated fibroblasts at least partially originate from DS and/or its progeny. Gene expression analysis of purified DS cells revealed that 44% DC signature genes are regulated, most of which are up-regulated. We found elevated expression of several growth factors, including Noggin, Fgf7 and Fgf10, which were previously implicated in HF induction. In summary, we confirm the high plasticity of DS cells by in vivo assays and report a mechanism by which Wnt/β-catenin signaling controls DS cells behaviors. We prospectively isolated control and cΔex3 DS cells (YFP+ve CD34-ve ALP-ve ITGα8-ve cells) from P15 dorsal skins by FACS.

真皮鞘（Dermal sheath, DS）具备强大的毛囊诱导能力与高度可塑性，且不会引发免疫排斥。近期研究发现，一类被鉴定为毛囊（hair follicle, HF）真皮干细胞的DS细胞亚群，可被动员以再生真皮鞘、维持或补充真皮乳头（dermal papilla, DP）的细胞数量，并调控毛发类型。然而目前尚不清楚Wnt/β-连环蛋白信号通路如何调控DS细胞的行为。本研究证实，在DS中激活β-连环蛋白可在一定程度上赋予其毛囊诱导能力，并重编程HF表皮细胞以产生新的表皮突起。紧邻该突起形成的新生真皮凝聚层（dermal condensates, DC）/DP，来源于DS及其子代细胞，而已存HF的稳态会被扰乱。此外，皮下组织中可见显著的进行性皮肤纤维化，其中过度激活的成纤维细胞至少部分来源于DS及其子代细胞。对纯化DS细胞的基因表达分析显示，44%的DC特征基因表达发生调控变化，其中大多数呈现上调。我们还发现包括Noggin、Fgf7及Fgf10在内的多种生长因子表达升高，这些因子此前已被证实与HF诱导相关。综上，本研究通过体内实验证实了DS细胞的高度可塑性，并揭示了Wnt/β-连环蛋白信号通路调控DS细胞行为的机制。我们通过荧光激活细胞分选术（fluorescence-activated cell sorting, FACS）从出生后第15天（P15）的小鼠背部皮肤中前瞻性分离得到对照组与cΔex3型DS细胞（YFP阳性、CD34阴性、ALP阴性、ITGα8阴性细胞）。