Normal hair growth occurs in cycles, comprising growth (anagen), cessation (catagen) and rest (telogen). Upon aging, the initiation of anagen is significantly delayed, which results in impaired hair regeneration. Hair regeneration is driven by hair follicle stem cells (HFSCs). We show here that aged HFSCs present with a decrease in canonical Wnt signaling and a shift towards non-canonical Wnt5a driven signaling which antagonizes canonical Wnt signaling. Elevated expression of Wnt5a in HFSCs upon aging results in elevated activity of the small RhoGTPase Cdc42 as well as a change in the spatial distribution of Cdc42 within HFSCs. Treatment of aged HFSC with a specific pharmacological inhibitor of Cdc42 activity termed CASIN to suppress the aging-associated elevated activity of Cdc42 restored canonical Wnt signaling in aged HFSCs. Treatment of aged mice in vivo with CASIN induced anagen onset and increased the percentage of anagen skin areas. Aging-associated functional deficits of HFSCs are at least in part intrinsic to HFSCs and can be restored by rational pharmacological approaches.

中文翻译：

---

Wnt5a-Cdc42轴控制毛囊干细胞的衰老和恢复活力

正常的头发生长以周期进行，包括生长（生长期），戒烟（生长期）和休息（休止期）。老化后，生长期的启动明显延迟，这会导致毛发再生受损。毛囊干细胞（HFSC）驱动头发再生。我们在这里显示衰老的HFSCs具有规范Wnt信号的减少和向非规范Wnt5a驱动的信号的转变，这与规范Wnt信号拮抗。衰老后，HFSC中Wnt5a的表达升高会导致小RhoGTPase Cdc42的活性升高，以及HFSC中Cdc42的空间分布发生变化。用一种称为CASIN的特定Cdc42活性药理抑制剂治疗衰老的HFSC，以抑制与衰老相关的Cdc42活性升高，从而恢复了衰老的HFSCs的经典Wnt信号传导。CASIN诱导的新生婴儿体内衰老小鼠的治疗，增加了新生婴儿皮肤面积的百分比。HFSC的与衰老相关的功能缺陷至少部分是HFSC固有的，可以通过合理的药理学方法加以修复。