Institute of Molecular Medicine, University of Ulm, Ulm 89081, Germany.
Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital Medical Center and University of Cincinnati, Cincinnati, OH 45229, USA.
Aging (Albany NY). 2021 Feb 25;13(4):4778-4793. doi: 10.18632/aging.202694.
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 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.
正常的毛发生长呈周期性，包括生长期（生长期）、静止期（退行期）和休止期（休止期）。随着年龄的增长，生长期的启动明显延迟，导致毛发生长受损。毛发生长由毛囊干细胞（HFSCs）驱动。我们在这里表明，衰老的 HFSCs 表现出经典 Wnt 信号的减少，以及向非经典 Wnt5a 驱动的信号的转变，这种信号拮抗经典 Wnt 信号。衰老时 HFSCs 中 Wnt5a 的高表达导致小 RhoGTPase Cdc42 的活性升高，以及 Cdc42 在 HFSCs 内的空间分布发生变化。用一种称为 CASIN 的 Cdc42 活性特异性药理学抑制剂处理衰老的 HFSC，以抑制与衰老相关的 Cdc42 活性的升高，可恢复衰老 HFSC 中的经典 Wnt 信号。用 CASIN 处理老年小鼠可诱导生长期的开始，并增加生长期皮肤区域的百分比。HFSCs 的衰老相关功能缺陷至少部分是 HFSCs 固有的，可以通过合理的药理方法恢复。
