A Wnt5a-Cdc42 axis controls aging and rejuvenation of hair-follicle stem cells

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.