Integrin β6-Deficient Mice Show Enhanced Keratinocyte Proliferation and Retarded Hair Follicle Regression after Depilation

Integrin alpha nu beta 6 is an epithelial-specific receptor that binds and activates latent transforming growth factor-beta 1 (TGF-beta 1). TGF-beta 1 has been implicated as an endogenous inducer of hair follicle (HF) regression during hair cycling. We hypothesized that alpha nu beta 6 integrin-mediated TGF-beta 1 signaling regulates hair regeneration and HF involution. In wild-type (WT) mice, the expression of integrin alpha nu beta 6 was strongly upregulated in the outer root sheath (ORS) during early hair regeneration, and was specifically enhanced in the HF bulge region. Expression gradually decreased in late anagen and remained restricted to the bulge region in the catagen and telogen stage HFs. The first spontaneous hair cycle was not altered in beta 6 integrin knockout (beta 6(-/-)) mice. However, after depilation, beta 6(-/-) mice exhibited retarded HF regression compared with WT controls. beta 6(-/-) follicles contained significantly higher numbers of proliferating Ki67-positive keratinocytes than WT follicles at an identical cycle stage. The beta 6(-/-) follicles also demonstrated significantly reduced levels of TGF-beta 1 expression and Smad2 phosphorylation during early anagen and anagen-catagen transition. Our study indicates that alpha nu beta 6 integrin has an important inhibitory role in keratinocyte proliferation in both HFs and interfollicular epidermis. Thus, downregulated TGF-beta 1 signaling in beta 6(-/-) mice may affect bulge niche stem cell behavior.