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Xie, Yanshuang.
The role of integrin alphavbeta6 in impaired wound healing and hair follicle regeneration.
Doctor of Philosophy - PhD -- University of British Columbia, 2010
Vancouver : University of British Columbia, 2010.
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Integrin v6 is an epithelial-specific receptor that is absent from the healthy epidermis but synthesized de novo during wound repair. However, its function in wound repair is unknown. Integrin-mediated activation of transforming growth factor-1 (TGF-1) is the main activation mechanism of this key cytokine in vivo. It has been previously reported that chronic human wounds continue to express v6 integrin and transgenic mice over-expressing v6 integrin produce chronic hypertrophic wounds that contain high levels of TGF-1. Therefore, we hypothesize that v6 integrin-mediated regulation of TGF-1 activity may play a role in the impaired wound healing process. To this end, a well-established dexamethasone-induced mouse impaired wound model was used in 6 integrin-deficient (6-/-) and WT mice. The dexamethasone-treated 6-/- mice demonstrated an accelerated wound repair and enhanced keratinocyte proliferation in wound epithelium and particularly in the hair follicles, while the production of pro-inflammatory cytokines and TGF-1 activation were reduced compared to the treated WT controls. TGF-1 has been implicated as an endogenous inducer of hair follicle regression. Since hair follicles constitutively express v6 integrin, we tested whether v6 integrin-mediated TGF-1 signaling regulates hair regeneration and hair follicle involution process. Using a depilation-induced mouse hair cycling model we showed that hair regeneration was accelerated and hair follicle regression retarded in the 6-/- mice compared to WT controls. These changes were associated with enhanced keratinocyte proliferation in both hair follicles and interfollicular epidermis (IFE). Additionally, the levels of TGF-1 and Smad2 phosphorylation were significantly reduced in 6-/- follicles during early anagen and anagen-catagen transition. Our study also demonstrated that the expression of integrin v6 was strongly upregulated and specifically enhanced in the bulge stem cell niche during early hair regeneration. In summary, the results indicate that v6 integrin plays an important inhibitory role in keratinocyte proliferation in both the IFE and hair follicles after wounding. The downregulated TGF-1 signaling in 6-/- mice may impact epidermal stem cell behavior via modulating the microenvironment of the bulge stem cell niche after injury, which suggests a possible manipulation target in the functions of epidermal stem cells in the future.
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