Abstract
The upregulation of TGF-β1 and integrin expression during wound healing has implicated these molecules in this process, but their precise regulation and roles remain unclear. Here we report that, notably, mice lacking β3-integrins show enhanced wound healing with re-epithelialization complete several days earlier than in wild-type mice. We show that this effect is the result of an increase in TGF-β1 and enhanced dermal fibroblast infiltration into wounds of β3-null mice. Specifically, β3-integrin deficiency is associated with elevated TGF-β receptor I and receptor II expression, reduced Smad3 levels, sustained Smad2 and Smad4 nuclear localization and enhanced TGF-β1-mediated dermal fibroblast migration. These data indicate that αvβ3–integrin can suppress TGF-β1-mediated signaling, thereby controlling the rate of wound healing, and highlight a new mechanism for TGF-β1 regulation by β3-integrins.
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Acknowledgements
We thank C. Hill, G. Inman F. Parkinson, I. Hart, F. Watt, D. Owens and A. Daley for their helpful advice and criticisms throughout the work; S. Watling and C. Wren for their technical assistance; G. Elias and colleagues for help with histology; F. Balkwill's laboratory for technical assistance.
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Supplementary information
Supplementary Fig. 1
Accelerated re-epithelialization is associated with enhanced epithelial migration. (PDF 60 kb)
Supplementary Fig. 2
Wound contraction is normal in β3-null wounds. (PDF 59 kb)
Supplementary Fig. 3
Sense control for in situ hybridization for Tgfb1 mRNA. (PDF 117 kb)
Supplementary Fig. 4
Negative control for TGF-β1 and P-smad2 immunostaining. (PDF 83 kb)
Supplementary Fig. 5
Keratinocyte proliferation is decreased, but dermal ECM deposition is increased in β3-integrin-deficient wounds. (PDF 663 kb)
Supplementary Fig. 6
Neutrophil numbers are not changed in β3-null wounds. (PDF 106 kb)
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Reynolds, L., Conti, F., Lucas, M. et al. Accelerated re-epithelialization in β3-integrin-deficient- mice is associated with enhanced TGF-β1 signaling. Nat Med 11, 167–174 (2005). https://doi.org/10.1038/nm1165
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DOI: https://doi.org/10.1038/nm1165
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