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Accelerated re-epithelialization in β3-integrin-deficient- mice is associated with enhanced TGF-β1 signaling

Nature Medicine volume 11, pages 167–174 (2005)Cite this article

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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Figure 1: Re-epithelialization is accelerated in β3-integrin–deficient mice.
Figure 2: Tgfb1 mRNA and TGF-β1 protein levels are elevated in β3-integrin–deficient wounds.
Figure 3: Re-epithelialization is decreased in β3-null wounds injected with a TGF-β1 neutralizing antibody.
Figure 4: Dermal fibroblast infiltration is significantly elevated in β3-null wounds and accelerates re-epithelialization.
Figure 5: β3-deficient dermal fibroblasts have elevated levels of TGF-β RI, TGF-β RII, increased pSmad2 and decreased levels of Smad3.
Figure 6: β3-integrin deficiency enhances nuclear translocation of Smad2 and Smad4 and accelerates fibroblast migration in the presence of TGF-β1.

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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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Author notes

  1. L E Reynolds and F J Conti: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Tumour Biology, Cell Adhesion and Disease Laboratory, Cancer Research UK, Bart's & The London, Queen Mary's School of Medicine & Dentistry, John Vane Science Centre, Charterhouse Square, London, EC1M 6BQ, UK

    L E Reynolds, F J Conti, S Robinson, M Stone, G Saunders & K Hodivala-Dilke

  2. London Research Institute, Cancer Research UK, Viral Carcinogenesis, Lab 213, 61 Lincoln's Inn Fields, London, WC2A 3PX, UK

    R Grose & C Dickson

  3. University of Edinburgh/ MRC Centre for Inflammation Research, College of Medicine and Veterinary Medicine, Teviot Place, Edinburgh, Scotland

    M Lucas & A Lacy-Hulbert

  4. Howard Hughes Medical Institute, Center for Cancer Research, Massachusetts Institute of Technology, Cambridge, 02139, Massachusetts, USA

    R O Hynes

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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)

Supplementary Methods (PDF 36 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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