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The matricellular protein CCN1 induces fibroblast senescence and restricts fibrosis in cutaneous wound healing

Nature Cell Biology volume 12, pages 676685 (2010) | Download Citation

  • An Erratum to this article was published on 01 December 2010

This article has been updated

Abstract

Cellular senescence is a recognized mechanism of tumour suppression; however, its contribution to other pathologies is not well understood. We show that the matricellular protein CCN1 (also known as CYR61; cysteine-rich protein 61), which is dynamically expressed at sites of wound repair, can induce fibroblast senescence by binding to integrin α6β1 and the heparan sulphate proteoglycans (receptors involved in cell adhesion). CCN1 induces DNA damage response pathways and activates p53 and the RAC1–NOX1 complex, which generates reactive oxygen species (ROS). This results in the ROS-dependent activation of the p16INK4a/pRb pathway, leading to senescence and concomitant expression of antifibrotic genes. Senescent fibroblasts accumulate in granulation tissues of healing cutaneous wounds and express antifibrotic genes in wild-type mice. These processes are lost in knockin mice that express a senescence-defective Ccn1 mutant, resulting in exacerbated fibrosis. Topical application of CCN1 protein to wounds reverses these defects. Thus, fibroblast senescence is a CCN1-dependent wound healing response in cutaneous injury that functions to curb fibrosis during tissue repair.

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Change history

  • 12 November 2010

    In the version of this article initially published online and in print, the labels BSA and CCN1 in Fig. 2a were swapped. Theis error has been corrected in both the HTML and PDF versions of the article.

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Acknowledgements

We thank L. DiPietro for advice, J. Campisi and S. Lowe for reagents, S. W. Shin for assistance, and members of the laboratory for discussion. This work was supported by grants from the National Institutes of Health to L.F.L.

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Affiliations

  1. Department of Biochemistry and Molecular Genetics, University of Illinois at Chicago College of Medicine, Chicago, IL 60607-7170 USA.

    • Joon-Il Jun
    •  & Lester F. Lau

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Contributions

J.-I.J. conducted the experiments and J.-I.J. and L.F.L. designed the experimental plan, analysed the data and wrote the paper.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Lester F. Lau.

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https://doi.org/10.1038/ncb2070