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First published online 30 September 2008
doi: 10.1242/jcs.029215

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Loss of protein kinase C results in impaired cutaneous wound closure and myofibroblast function

Andrew Leask^1,*,, Xu Shi-wen^2,*, Korsa Khan², Yunliang Chen³, Alan Holmes², Mark Eastwood³, Christopher P. Denton², Carol M. Black² and David J. Abraham²

¹ CIHR Group in Skeletal Development and Remodeling, Division of Oral Biology and Department of Physiology and Pharmacology, Schulich School of Medicine and Dentistry, University of Western Ontario, London ON, Canada N6A 5C1
² Centre for Rheumatology, Department of Medicine, Royal Free and University College Medical School, University College London (Royal Free Campus), Rowland Hill Street, London NW3 2PF, UK
³ Centre for Tissue Engineering Research, Department of Biomedical Sciences, University of Westminster, London W1W 6UW, UK

Author for correspondence (e-mail: andrew.leask{at}schulich.uwo.ca)

Accepted 20 July 2008

Cutaneous wound repair requires the de novo induction of a specialized form of fibroblast, the -smooth muscle actin (-SMA)-expressing myofibroblast, which migrates into the wound where it adheres to and contracts extracellular matrix (ECM), resulting in wound closure. Persistence of the myofibroblast results in scarring and fibrotic disease. In this report, we show that, compared with wild-type littermates, PKC^-/- mice display delayed impaired cutaneous wound closure and a reduction in myofibroblasts. Moreover, both in the presence and absence of TGFβ, dermal fibroblasts from PKC^-/- mice cultured on fibronectin show impaired abilities to form `supermature' focal adhesions and -SMA stress fibers, and reduced pro-fibrotic gene expression. Smad3 phosphorylation in response to TGFβ1 was impaired in PKC^-/- fibroblasts. PKC^-/- fibroblasts show reduced FAK and Rac activation, and adhesive, contractile and migratory abilities. Overexpressing constitutively active Rac1 rescues the defective FAK phosphorylation, cell migration, adhesion and stress fiber formation of these PKC^-/- fibroblasts, indicating that Rac1 operates downstream of PKC, yet upstream of FAK. These results suggest that loss of PKC severely impairs myofibroblast formation and function, and that targeting PKC may be beneficial in selectively modulating wound healing and fibrotic responses in vivo.

Key words: Myofibroblasts, TGFβ, Wound healing