Editors' ChoiceWOUND REPAIR

Speedy repair with stabilized β-catenin

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Science Translational Medicine  22 Jul 2015:
Vol. 7, Issue 297, pp. 297ec125
DOI: 10.1126/scitranslmed.aac8568

Animal survival depends on efficient repair of skin wounds, yet there are still many unknowns about the mechanisms regulating this process. The canonical Wnt/β-catenin signaling pathway, which is critical for development, is induced during wound repair; however, its effects are uncertain, as Wnt/β-catenin signaling is reported to both positively and negatively affect re-epithelialization, although it consistently promotes scarring. Lee et al. now enrich our understanding of the role of Wnt/β-catenin signaling in tissue repair by reporting on the function of CXXC5, a zinc finger family protein that inhibits β-catenin and blocks wound healing.

After finding that epidermal keratinocytes and dermal fibroblasts within human scars have elevated β-catenin and concomitantly low levels of CXXC5, the authors demonstrated that CXXC5 decreases contraction, migration, and collagen production (features of scar-forming myofibroblasts) in dermal fibroblast cultures. Consistent with this, CXXC5-null mice had dramatically accelerated healing, with more rapid re-epithelialization and enhanced collagen production compared with wild-type animals. Lee et al. revealed that the actions of CXXC5 required Dishevelled (Dvl), a mediator of Wnt ligand signaling; by binding Dvl, CXXC5 promotes β-catenin degradation. The regenerative effects of CXXC5 were identified to be largely mediated by the β-catenin target gene endothelin-1 and therefore could be blocked by the endothelin receptor inhibitor, bosentan. Lee and colleagues subsequently developed synthetic peptides to block the CXXC5–Dvl interaction. Topical treatment of skin wounds in mice with these inhibitory peptides increased the rate of repair, which could be further boosted by stimulation of the Wnt signaling pathway—for example, with Wnt3a ligand or other less-specific drugs.

This study points towards β-catenin having a repair-promoting role and proposes CXXC5 inhibition as a novel strategy to accelerate wound healing through its stabilization. Although negative side effects were not identified with this work, the potentially profibrotic and tumorigenic consequences of “removing the brakes” from this potent pathway will require careful consideration prior to translation.

S.-H. Lee et al., The Dishevelled-binding protein CXXC5 negatively regulates cutaneous wound healing. J. Exp. Med. 212, 1061–1080 (2015). [Abstract]

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