Wound healing in mammals is a fibrotic process. The mechanisms driving fibrotic (as opposed to regenerative) repair are poorly understood. Herein we report that therapeutic Wnt inhibition with topical application of small-molecule Wnt inhibitors can reduce
fibrosis and promote regenerative cutaneous
wound repair. In the naturally stented model of ear punch injury, we found that Wnt/β-
catenin pathway is activated most notably in the dermis of the
wound bed early (d 2) after injury and subsides to baseline levels by d10. Topical application of either of 2 mechanistically distinct small-molecule Wnt pathway inhibitors (a
tankyrase inhibitor,
XAV-939, and the U.S. Food and Drug Administration-approved
casein kinase activator,
pyrvinium) in C57Bl/6J mice resulted in significantly increased rates of
wound closure (72.3 ± 14.7% with
XAV-939; and 52.1 ± 20.9% with
pyrvinium) compared with contralateral controls (38.1 ± 23.0 and 40.4.± 16.7%, respectively). Histologically, Wnt inhibition reduced
fibrosis as measured by α-smooth muscle actin positive myofibroblasts and
collagen type I α1 synthesis. Wnt inhibition also restored skin architecture including adnexal structures in ear
wounds and dermal-epidermal junction with rete pegs in excisional
wounds. Additionally, in ear punch injury Wnt inhibitor treatment enabled regeneration of auricular cartilage. Our study shows that pharmacologic Wnt inhibition holds therapeutic utility for regenerative repair of cutaneous
wounds.