1448 Ligand-dependent Wnt signaling attenuates mechanotransduction and protects against wound occlusion-mediated abolishment of hair follicle regeneration

Occlusive dressings are commonly used to treat acute wounds. However, wound occlusion's effects on regeneration are poorly characterized, and clinical evidence from wounds with high regenerative capacity suggests a potential negative impact. We interrogated how occlusion impacts regeneration using the murine wound-induced hair neogenesis (WIHN) model, characterized by Wnt-dependent regeneration of hair follicles at the center of large, full-thickness wounds. Strikingly, wound occlusion with commonly used dressings (e.g., film and hydrocolloid) for 3 days between post-wound days (PWDs) 0-7 completely eliminated WIHN.vBetween PWDs 0-7, occlusion (i) upregulated mechanotransduction, a mechanosensitive pathway that promotes fibrosis, (ii) induced TGF-β2 expression without impacting the levels of TGF-β1 or -β3, and (iii) suppressed Wnt signaling. Since the spatial rigidity gradient of the wound bed provides the symmetry breaking required for WIHN in open wounds, we measured the tissue rigidity of wounds on scab detachment day using atomic force microscopy. The occluded wounds demonstrated no observable spatial rigidity gradient, and their wound centers were equally as rigid as their peripheries.vInhibiting mechanotransduction in the occluded wounds restored the spatial rigidity gradient, normalized the TGF-β2 expression and restored WIHN partially. Transgenic mice with amplified ligand-dependent Wnt signaling were protected against the occlusion-induced disruption of tissue mechanics, and WIHN was observed in their occluded wounds. Our mechanistic studies revealed a novel function of Wnt signaling that directly attenuated mechanotransduction in epidermal keratinocytes but not dermal fibroblasts.vThese findings in the WIHN model suggest that (i) occlusion elicits mechanotransduction to promote fibrosis at the expense of regeneration, and (ii) Wnt signaling orchestrates the symmetry breaking of tissue mechanics needed for WIHN.