The activation of beta-catenin and TCF-dependent signaling during wound repair

Cutaneous wound healing involves inflammatory, proliferative, and remodeling phases. During the proliferative phase, fibroblasts accumulate in the dermis where they synthesize matrix. These fibroblasts share cytologic similarity with cells in fibroproliferative processes. One such process, aggressive fibromatosis, a monoclonal neoplasm of fibroblast origin, arises from the activation of beta-catenin mediated TCF-dependent signaling in which beta-catenin protein translocates to the nucleus where it complexes with TCF transcription factors, activating target genes involved in cellular proliferation. Here we show that fibroblasts involved in wound healing undergo a similar, but transient beta-catenin elevation and transcriptional activation during the proliferative phase. Moreover, wounds in conditionally stabilized beta-catenin-overexpressing mice are larger and have a higher proportion of proliferating fibroblasts compared to control mice, suggesting that beta-catenin modulates dermal fibroblast activity during the proliferative phase of cutaneous wound healing, and that its overexpression can lead to excessive scar formation. We also demonstrate that growth factors liberated during the initial inflammatory phase of wound healing trigger activation of beta-catenin-mediated TCF-dependent signaling during the subsequent proliferative phase. EGF and TGF-beta1 most potently increase beta-catenin protein levels and transcriptional activity, whereas beta-catenin mRNA expression is unaffected. Furthermore, this increase is attributed to the inactivation of GSK-3beta, a kinase important for beta-catenin destabilization. To examine this relationship in-vivo, subcutaneous injection of EGF or TGF-beta1 prior to wounding of TCF reporter mice resulted in larger scars and significant TCF activity. Knockout of smad3, a TGF-beta1 signaling intermediate, attenuated elevation of beta-catenin protein level and transcriptional activity in wounds. However, wounds from mice harboring a mutation in the EGF receptor exhibited only a slight reduction in beta-catenin expression and transactivation ability. Thus, smad3-dependent TGF-beta1, and to a lesser extent EGF signaling, play important roles in regulating beta-catenin-mediated TCF dependent signaling during the proliferative phase of repair. Our results suggest that beta-catenin acts during the proliferative phase of wound healing to integrate signals from initial phase growth factors into the expression of genes important during the later, remodeling phase. beta-catenin plays a central role in regulating mesenchymal cells during repair and may be an appealing therapeutic target for the specific control of aberrant repair.