Fig. 4

Crosstalk between Wnt/β-catenin, Notch, and TGF-β signaling pathways during wound healing. During the inflammatory response, the Notch signaling pathway is activated and interacts with necrosis factor kappa B (NFκB) to induce production of interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α). The crosstalk between β-catenin and Notch has been reported from the onset of injury. However, it is unknown if this crosstalk is activated at the start of the inflammatory phase or start of the proliferative phase. Nevertheless, this crosstalk has been shown to activate expression of C-MYC and HES1, which are both expressed at the overlap of the inflammatory phase and proliferative phase. At the proliferative phase all three of these pathways are activated, possibly in a temporal manner. It has not been indicated if NICD directly binds to β-catenin for the crosstalk between these pathways. We hypothesize that there is temporal crosstalk between Notch (NICD) and β-catenin as transcriptional co-activators at the proliferative phase. Β-catenin is known to interact with SMAD3 however it is uncertain if this interaction occurs via CBP/p300 at both the proliferative and remodeling phases. Notch signaling has also been indicated to negatively regulate Wnt/β-catenin signaling during osteogenic proliferation, while Wnt/β-catenin inhibits Notch signaling during osteogenic differentiation. This interplay has however, not been shown in cutaneous wound repair. We hypothesize that this interplay is also involved in cutaneous wound repair in a temporal manner, where β-catenin inhibits Notch activity during tissue remodeling for the trans differentiation of fibroblasts to myofibroblasts as well as for formation of the new ECM for scar formation and wound closure