Wound Healing Society

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Notch Activation Stimulates Wound Healing

Introduction: We are interested in improving wound healing therapies through the understanding of potential cellular and molecular mechanisms, especially those influenced by the Notch signaling cascade. We have previously shown that inhibiting Notch inhibits wound healing. Based upon our previous work, our hypothesis is that topical application of the Notch ligand, JAG1, to ex vivo excisional wounds of mice increases wound healing rates as compared to untreated wounds. We also wanted to determine if age and gender influence the wound healing rates. Methods: Skin biopsies 6-mm in diameter with another wound of 3-mm in the center were cultured ex vivo from 10-12 week-old (young) and at least one-year-old (aged) mice. We included both male and female mice from control and skin specific (K14) knockouts of Notch1 and Notch2. Topical application of JAG1 (1 μg/ml, 7 nM), vehicle (PBS), PBS+DAPT (gamma secretase/Notch signaling inhibitor) or JAG1+DAPT were applied every two days. Photomicrographs were taken and histological analysis performed. The tissue growth was calculated as the difference of the area at each timepoint minus the area at time=0. Significance was defined as p<0.05 using two-way ANOVA. Results: Significant tissue growth was seen in the biopsies from control mice, young and aged, males and females; compared to K14-Notch1 or K14-Notch2 knockouts. Treatment with DAPT inhibited the growth in mice where JAG1 had an effect. Conclusions: Notch activation by JAG1 increases the rate of tissue growth of cutaneous wounds in an ex vivo murine wound-healing model, regardless age/gender, but not in Notch1 or Notch2 knockouts, indicating that Notch signaling is crucial in wound healing. Further study of Notch in wound healing should be conducted which may then lead to better therapeutics.

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