Abstract
IntroductionWnt and Notch signaling pathways are critically involved in relative cell fate decisions within the development of cutaneous tissues. Moreover, several studies identified the above two pathways as having a significant role during wound healing. However, their biological effects during cutaneous tissues repair are unclear.MethodsWe employed a self-controlled model (Sprague–Dawley rats with full-thickness skin wounds) to observe the action and effect of Wnt/β-catenin and Notch signalings in vivo. The quality of wound repair relevant to the gain/loss-of-function Wnt/β-catenin and Notch activation was estimated by hematoxylin-and-eosin and Masson staining. Immunofluorescence analysis and Western blot analysis were used to elucidate the underlying mechanism of the regulation of Wnt and Notch signaling pathways in wound healing. Meanwhile, epidermal stem cells (ESCs) were cultured in keratinocyte serum-free medium with Jaggedl or in DAPT (N-[(3,5-difluorophenyl)acetyl]-L-alanyl-2-phenyl]glycine-1,1-dimethylethyl) to investigate whether the interruption of Notch signaling contributes to the expression of Wnt/β-catenin signaling.ResultsThe results showed that in vivo the gain-of-function Wnt/β-catenin and Notch activation extended the ability to promote wound closure. We further determined that activation or inhibition of Wnt signaling and Notch signaling can affect the proliferation of ESCs, the differentiation and migration of keratinocytes, and follicle regeneration by targeting c-Myc and Hes1, which ultimately lead to enhanced or delayed wound healing. Furthermore, Western blot analysis suggested that the two pathways might interact in vivo and in vitro.ConclusionThese results suggest that Wnt and Notch signalings play important roles in cutaneous repair by targeting c-Myc and Hes1 separately. What’s more, interaction between the above two pathways might act as a vital role in regulation of wound healing.
Highlights
Wnt and Notch signaling pathways are critically involved in relative cell fate decisions within the development of cutaneous tissues
Lithium chloride (LiCl), Dickkopf-1 (DKK1), recombinant human nuclear factor-kappa-B, and DAPT (N-[(3,5-difluorophenyl)acetyl]-L-alanyl-2-phenyl]glycine1,1-dimethylethyl) were topically and respectively applied to the wound under the occlusive dressing once daily until wound closure according to the requirement, allowing the solution to bathe the wound [9,10,11], but there was no treatment in the control group
Effects of several disturbing reagents on Wnt/β-catenin signaling pathway and Notch signaling pathway during wound healing To achieve the gain- and loss-of-function studies of Wnt/ β-catenin and Notch signalings during wound healing, LiCl, DKK1, Recombinant human nuclear factor-kappa-B (rhNF-κB), and DAPT were respectively applied to the wounded skin
Summary
Wnt and Notch signaling pathways are critically involved in relative cell fate decisions within the development of cutaneous tissues. Several studies identified the above two pathways as having a significant role during wound healing Their biological effects during cutaneous tissues repair are unclear. C-Myc, a downstream target of canonical Wnt/β-catenin signaling, functions as a regulator of stem cell maintenance. Notch signaling is involved in regulating cell fate; in light of different cell types and contexts, Notch signaling induces cell differentiation or maintains cells in an undifferentiated proliferation state [5]. When intestinal adenomas expressed Hes at a low level, many tumor cells exited the cell cycle and did not continue to proliferate [7] in vivo It was unclear whether Hes is important for regulating epidermal cells within wound healing
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