nWASP Inhibition Increases Wound Healing via TrKb/PLCγ Signalling
Bethan A Frugtniet1, Fiona Ruge1, Andrew J Sanders2
1Division of Cancer and Genetics, Cardiff University School of Medicine, Cardiff University, Cardiff CF14 4XN, UK.
Abstract:
(1) Background: Chronic wounds represent a major burden to patients and healthcare systems and identifying new therapeutic targets to encourage wound healing is a significant challenge. This study evaluated nWASP as a new therapeutic target in human wound healing and determined how this can be regulated. (2) Methods: Clinical cohorts from patients with chronic wounds were tested for the expression of nWASP and cell models were employed to evaluate the influence of nWASP on cellular functions that are key to the healing process following knockdown and/or the use of nWASP-specific inhibitors. (3) Results: nWASP was significantly elevated at transcript levels in human non-healing chronic wounds versus healing tissues. nWASP inhibitors, wiskostatin and 187-1, along with the knockdown of nWASP, modified both HaCaT and HECV cell behaviour. We then identified two signalling pathways affected by nWASP inhibition: TrkB signalling and downstream PLCγ1 phosphorylation were impaired by nWASP inhibition in HaCaT cells. The healing of wounds in a diabetic murine model was significantly improved with an nWASP inhibitor treatment. (4) Conclusions: This study showed that nWASP activity was related to the non-healing behaviour of chronic wounds and together with the findings in the in vivo models, it strongly suggested nWASP as a therapeutic target in non-healing wounds that are regulated via TrkB and PLCγ1 signalling.
Insights
Neural Wiskott-Aldrich syndrome protein (nWASP) is elevated in chronic wounds. Inhibiting nWASP promotes wound healing by affecting cell behavior and signaling pathways, suggesting it as a therapeutic target.
Area of Science:
- Wound Healing Research
- Cellular Biology
- Molecular Medicine
Background:
- Chronic wounds pose a significant clinical and economic burden.
- Identifying novel therapeutic targets for chronic wound healing remains a critical challenge.
- The role of neural Wiskott-Aldrich syndrome protein (nWASP) in wound healing requires further investigation.
Purpose of the Study:
- To evaluate nWASP as a potential therapeutic target for human wound healing.
- To determine the regulatory mechanisms of nWASP in the context of wound repair.
- To assess the impact of nWASP modulation on cellular functions essential for healing.
Main Methods:
- Analysis of nWASP expression in clinical chronic wound cohorts.
- Utilizing cell models (HaCaT and HECV) to study nWASP's influence on cellular functions.
- Employing nWASP knockdown and specific inhibitors (wiskostatin, 187-1) in vitro.
- Investigating the effects of nWASP inhibition on TrkB and PLCγ1 signaling pathways.
- Evaluating nWASP inhibitor efficacy in a diabetic murine wound healing model.
Main Results:
- nWASP transcript levels were significantly higher in human non-healing chronic wounds compared to healing tissues.
- nWASP inhibition or knockdown altered the behavior of HaCaT and HECV cells.
- TrkB signaling and downstream PLCγ1 phosphorylation were impaired by nWASP inhibition in HaCaT cells.
- Treatment with an nWASP inhibitor significantly accelerated wound healing in a diabetic murine model.
Conclusions:
- nWASP activity is associated with the non-healing phenotype of chronic wounds.
- Modulation of nWASP impacts key cellular functions and signaling pathways (TrkB, PLCγ1) involved in wound repair.
- nWASP represents a promising therapeutic target for non-healing chronic wounds.
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