Exploring the role of metals and senescence in cutaneous wound repair

Wilkinson, Holly Nicola

Abstract

Acute wound healing involves a tightly regulated cascade of cellular signalling and functional events. Deterioration at any stage of this sophisticated system can lead to healing impairment and chronic, non-healing wounds. Chronic wounds, which are prevalent in the elderly and diabetic, are a global socioeconomic burden and remain a major area of clinical unmet need. Improved understanding of the cellular and molecular aetiology of chronic wounds is essential to develop new therapies. The aim of this work was to explore the role of cellular senescence and the metallome in governing normal and pathological wound repair. Novel data presented in this thesis show increased senescence in both aged and diabetic wounds, while biologically-important metals, such as calcium, were reduced. Transcriptional profiling of wounds strongly linked the transcriptome, metallome and senescence. A direct role for senescence in pathological healing was mechanistically demonstrated in vitro, ex vivo and in vivo. Crucially, pharmacological inhibition of the explicated senescence receptor, Cxcr2, accelerated diabetic wound healing in vivo. Collectively, these data reveal a hitherto unappreciated role for Cxcr2 in mediating cellular senescence during pathological skin repair. Global profiling of the wound metallome highlighted significant changes in wound iron levels during late-stage healing. In vitro studies uncovered a new role for iron in mediating extracellular matrix deposition during wound remodelling, while reduced iron levels in diabetic wounds correlated with impaired ECM deposition. In summary, temporospatial metallome profiling identified multiple defects in metal-linked cellular processes in the pathological wound environment. Taken together, the research platform delivered in this work will provide an unprecedented opportunity to further interrogate transcriptional and functional relationships between cellular senescence and the metallome in wound repair. Indeed, this research may underpin the development of novel, efficacious metal-targeted therapies for chronic healing wounds in the future.

Citation

Wilkinson, H. N. (2019). Exploring the role of metals and senescence in cutaneous wound repair. (Thesis). University of Hull. Retrieved from https://hull-repository.worktribe.com/output/4227385

• Thesis Type: Thesis
• Deposit Date: Oct 13, 2021
• Publicly Available Date: Sep 2, 2025
• Keywords: Biomedical sciences
• Public URL: https://hull-repository.worktribe.com/output/4227385
• Additional Information: Department of Biomedical Sciences, The University of Hull
• Award Date: Sep 1, 2019