P08 Exploring the role of cellular senescence in cutaneous repair

Abstract Introduction and aims Chronic nonhealing wounds are a life-threatening skin disease in elderly patients and patients with diabetes that costs the National Health Service over £8 billion per year to treat. Unfortunately, current treatments are inadequate, thus there is an urgent need to develop effective therapies. Cellular senescence is emerging as a potential therapeutic target owing to its association with a wide range of age-related pathologies. Cells undergo senescence in response to ageing and stress, losing their ability to proliferate or perform normal tissue functions. Our previous work in mice provided the first mechanistic demonstration that senescent cell accumulation drives poor healing. Moreover, clinical trials currently assessing the efficacy of senescence-targeted drugs (senolytics) are providing repurposing opportunities for cutaneous pathologies. Therefore, the aim of this research is to (i) investigate the role of senescence in human chronic wounds and (ii) determine whether senolytics can be repurposed to promote pathological skin repair. Methods Skin and wounds were collected from healthy, aged and diabetic donors to quantify senescence levels (senescence-associated β-galactosidase), characterize senescent cell types (immunofluorescence) and determine key drivers of skin senescence (RNA sequencing). Additionally, we screened the wound healing potential of a panel of senolytics in healthy skin vs. skin from patients with chronic wounds. Results We found significant accumulation of senescence in pathological skin wounds, localized to stromal cells. Senescence levels also correlated substantially with clinical parameters, such as wound site, diabetic status and infection. RNA sequencing revealed key links between senescence and immunity, suggesting inflammation as a crucial driver of skin senescence. Finally, senolytic treatment significantly accelerated healing in skin from patients with chronic wounds. Conclusions Our data provide the first in-depth characterization of senescence in human chronic skin wounds, crucially identifying novel therapeutic targets of senescence, while simultaneously assessing the potential of drug repurposing for patient benefit.