Ageing-induced cell type-specific transcriptomic changes in the skin are associated with abnormal early healing responses to injury

The progression of wound healing is delayed in aged skin. Previous studies have demonstrated that early healing responses are the most impacted upon ageing. However, cellular changes that drive a perturbed wound microenvironment have not been fully defined. To glean a comprehensive understanding of cell-intrinsic changes that are acquired during ageing and may perhaps impact early responses to wounds, we performed single-cell RNA sequencing of 78670 cells from young and aged C57BL6/J wild-type mouse skin and Day 3 wounds. Our data underscore substantial changes in the mean proportional distribution and transcriptomic state of skin resident subpopulations in aged but not young tissues. We found that in comparison to young skin, aged skin was characterised by a global increase in basal inflammation sustained by an altered signalling environment driven by impaired keratinocyte differentiation, loss of fibroblast identity and defective macrophage function. Further, we showed that acquired changes in aged skin resident cells persisted after injury resulting in impaired and exacerbated inflammatory responses. Overall design: Single cell sequencing was performed on live cells from whole intact skin and whole Day 3 wounds from 3 female C57BL/6J wild-type young (8-12 weeks) and 3 aged (22-24 months) mice.