Senescence-induced reparative fibroblasts enable scarless wound healing in aged murine skin.

Abstract

It has been reported that elderly individuals exhibit reduced scarring during the wound healing process compared to younger adults. However, the underlying mechanisms responsible for this phenomenon remain poorly understood. Here, we revealed that aged mice exhibited more pronounced regenerative outcomes compared to young mice, characterized by increased hair follicle numbers and collagen fiber features closer to normal skin. Single-cell sequencing identified a reparative fibroblast subpopulation (Prss35+Fib) enriched in the aged group, which promotes regeneration through communication with epithelial cells, macrophages, and T cell subpopulations via PTN and EREG signaling. Spatial transcriptomics validated this communication pattern by elucidating cell proximity and locating the regenerative niche in the upper dermis. Finally, EREG treatment significantly enhanced regenerative outcomes in young mice, while the small wound model of aged mice, lacking the reparative fibroblast and EREG signaling, failed to achieve regeneration. Collectively, our findings advance the understanding of regenerative plasticity in aging and provide new insights for designing scarless therapeutic strategies.