Senescence Programs Shape the Chronic Wound Microenvironment

Significance: Chronic wounds such as diabetic foot ulcers, venous leg ulcers, and pressure ulcers are characterized by impaired healing and persistent inflammation. Cellular senescence, defined as irreversible growth arrest with a pro-inflammatory secretory phenotype (senescence-associated secretory phenotype), has emerged as a potential driver of these nonhealing states. While transient induction of senescence may aid acute repair, chronic accumulation of senescent cells is thought to disrupt tissue regeneration, promote extracellular matrix degradation, and sustain inflammation. Recent Advances: Single-cell RNA sequencing and spatial transcriptomics have revealed diverse cell states in chronic wounds, including senescent subsets. Studies in diabetic, venous, and pressure ulcers implicate senescent fibroblasts and immune cells in impaired remodeling, often triggered by oxidative stress, hyperglycemia, or ischemia–reperfusion injury. Therapeutic strategies targeting senescent cells in delayed wound healing have demonstrated promise in preclinical models; however, interventions must be timed and targeted precisely. Critical Issues: Despite emerging evidence, the identity, abundance, and location of senescent cells in chronic wounds remain poorly defined. Reliance on nonspecific markers such as p21 or SA-β-gal complicates interpretation. Senescence appears to play context-dependent roles, with beneficial effects during acute healing but harmful persistence in chronic wounds, presenting challenges for therapeutic targeting. Future Directions: More studies using single-cell RNA sequencing, spatial transcriptomics, and longitudinal profiling are needed to define senescent subpopulations, map their spatial distribution, and track dynamics during wound progression. These approaches will help distinguish transient from persistent senescence. A deeper understanding of interactions with immune, epithelial, and stromal components will guide precisely timed, cell type–specific interventions to improve outcomes.