Targeted elimination of senescent cells by ProcyanidinC1 improves diabetic wound healing and restores skin quality.

Abstract

For diabetic patients, impaired wound healing is a serious complication, which characterized by prolonged inflammation, wound granulation tissue formation obstruction and impaired re-epithelialization. Accumulating evidence shows that senescent cells play a crucial role in the pathomechanism of diabetic wounds. In this study, we systematically evaluated the role of senescent cells in diabetic wound healing through diabetic mice (DM mice) model (including streptozotocin-induced type I DM mice model and db/db (type II DM) mice model, and actively assessed the therapeutic potential of ProcyanidinC1 (PCC1), the novel senolytic compound. We demonstrated that diabetic mice accumulated a significant number of senescent cells, primarily fibroblasts, in their normal skin and wound tissues. Local application of PCC1 selectively eliminated these senescent cells, leading to improved wound healing outcomes. By modulating the NF-κB signaling axis, PCC1 administration effectively downregulated senescence-associated secretory phenotype components, thereby ameliorating immune dysregulation in diabetic wounds. This therapeutic intervention concurrently revitalized the functional capacity of dermal fibroblasts and vascular endothelial cells, while stimulating coordinated matrix deposition and architectural remodeling of the extracellular compartment. Furthermore, PCC1 treatment enhanced epidermal barrier function after healing, a crucial aspect of wound repair which is often impaired in diabetes. And we also found that PCC1 would improve wound healing at type II diabetic mouse. Collectively, our findings elucidate the complex detrimental roles of senescent cells in diabetic wound repair and establish PCC1-mediated senolytic clearance as a promising therapeutic intervention.