Mesenchymal stem cell-derived extracellular vesicles accelerate diabetic wound healing by inhibiting NET-induced ferroptosis of endothelial cells

Abstract

Abstract The impaired healing of chronic wounds poses a significant challenge in diabetes. Hindrance to angiogenesis is considered a key driver of delayed wound healing in diabetes. Neutrophil extracellular traps (NETs) have been identified as a detrimental factor impeding wound healing in diabetes, but the precise mechanisms are not fully elucidated. Traditional approaches for wound healing exhibit constrained therapeutic effectiveness due to prolonged recovery periods and increased susceptibility to infections. Extracellular vesicles derived from mesenchymal stem cells (MSC-EVs) have been identified as agents capable of facilitating tissue regeneration and enhancing wound repair. In this study, NET-induced ferroptosis of endothelial cells (ECs) was verified as a crucial factor contributing to angiogenesis hindrance in diabetic wound healing in both clinical samples and animal models. NETs regulated the ferroptosis of ECs by suppressing the PI3K/AKT pathway. Furthermore, MSC-EVs transferred functional mitochondria to neutrophils within the wound tissue, triggered mitochondrial fusion, and subsequently restored mitochondrial function to reduce NET formation. Treatments targeting the inhibition of NET formation and EC ferroptosis or activation of the PI3K/AKT pathway remarkably improved wound healing. This study reveals a novel NET-related mechanism underlying diabetic wound healing and proposes a promising strategy for expediting the recovery of diabetic wounds.