Mesenchymal stem cell-derived extracellular vesicles accelerate diabetic wound healing by inhibiting NET-induced ferroptosis of endothelial cells.
Wei Lu, Xiaoyang Li, Zheyu Wang, Changbo Zhao, Qi Li, Lei Zhang, Shuofei Yang
Author Information
Wei Lu: Department of Vascular Surgery, The Quzhou Affliated Hospital of Wenzhou Medical University, Quzhou People's Hospital, No. 100 Minjiang Avenue, Quzhou 324000, China.
Xiaoyang Li: Department of Vascular Surgery, The Quzhou Affliated Hospital of Wenzhou Medical University, Quzhou People's Hospital, No. 100 Minjiang Avenue, Quzhou 324000, China.
Zheyu Wang: Department of Vascular Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Pujian Road 160, Shanghai 200127, China.
Changbo Zhao: Department of Vascular Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Pujian Road 160, Shanghai 200127, China.
Qi Li: Department of Vascular Surgery, Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Ganhe Road 110, Shanghai 200437, PR China.
Lei Zhang: Department of Vascular Surgery, Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Ganhe Road 110, Shanghai 200437, PR China.
Shuofei Yang: Department of Vascular Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Pujian Road 160, Shanghai 200127, China.
Impaired angiogenesis is a major factor contributing to delayed wound healing in diabetes. Dysfunctional mitochondria promote the formation of neutrophil extracellular traps (NETs), obstructing angiogenesis during wound healing. Mesenchymal stem cell-derived extracellular vesicles (MSC-EVs) have shown promise in promoting tissue repair and regeneration in diabetes; however, the precise pathways involved in this process remain unclear. In this study, NET-induced ferroptosis of endothelial cells (ECs) and angiogenesis were assessed in diabetic wound samples from both patients and animal models. and experiments were performed to examine the regulatory mechanisms of NETs in ECs using specific inhibitors and gene-knockout mice. MSC-EVs encapsulating dysfunctional mitochondria were used to trigger mitochondrial fusion and restore mitochondrial function in neutrophils to suppress NET formation. Angiogenesis in wound tissue was evaluated using color laser Doppler imaging and vascular density analysis. Wound healing was evaluated via macroscopic analysis and histological evaluation of the epithelial gap. NET-induced ferroptosis of ECs was validated as a crucial factor contributing to the impairment of angiogenesis in diabetic wounds. Mechanistically, NETs regulated ferroptosis by suppressing the PI3K/AKT pathway. Furthermore, MSC-EVs transferred functional mitochondria to neutrophils in wound tissue, triggered mitochondrial fusion, and restored mitochondrial function, thereby reducing NET formation. These results suggest that inhibiting NET formation and EC ferroptosis or activating the PI3K/AKT pathway can remarkably improve wound healing. In conclusion, this study reveals a novel NET-mediated pathway involved in wound healing in diabetes and suggests an effective therapeutic strategy for accelerating wound healing.
