Novel neutrophil extracellular trap-related mechanisms in diabetic wounds inspire a promising treatment strategy with hypoxia-challenged small extracellular vesicles

Ziqiang Chu; Qilin Huang; Kui Ma; Xi Liu; Wenhua Zhang; Shengnan Cui; Qian Wei; Huanhuan Gao; Wenzhi Hu; Zihao Wang; Sheng Meng; Lige Tian; Haihong Li; Xiaobing Fu; Cuiping Zhang

doi:10.1016/j.bioactmat.2023.04.007

Novel neutrophil extracellular trap-related mechanisms in diabetic wounds inspire a promising treatment strategy with hypoxia-challenged small extracellular vesicles

Bioact Mater. 2023 Apr 14:27:257-270. doi: 10.1016/j.bioactmat.2023.04.007. eCollection 2023 Sep.

Authors

Ziqiang Chu^{1

2}, Qilin Huang³, Kui Ma^{1

4

5}, Xi Liu^{1

4

5}, Wenhua Zhang^{1

4

5}, Shengnan Cui^{1

6}, Qian Wei^{1

2}, Huanhuan Gao^{1

2}, Wenzhi Hu¹, Zihao Wang^{1

2}, Sheng Meng^{1

2}, Lige Tian³, Haihong Li⁷, Xiaobing Fu^{1

2

3

4

5

6}, Cuiping Zhang^{1

4

5}

Affiliations

¹ Research Center for Tissue Repair and Regeneration Affiliated to the Medical Innovation Research Department, PLA General Hospital, 28 Fuxing Road, Beijing, 100853, PR China.
² Chinese PLA Medical School, 28 Fuxing Road, Beijing, 100853, PR China.
³ College of Graduate, Tianjin Medical University, Tianjin, 300070, PR China.
⁴ Research Unit of Trauma Care, Tissue Repair and Regeneration, Chinese Academy of Medical Sciences, 2019RU051, 51 Fucheng Road, Beijing, 100048, PR China.
⁵ PLA Key Laboratory of Tissue Repair and Regenerative Medicine and Beijing Key Research Laboratory of Skin Injury, Repair and Regeneration, Chinese PLA Hospital and PLA Medical College, 51 Fucheng Road, Beijing, 100048, PR China.
⁶ Department of Dermatology, China Academy of Chinese Medical Science, Xiyuan Hospital, Beijing, 100091, PR China.
⁷ Department of Wound Repair, Institute of Wound Repair and Regeneration Medicine, Southern University of Science and Technology Hospital, Southern University of Science and Technology School of Medicine, Shenzhen, 518055, PR China.

Abstract

Neutrophil extracellular traps (NETs) have been considered a significant unfavorable factor for wound healing in diabetes, but the mechanisms remain unclear. The therapeutic application of small extracellular vesicles (sEVs) derived from mesenchymal stem cells (MSCs) has received considerable attention for their properties. Hypoxic preconditioning is reported to enhance the therapeutic potential of MSC-derived sEVs in regenerative medicine. Therefore, the aim of this study is to illustrate the detailed mechanism of NETs in impairment of diabetic wound healing and develop a promising NET-targeting treatment based on hypoxic pretreated MSC-derived sEVs (Hypo-sEVs). Excessive NETs were found in diabetic wounds and in high glucose (HG)-induced neutrophils. Further research showed that high concentration of NETs impaired the function of fibroblasts through activating endoplasmic reticulum (ER) stress. Hypo-sEVs efficiently promoted diabetic wound healing and reduced the excessive NET formation by transferring miR-17-5p. Bioinformatic analysis and RNA interference experiment revealed that miR-17-5p in Hypo-sEVs obstructed the NET formation by targeting TLR4/ROS/MAPK pathway. Additionally, miR-17-5p overexpression decreased NET formation and overcame NET-induced impairment in fibroblasts, similar to the effects of Hypo-sEVs. Overall, we identify a previously unrecognized NET-related mechanism in diabetic wounds and provide a promising NET-targeting strategy for wound treatment.

Keywords: Diabetic wound healing; Endoplasmic reticulum stress; Hypoxia; Neutrophil extracellular traps; Small extracellular vesicles.