Hypoxia endothelial cells-derived exosomes facilitate diabetic wound healing through improving endothelial cell function and promoting M2 macrophages polarization

Peng Cheng; Xudong Xie; Liangcong Hu; Wu Zhou; Bobin Mi; Yuan Xiong; Hang Xue; Kunyu Zhang; Yuxiao Zhang; Yiqiang Hu; Lang Chen; Kangkang Zha; Bin Lv; Ze Lin; Chuanlu Lin; Guandong Dai; Yixin Hu; Tengbo Yu; Hankun Hu; Guohui Liu; Yingze Zhang

doi:10.1016/j.bioactmat.2023.10.020

Hypoxia endothelial cells-derived exosomes facilitate diabetic wound healing through improving endothelial cell function and promoting M2 macrophages polarization

Bioact Mater. 2023 Nov 10:33:157-173. doi: 10.1016/j.bioactmat.2023.10.020. eCollection 2024 Mar.

Authors

Peng Cheng^{1

2}, Xudong Xie^{1

2}, Liangcong Hu^{1

2}, Wu Zhou^{1

2}, Bobin Mi^{1

2}, Yuan Xiong^{1

2}, Hang Xue^{1

2}, Kunyu Zhang³, Yuxiao Zhang³, Yiqiang Hu^{1

2}, Lang Chen^{1

2}, Kangkang Zha^{1

2}, Bin Lv^{1

2}, Ze Lin^{1

2}, Chuanlu Lin^{1

2}, Guandong Dai⁴, Yixin Hu^{5

6}, Tengbo Yu⁷, Hankun Hu^{5

6

8}, Guohui Liu^{1

2}, Yingze Zhang^{1

9}

Affiliations

¹ Department of Orthopedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China.
² Hubei Province Key Laboratory of Oral and Maxillofacial Development and Regeneration, Wuhan, 430022, China.
³ School of Biomedical Sciences and Engineering, South China University of Technology, Guangzhou International Campus, Guangzhou, 511442, China.
⁴ Department of Orthopaedics, Pingshan District People's Hospital of Shenzhen, Pingshan General Hospital of Southern Medical University, Shenzhen, Guangdong, 518118, China.
⁵ Hubei Micro-explore Innovative Pharmaceutical Research Co, Ltd, Wuhan, Hubei, 430071, China.
⁶ Suzhou Organ-on-a-Chip System Science and Technology Co, Ltd, Suzhou, Jiangsu, 215000, China.
⁷ Department of Sports Medicine, The Affiliated Hospital of Qingdao University, Qingdao, China.
⁸ Department of Pharmacy, Zhongnan Hospital of Wuhan University, School of Pharmaceutical Sciences, Wuhan University, Wuhan, 430071, China.
⁹ Department of Orthopaedic Surgery, The Third Hospital of Hebei Medical University, NO.139 Ziqiang Road, Shijiazhuang, 050051, China.

Abstract

It is imperative to develop and implement newer, more effective strategies to address refractory diabetic wounds. As of now, there is currently no optimal solution for these wounds. Hypoxic human umbilical vein endothelial cells (HUVECs)-derived exosomes have been postulated to promote diabetic wound healing, however, its effect and molecular mechanism need further study. In this study, we aimed to investigate whether hypoxic exosomes enhance wound healing in diabetics. Based on our high-throughput sequencing, differentially expressed lncRNAs (including 64 upregulated lncRNAs and 94 downregulated lncRNAs) were found in hypoxic exosomes compared to normoxic exosomes. Interestingly, lncHAR1B was one of the prominently upregulated lncRNAs in hypoxic exosomes, showing a notable correlation with diabetic wound healing. More specifically, hypoxic exosomes were transmitted to surrounding cells, which resulted in a significant increase in lncHAR1B level, thereby relieving the dysfunction of endothelial cells and promoting the switch from M1 to M2 macrophages under high glucose conditions. Mechanistically, lncHAR1B directly interacted with the transcription factor basic helix-loop-helix family member e23 (BHLHE23), which subsequently led to its binding to the KLF transcription factor 4 (KLF4) and promoted KLF4 expression. In our in vivo experiments, the use of hypoxic exosomes-loaded HGM-QCS hydrogels (Gel-H-Exos) resulted in rapid wound healing compared to that of normoxic exosomes-loaded HGM-QCS hydrogels (Gel-N-Exos) and diabetic groups. Consequently, our study provides potentially novel therapeutic approaches aimed at accelerating wound healing and developing a practical exosomes delivery platform.

Keywords: Diabetic wound; Hypoxic exosomes; KLF4; Macrophage polarization; lncHAR1B.