Exosomal miRNA-155-5p from M1-polarized macrophages suppresses angiogenesis by targeting GDF6 to interrupt diabetic wound healing

Ruohan Lou; Jiali Chen; Fei Zhou; Tian Zhang; Xiuping Chen; Chunming Wang; Bing Guo; Ligen Lin

doi:10.1016/j.omtn.2023.102074

Exosomal miRNA-155-5p from M1-polarized macrophages suppresses angiogenesis by targeting GDF6 to interrupt diabetic wound healing

Mol Ther Nucleic Acids. 2023 Nov 10:34:102074. doi: 10.1016/j.omtn.2023.102074. eCollection 2023 Dec 12.

Authors

Ruohan Lou¹, Jiali Chen¹, Fei Zhou¹, Tian Zhang², Xiuping Chen^{1

3}, Chunming Wang^{1

3}, Bing Guo², Ligen Lin^{1

3}

Affiliations

¹ State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Taipa, Macau 999078, China.
² Guizhou Provincial Key Laboratory of Pathogenesis and Drug Research on Common Chronic Diseases, Guizhou Medical University, Guiyang 550025, China.
³ Department of Pharmaceutical Sciences and Technology, Faculty of Health Sciences, University of Macau, Taipa, Macau 999078, China.

Abstract

Unprogrammed macrophage polarization, especially prolonged activation of proinflammatory macrophages, is associated with delayed wound healing in diabetic objectives. Macrophage-derived exosomes cargo a variety of microRNAs (miRNAs), participating in different stages in wound healing. Here, exosomes were isolated from naive bone marrow-derived macrophages (BMDMs) (M0-Exos), interferon-γ plus lipopolysaccharide-polarized BMDMs (M1-Exos), and interleukin-4-polarized BMDMs (M2-Exos). M1-Exos impaired migration and tube formation in human umbilical vein endothelial cells (HUVECs) compared to M0-Exos, whereas M2-Exos exhibited the opposite effects. High-throughput sequencing was performed to decipher the miRNA expression profiles in M0-Exos, M1-Exos, and M2-Exos. A total of 63 miRNAs were identified to be differentially expressed in exosomes derived from polarized BMDMs. Among them, miRNA-155-5p is highly expressed in M1-Exos, which interrupted angiogenesis in HUVECs. Furthermore, miRNA-155-5p directly binds to the 3' UTR of growth differentiation factor 6 (GDF6) mRNA to suppress its protein expression. Lastly, local administration of a temperature-sensitive hydrogel Pluronic F-127 loading miRNA-155-5p antagomiR promoted angiogenesis and accelerated wound healing in diabetic db/db mice via enhancing GDF6. In summary, this study deciphered the miRNA expression profiles in exosomes from polarized macrophages. M2-like macrophage-derived exosomes and miRNA-155-5p inhibitors could be promising therapeutics against diabetic foot ulcers.

Keywords: MT: Oligonucleotides: Therapies and Applications; angiogenesis; diabetic wound healing; growth differentiation factor 6; microRNA expression profiles; polarized macrophage-derived exosomes; thermosensitive hydrogel.