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.