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Updated: Jul 8, 2025
Analysis of Combinatorial miRNA Treatments to Regulate Cell Cycle and Angiogenesis
Published on: March 30, 2019
Exosomal miRNA-155-5p from M1-polarized macrophages suppresses angiogenesis by targeting GDF6 to interrupt diabetic
Ruohan Lou1, Jiali Chen1, Fei Zhou1
1State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical 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.
Insights
Macrophage exosomes influence wound healing; M1 exosomes hinder it, while M2 exosomes promote it. Inhibiting miRNA-155-5p in M1 exosomes accelerated healing in diabetic mice by boosting GDF6 levels.
Area of Science:
- Cell Biology
- Molecular Biology
- Regenerative Medicine
Background:
- Uncontrolled macrophage polarization, particularly sustained pro-inflammatory macrophage activation, delays wound healing in diabetic patients.
- Macrophage-derived exosomes contain microRNAs (miRNAs) crucial for various wound healing stages.
Purpose of the Study:
- To investigate the role of macrophage-derived exosomes and their miRNA cargo in diabetic wound healing.
- To identify specific miRNAs in exosomes from polarized macrophages that affect angiogenesis and wound repair.
Main Methods:
- Exosomes were isolated from naive (M0), M1, and M2 polarized bone marrow-derived macrophages (BMDMs).
- Exosome effects on human umbilical vein endothelial cell (HUVEC) migration and tube formation were assessed.
- High-throughput sequencing identified differentially expressed miRNAs in exosomes.
- miRNA-155-5p's target (GDF6) and its role in angiogenesis were studied.
- A miRNA-155-5p antagomiR was delivered via hydrogel in diabetic mice (db/db).
Main Results:
- M1 exosomes impaired HUVEC migration and tube formation, while M2 exosomes enhanced these processes.
- miRNA-155-5p was highly expressed in M1 exosomes and inhibited angiogenesis by suppressing GDF6.
- Administration of miRNA-155-5p antagomiR promoted angiogenesis and accelerated wound healing in diabetic mice by upregulating GDF6.
Conclusions:
- Exosomes from M2-like macrophages show therapeutic potential for diabetic wounds.
- miRNA-155-5p inhibitors represent a promising strategy for treating diabetic foot ulcers by enhancing angiogenesis via GDF6.
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