Microglia-derived exosomes modulate myelin regeneration via miR-615-5p/MYRF axis
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Published on: April 13, 2017
Xiao-Yu Ji1, Yu-Xin Guo1, Li-Bin Wang2
1National Engineering Laboratory for Resource Development of Endangered Crude Drugs in Northwest China, The Key Laboratory of Medicinal Resources and Natural Pharmaceutical Chemistry, The Ministry of Education, College of Life Sciences, Shaanxi Normal University, Xi'an, 710119, Shaanxi, China.
Abstract:
Demyelination and failure of remyelination in the central nervous system (CNS) characterize a number of neurological disorders. Spontaneous remyelination in demyelinating diseases is limited, as oligodendrocyte precursor cells (OPCs), which are often present in demyelinated lesions in abundance, mostly fail to differentiate into oligodendrocytes, the myelinating cells in the CNS. In addition to OPCs, the lesions are assembled numbers of activated resident microglia/infiltrated macrophages; however, the mechanisms and potential role of interactions between the microglia/macrophages and OPCs are poorly understood. Here, we generated a transcriptional profile of exosomes from activated microglia, and found that miR-615-5p was elevated. miR-615-5p bound to 3'UTR of myelin regulator factor (MYRF), a crucial myelination transcription factor expressed in oligodendrocyte lineage cells. Mechanistically, exosomes from activated microglia transferred miR-615-5p to OPCs, which directly bound to MYRF and inhibited OPC maturation. Furthermore, an effect of AAV expressing miR-615-5p sponge in microglia was tested in experimental autoimmune encephalomyelitis (EAE) and cuprizone (CPZ)-induced demyelination model, the classical mouse models of multiple sclerosis. miR-615-5p sponge effectively alleviated disease progression and promoted remyelination. This study identifies miR-615-5p/MYRF as a new target for the therapy of demyelinating diseases.
Insights
Microglia-derived miR-615-5p inhibits oligodendrocyte precursor cell maturation by targeting MYRF. Inhibiting this microRNA promotes remyelination and alleviates disease in demyelinating conditions.
Area of Science:
- Neuroscience
- Cell Biology
- Molecular Biology
Background:
- Demyelinating diseases like multiple sclerosis involve CNS damage and failed myelin repair.
- Oligodendrocyte precursor cells (OPCs) are abundant in lesions but fail to mature into myelinating oligodendrocytes.
- Microglia/macrophages interact with OPCs, but the mechanisms are unclear.
Purpose of the Study:
- To investigate the role of microglia-derived exosomes in OPC differentiation.
- To identify specific microRNAs involved in regulating OPC maturation.
- To explore therapeutic targets for promoting remyelination in demyelinating diseases.
Main Methods:
- Transcriptional profiling of activated microglia-derived exosomes.
- Identification of microRNA-mRNA interactions using 3'UTR binding assays.
- In vivo studies using mouse models of demyelination (EAE and cuprizone).
- Viral vector-mediated delivery of a miR-615-5p sponge in microglia.
Main Results:
- Exosomes from activated microglia showed elevated miR-615-5p.
- miR-615-5p directly targets and inhibits MYRF, a key transcription factor for OPC maturation.
- Exosomal transfer of miR-615-5p from microglia to OPCs impaired OPC maturation.
- In vivo inhibition of miR-615-5p in microglia promoted remyelination and reduced disease severity in EAE and cuprizone models.
Conclusions:
- Microglia-derived miR-615-5p is a novel inhibitor of OPC maturation.
- The miR-615-5p/MYRF axis represents a potential therapeutic target for demyelinating diseases.
- Modulating microglial exosome content offers a strategy to enhance CNS repair.
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