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Exosome reporter mice reveal the involvement of exosomes in mediating neuron to astroglia communication in the CNS

Men, Yuqin, Yelick, Julia, Jin, Shijie, Tian, Yang, Chiang, Ming Sum R., Higashimori, Haruki, Brown, Eoin, Jarvis, Rachel +1 more·2019·Nature Communications
DOI 10.1038/s41467-019-11534-wPMC PMC6742670
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Abstract

Astroglia play active and diverse roles in modulating neuronal/synaptic functions in the CNS. How these astroglial functions are regulated, especially by neuronal signals, remains largely unknown. Exosomes, a major type of extracellular vesicles (EVs) that originate from endosomal intraluminal vesicles (ILVs), have emerged as a new intercellular communication process. By generating cell-type-specific ILVs/exosome reporter (CD63-GFP f/f ) mice and immuno-EM/confocal image analysis, we found that neuronal CD63-GFP + ILVs are primarily localized in soma and dendrites, but not in axonal terminals in vitro and in vivo. Secreted neuronal exosomes contain a subset of microRNAs (miRs) that is distinct from the miR profile of neurons. These miRs, especially the neuron-specific miR-124-3p, are potentially internalized into astrocytes. MiR-124-3p further up-regulates the predominant glutamate transporter GLT1 by suppressing GLT1-inhibiting miRs. Our findings suggest a previously undescribed neuronal exosomal miR-mediated genetic regulation of astrocyte functions, potentially opening a new frontier in understanding CNS intercellular communication.

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  • miRNAs can be transferred between cells via EVs and other carriers, enabling them to act as intercellular signaling molecules that propagate or mitigate pathology across the CNS.

    “Notably, miRNAs can be transferred between cells via EVs and other carriers, enabling them to act as intercellular signaling molecules that propagate or mitigate pathology across the CNS (Kumar et al., 2022; Men et al., 2019; Walgrave et al., 2021b).”

    From Cell-specific MicroRNA networks orchestrate the pathogenesis of Alzheimer’s disease (2026) · cites this paper as Men et al., 2019

  • miRNAs are trafficked between CNS cell types via EVs/exosomes and potentially synaptosomal compartments, enabling long-range post-transcriptional signaling across neural circuits.

    “MiRNAs are trafficked between CNS cell types via EVs/exosomes and potentially synaptosomal compartments, enabling long-range post-transcriptional signaling across neural circuits (Kumar et al., 2022; Men et al., 2019; Walgrave et al., 2021b).”

    From Cell-specific MicroRNA networks orchestrate the pathogenesis of Alzheimer’s disease (2026) · cites this paper as Men et al., 2019

  • Many miRNAs function as multifunctional regulators across a complex intercellular network in the brain, not confined to a single cell type.

    “Growing evidence indicates that many miRNAs are not confined to a single cell type but function as multifunctional regulators across a complex intercellular network in the brain (Kumar et al., 2022; Men et al., 2019; Salta et al., 2016; Walgrave et al., 2021b).”

    From Cell-specific MicroRNA networks orchestrate the pathogenesis of Alzheimer’s disease (2026) · cites this paper as Men et al., 2019

  • The distinct cell-type and stage-specific miRNA signatures in AD likely reflect a combination of cell-type-restricted transcription factor networks, differences in pri-miRNA processing/Dicer/Argonaute loading, subcellular localization of miRNAs, and selective EV packaging/uptake varying by donor and recipient cell type.

    “This likely reflects a combination of factors: (i) cell-type–restricted transcription factor networks that regulate primary miRNA transcription; (ii) differences in primary microRNA (pri-miRNA) processing, Dicer activity, and Argonaute loading; (iii) subcellular localization of miRNAs to synapses, myelin, or perivascular end-feet; and (iv) selective packaging and uptake of miRNAs into EVs”

    From Cell-specific MicroRNA networks orchestrate the pathogenesis of Alzheimer’s disease (2026) · cites this paper as Men et al., 2019

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Cited by

Sorted by citations

Authors
Men, Y., Yelick, J., Jin, S., Tian, Y., Chiang, M. S. R., Higashimori, H., Brown, E., Jarvis, R., & Yang, Y.
ORCID
Venue
Nature Communications
Publisher
Springer Science and Business Media LLC
Published
2019-09-12
Volume
10
Issue
1
ISSN
2041-1723
DOI
10.1038/s41467-019-11534-w
PMC
PMC6742670
Cited by
331
References
6
Language
en
Licence
Funders
FRAXA Research Foundation

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