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Cited by 135Extracellular vesicles in diseaseAmyotrophic Lateral Sclerosis ResearchNeuroinflammation and Neurodegeneration Mechanisms

Exosomes from NSC-34 Cells Transfected with hSOD1-G93A Are Enriched in miR-124 and Drive Alterations in Microglia Phenotype

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Pinto, Sara, Cunha, Carolina, Barbosa, Marta, Vaz, Ana R., Brites, Dora·2017·Frontiers in Neuroscience
DOI 10.3389/fnins.2017.00273PMC PMC5434170
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Abstract

Amyotrophic lateral sclerosis (ALS) is a fatal adult-onset neurodegenerative disorder affecting motor neurons (MNs). Evidences indicate that ALS is a non-cell autonomous disease in which glial cells participate in both disease onset and progression. Exosomal transfer of mutant copper-zinc superoxide dismutase 1 (mSOD1) from cell-to-cell was suggested to contribute to disease dissemination. Data from our group and others showed that exosomes from activated cells contain inflammatory-related microRNAs (inflamma-miRNAs) that recapitulate the donor cell. While glia-derived exosomes and their effects in neurons have been addressed by several studies, only a few investigated the influence of motor neuron (MN)-derived exosomes in other cell function, the aim of the present study. We assessed a set of inflamma-miRs in NSC-34 MN-like cells transfected with mutant SOD1(G93A) and extended the study into their derived exosomes (mSOD1 exosomes). Then, the effects produced by mSOD1 exosomes in the activation and polarization of the recipient N9 microglial cells were investigated. Exosomes in coculture with N9 microglia and NSC-34 cells [either transfected with either wild-type (wt) human SOD1 or mutant SOD1(G93A)] showed to be transferred into N9 cells. Increased miR-124 expression was found in mSOD1 NSC-34 cells and in their derived exosomes. Incubation of mSOD1 exosomes with N9 cells determined a sustained 50% reduction in the cell phagocytic ability. It also caused a persistent NF-kB activation and an acute generation of NO, MMP-2, and MMP-9 activation, as well as upregulation of IL-1β, TNF-α, MHC-II, and iNOS gene expression, suggestive of induced M1 polarization. Marked elevation of IL-10, Arginase 1, TREM2, RAGE, and TLR4 mRNA levels, together with increased miR-124, miR-146a, and miR-155, at 24 h incubation, suggest the switch to mixed M1 and M2 subpopulations in the exosome-treated N9 microglial cells. Exosomes from mSOD1 NSC-34 MNs also enhanced the number of senescent-like positive N9 cells. Data suggest that miR-124 is translocated from the mSOD1 MNs to exosomes, which determine early and late phenotypic alterations in the recipient N9-microglial cells. In conclusion, modulation of the inflammatory-associated miR-124, in mSOD1 NSC-34 MNs, with potential benefits in the cargo of their exosomes may reveal a promising therapeutic strategy in halting microglia activation and associated effects in MN degeneration.

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  • miRNAs can be released by cells as free species directly into their secretome or selectively enriched in exosomes (diameter <150 nm) that, when internalized by target cells, affect their biological functions.

    “In general, miRNAs can be released by cells as free species directly into their secretome or selectively enriched in small extracellular vesicles (exosomes, diameter size <150 nm) that, when internalized by target cells, affect their biological functions [38,39,40,41].”

    From Emerging Role of miR-21-5p in Neuron–Glia Dysregulation and Exosome Transfer Using Multiple Models of Alzheimer’s Disease (2022) · cites this paper as [38]

    The Results report miR-124 enrichment in exosomes from mSOD1 cells and describe those exosomes as averaging about 130 nm in diameter. The Results also state that exosomal miRNAs can enter recipient cells and change their function. Our copy does not establish the alternative claim that cells release free miRNAs directly into their secretome, or define all exosomes as smaller than 150 nm. (LLM, conf=0.88)

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Cited by

Sorted by citations

Authors
Pinto, S., Cunha, C., Barbosa, M., Vaz, A. R., & Brites, D.
Affiliations
University of Lisbon (PT)
Corresponding author
Brites, Dora
ORCID
Venue
Frontiers in Neuroscience
Publisher
Frontiers Media SA
Published
2017-05-17
Volume
11
Pages
273-273
ISSN
1662-453X (ISSN-L)
DOI
10.3389/fnins.2017.00273
PMC
PMC5434170
OpenAlex
W2615003101
Cited by
135
References
21
Citations by year
2026: 5 · 2025: 9 · 2024: 16 · 2023: 12 · 2022: 21 · 2021: 27 · 2020: 20 · 2019: 10 · 2018: 12 · 2017: 3
FWCI
5.03
Type
journal article
Language
en
Open access
Licence
cc-by
Locations
  • Frontiers in Neuroscience (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
Fundação para a Ciência e a Tecnologia (EU Joint Programme - Neurodegenerative Disease Research (JPND) MADGIC project (JPco-fuND/0003/2015), UID/DTP/04138/2013, SFRH/BPD/76590/2011, SFRH/BD/91316/2012)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Extracellular vesicles in disease
  • Health Sciences › Medicine › Neurology › Amyotrophic Lateral Sclerosis Research
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
Keywords
amyotrophic lateral sclerosis, exosomes, miR-124, mutant SOD1, microglial polarization, M1/M2 microglia, neuroinflammation, miR-146a, miR-155, miR-100, miR-101, miR-103, miR-107, miR-122, miR-125b, miR-133, miR-145, miR-148a, miR-150, miR-152

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