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Cited by 199Extracellular vesicles in diseaseMicroRNA in disease regulationNeuroinflammation and Neurodegeneration Mechanisms

Glioblastoma-Associated Microglia Reprogramming Is Mediated by Functional Transfer of Extracellular miR-21

Open access
Abels, Erik R., Maas, Sybren L.N., Nieland, Lisa, Wei, Zhiyun, Cheah, Pike See, Tai, Eric, Kolsteeg, Christy-Joy, Dusoswa, Sophie A. +6 more·2019·Cell Reports
DOI 10.1016/j.celrep.2019.08.036PMC PMC6817978
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Abstract

Gliomas are primary, diffusely infiltrating brain tumors. Microglia are innate immune cells in the CNS and make up a substantial portion of the tumor mass. Glioma cells shape their microenvironment, communicating with and reprogramming surrounding cells, resulting in enhanced angiogenesis, immune suppression, and remodeling of the extracellular matrix. Glioma cells communicate with microglia, in part by releasing extracellular vesicles (EVs). Mouse glioma cells stably expressing a palmitoylated GFP to label EVs were implanted intracranially into syngeneic miR-21-null mice. Here, we demonstrate functional delivery of miR-21, regulating specific downstream mRNA targets in microglia after uptake of tumor-derived EVs. These findings attest to EV-dependent microRNA delivery as studied in an in vivo-based model and provide insight into the reprograming of microglial cells by tumor cells to create a favorable microenvironment for cancer progression.

AI snapshot

Written from the paper’s full text.

TL;DR

Glioma-derived extracellular vesicles (EVs) transfer functional miR-21 to microglia in vivo, where it downregulates specific target mRNAs and promotes microglial proliferation. Using miR-21-null mice and fluorescently labeled GL261 EVs, the study shows EV-mediated miRNA delivery can reprogram tumor-associated microglia.

Key findings

  • GL261-derived EVs contain high levels of miR-21, with significantly higher miR-21 in the 100,000 × g EV fraction than in cellular levels; EVs ranged from 100 to 500 nm by nanoparticle tracking analysis.
  • After intracranial implantation of GL261.pGHR cells into miR-21-null mice, microglia and monocytes/macrophages that took up EV-GFP had significantly higher miR-21 than GFP-negative cells; transfer was most efficient in microglia compared with monocytes/macrophages.
  • RNA sequencing of EV-GFPpos versus EV-GFPneg microglia found 441 upregulated and 359 downregulated genes; among 59 curated miR-21 targets, 25 had lowest expression in EV-GFPpos microglia, with significant reduction of Nfat5, Bmpr2, Btg2, Rhob, and Kbtbd2 (adjusted p < 0.05), while FasL and Tgfbi were significantly higher.
  • In vitro, primary miR-21-null microglia exposed to GL261 EVs (2.43 × 10^10 particles) showed increased miR-21 and downregulation of Bmpr2, Btg2, Kbtbd2, Pdcd4, Pten, and Rhob, with Gapdh unaffected; intracranial injection of GL261 EVs (1.26 × 10^9 particles) led to EV uptake in about 0.3% of all microglia and significant Btg2 reduction. miR-21 mimic or Btg2 siRNA increased Ki67-positive microglia.

Methods

  • GL261 glioma cells stably expressing palmitoylated GFP and H2B.mRFP (GL261.pGHR) were implanted intracranially (1 × 10^5 cells) into the left striatum of adult syngeneic miR-21-null mice; after three weeks, brains were digested and cells sorted by FACS for microglia (CD11b/CD45, RFP-negative) and monocytes/macrophages, with ImageStream used to visualize EV-sized GFP uptake.
  • EVs were isolated from GL261 conditioned medium by differential ultracentrifugation (300 × g, 2,000 × g, 100,000 × g), characterized by nanoparticle tracking analysis, western blot, and iodixanol density gradient; primary neonatal miR-21-null or wild-type microglia were exposed to EVs or transfected with miR-21 mimic, scrambled control, Btg2 siRNA, or siRNA control.
  • RNA sequencing used DESeq2 with Benjamini-Hochberg adjusted p values; qRT-PCR and droplet digital PCR measured miRNA/mRNA targets; proliferation was quantified as Ki67-positive cells per DAPI-positive cells; statistics used unpaired t tests, multiple t tests, and one-way ANOVA with Tukey’s multiple comparisons, with significance at p < 0.05.

Limitations

  • The paper states that the palmitoylated GFP reporter is not specific to one EV subtype (exosomes, ectosomes, or microvesicles) but tracks all naturally formed membrane-bound vesicles.
  • The authors state they do not exclude additional involvement of other miR-21 carriers, such as large EVs or non-floating non-EV components; high-density fractions containing high-density lipoproteins may also contribute to miR-21 transfer and could explain miR-21 in GFP-negative microglia.
  • The paper notes that incomplete Pdcd4 downregulation after intracranial EV injection may reflect relatively low miR-21 levels in that experiment; evident from the text, the main in vivo model uses miR-21-null recipient mice, and RNA sequencing and EV injection experiments used 3 mice per group.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.1016/j.celrep.2019.08.036

Cites

108 of 108 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

5 of 7 cited sources checked · 2 supported · 1 flagged · accuracy not yet measured

  • Premisereasoning

    The presence of GFP in microglia indicates tumor-derived EV uptake.

    “The presence of GFP in microglia thus indicates tumor-derived EV uptake (Figure 2C).”
    Quote in the paperSubstantial claim2 of 2 sources checked
    • cites Lai et al., 2015 source

      The Results section, “Visualizing tumour-derived EVs in vivo,” identifies membrane-targeted PalmGFP as a label for tumour-derived vesicles, supporting the use of that signal to track EVs. But the Discussion says the identity of non-tumour cells taking up EVs remains to be established; the paper does not show uptake by microglia specifically. It also distinguishes membrane-targeted PalmGFP from soluble GFP, so GFP presence alone is not established as proof of EV uptake. (LLM, conf=0.86)

      Experimental — accuracy not yet measured
    • cites van der Vos et al., 2016 source

      In the in vivo uptake section (Figs. 5–6), GFP labels microglia and monocyte-derived macrophages, while tumor-derived EVs carry a red fluorescent label. The paper identifies red puncta within GFP-positive cells—not GFP in microglia alone—as evidence of EV uptake. (LLM, conf=0.90)

      Checked by a reasoning model — may be wrong.

      Experimental — accuracy not yet measured
  • Study design and conductown data

    Heterogeneity of EV fractions was confirmed by probing for different vesicular protein markers.

    “Heterogeneity of these different fractions was confirmed by probing for different vesicular protein markers that are present in all types of EVs and larger vesicle fractions (Flotillin-1) (Kowal et al., 2016), those typically associated with exosomes and absent in 2,000 × g (ALIX and TSG101), and GAPDH found to be enriched in the 2,000 × g and cellular fraction (McNamara et al., 2018).”
    Quote in the paperNot a substantial claim2 of 2 sources checked
    • cites Kowal et al., 2016 source
    • cites McNamara et al., 2018 source

      The Materials and Methods section (“Protein analysis”; page unavailable) says the authors immunoblotted EV and control fractions using an antibody to GAPDH. It does not report GAPDH enrichment in a 2,000 × g fraction or show that this marker confirmed heterogeneity among the fractions in the citing sentence. The “EV isolation” section instead describes centrifugation at 800 × g and 16,000 × g. (LLM, conf=0.84)

      Experimental — accuracy not yet measured
  • Findingown data

    In miR-21-null microglia exposed to GL261-derived EVs, miR-21 expression was significantly increased compared with UcM.

    “Twenty-four hours later, the expression level of miR-21 was significantly increased in microglia exposed to GL261-derived EVs, compared with UcM (Figure 5D).”
    Quote in the paperSubstantial claim
  • Findingown data

    Among 59 selected miR-21 target genes, 25 genes showed lowest expression in EV-GFPpos microglia.

    “Relative gene expression of the selected 59 target genes showed 25 genes with lowest expression in EV-GFPpos microglia (Figure 4C).”
    Quote in the paperSubstantial claim
  • Findingown data

    Intracranial injection of GL261-derived EVs into miR-21-null mice results in about 0.3% of all microglia taking up EVs.

    “Sixteen hours after injection of the EVs into the left striatum (using similar coordinates as tumor implantation) of miR-21-null mice, about 0.3% of all microglia in the brain (blue circle) that had taken up EVs (green box) were detected (Figure 6B).”
    Quote in the paperNot a substantial claim
  • May combine two claims. 16
  • Classified as probably not a substantial claim. 19
  • The quote only partly states this claim. 1

  • May combine two claims.

    Findingcitation

    miR-21 co-localizes with GFP in EVs, but is also present in high-density fractions possibly associated with high-density lipoproteins.

    “Overall, miR-21 was found to co-localize with GFP, but miR-21 was also present in the high-density fractions, possibly associated with high-density lipoproteins (Figures S2B and S2C) (Vickers et al., 2011).”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites Vickers et al., 2011 source

  • May combine two claims.

    Findingreasoning

    miR-21 transfer is most efficient in microglia compared with MOs/macrophages, although percentage of EV-GFP uptake is highest in MOs/macrophages.

    “Analysis of the EV-GFP uptake and the subsequent miR-21 levels in miR-21-null mice showed that although the percentage of cells positive for EV-GFP uptake was highest in the MO and/or macrophage population, the miR-21 transfer was most efficient in microglia.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    In miR-21-null microglia exposed to GL261-derived EVs, transcripts Bmpr2, Btg2, Kbtbd2, Pdcd4, Pten, and Rhob were significantly downregulated, while Gapdh was unaffected.

    “We also observed significant downregulation of the in vivo EV downregulated miR-21 targets Bmpr2, Btg2, Kbtbd2, Pdcd4, Pten, and Rhob transcripts, while Gapdh expression appeared unaffected (Figures 5E and 5F).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    In EV-GFPpos versus EV-GFPneg microglia, 441 genes were significantly upregulated and 359 genes were downregulated.

    “Four hundred forty-one genes were significantly upregulated and 359 genes were downregulated in EV-GFPneg versus EV-GFPpos (Figure 4B, significantly changed genes in red).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    The difference in miR-21 levels between EV-GFPneg and EV-GFPpos is smaller in MOs/macrophages, and relative levels in EV-GFPpos MOs/macrophages are lower than in EV-GFPpos microglia.

    “Surprisingly the difference between EV-GFPneg and GFPpos in MOs and/or macrophages was smaller, and the relative levels in EV-GFPpos MOs and/or macrophages were lower compared with EV-GFPpos microglia (Figures 2D and 3C).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    The heterogeneous population of EVs shed by GL261 tumor cells is labeled with membrane-bound GFP and contains high levels of miR-21.

    “Taken together, the heterogeneous population of EVs shed by tumor cells is labeled with membrane-bound GFP and contains high levels of miR-21.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Gapdh, a control gene not targeted by miR-21, was not affected, indicating that mRNA target gene downregulation is miR-21 specific.

    “A control gene not targeted by miR-21, Gapdh, was not affected, an indication that mRNA target gene downregulation is miR-21 specific (Figure 5B).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Btg2, Nfat5, and Pdcd4 expression levels were significantly downregulated after EV uptake in vivo and by miR-21 mimic in vitro.

    “From the selected genes, expression levels for Btg2 and Nfat5 as well as Pdcd4 were significantly downregulated after EV uptake in vivo and were shown to be significantly downregulated by the miR-21 mimic (Figure 5A).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    NTA revealed a broad size distribution of EVs ranging from 100 to 500 nm, confirming their heterogeneity.

    “Nanoparticle tracking analysis (NTA) of the EVs isolated by 100,000 × g ultracentrifugation revealed a broad size distribution of EVs ranging from 100 to 500 nm, further confirming their heterogeneity (Figure S1A).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    In the intracranial EV injection experiment, both Pdcd4 and Btg2 transcript levels were reduced in microglia that took up EV-GFP, but reduction reached significance only for Btg2.

    “In this experiment, both transcript levels were reduced in microglia that took up EV-GFP, but this reduction reached significance only for the Btg2 replicates (Figure 6D).”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Findingown data

    A similar trend of higher miR-10b expression is seen in EV-GFPpos microglia compared with EV-GFPneg microglia.

    “A similar trend between EV-GFPneg and EV-GFPpos microglia was seen in glioma-specific miR-10b, in which the expression level was higher than in EV-GFPneg microglia (Figure S1D).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    miR-21 is detected in EV-GFPpos microglia but not in EV-GFPneg microglia after intracranial EV injection, demonstrating effective transfer of miR-21 via EVs derived from in vitro cultured tumor cells to microglia in vivo.

    “Interestingly, miR-21 was detected in the EV-GFPpos microglia, compared with being at non-detectable levels in EV-GFPneg microglia, demonstrating that miR-21 was effectively transferred via EVs derived from in vitro cultured tumor cells and delivered to microglia in vivo (Figure 6C).”
    Quote in the paperSubstantial claim

  • The quote only partly states this claim.

    Findingown data

    A smaller percentage of CD11blowCD45high lymphocytes have taken up EV-GFP compared with other immune cells.

    “In this population of non-phagocytic cells, we found a smaller percentage of cells that have taken up EV-GFP (Figures S3A and S3B).”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    Male and female mice were randomly assigned to experimental groups.

    “Male and female mice ranging from 12 – 14 weeks in age were randomly assigned to experimental groups.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Study design and conductnone given

    Statistical significance was defined as p < 0.05.

    “Significance was calculated using unpaired t test, multiple t tests and One-way ANOVA with Tukey’s multiple comparisons test, with statistical significance defined as p < 0.05.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    Animal experiments were conducted under oversight of the Massachusetts General Hospital Institution Animal Care and Use Committee.

    “All animal experiments were conducted under the oversight of the Massachusetts General Hospital Institution Animal Care and Use Committee.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    Libraries were diluted and denatured with the addition of 1% PhiX Sequencing Control V3.

    “Finally, libraries were diluted and denatured with the addition of 1% PhiX Sequencing Control V3 (Illumina).”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductown data

    EVs were characterized by size distribution analysis using nanoparticle-tracking analysis (NTA 3.2; Malvern).

    “Final EV pellet was resuspended in DPBS and characterization of EVs was performed by size distribution analysis using nanoparticle-tracking analysis (NTA 3.2; Malvern), with screen gain set at 3.0 and camera level at 13.0.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationown data

    The combination of CD11b and CD45 can be used to isolate microglia and MOs/macrophages, and GFP-positive EVs released by tumor cells in vivo can transfer miR-21 to microglia.

    “Taken together, this demonstrates that the combination of CD11b and CD45 can be used to isolate microglia and MOs and/or macrophages cells and that GFP-positive EVs released by tumor cells in vivo can transfer miR-21 to microglia.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    All qPCR reactions were done in triplicate.

    “All qPCR reactions were done in triplicate and normalized to β-Actin mRNA levels.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Study design and conductown data

    GFP protein was detected in both cellular and extracellular fractions, confirming that this marker can be used to track the fate of all different subtypes of EVs.

    “Importantly, GFP protein was detected in both cellular and extracellular fractions, confirming that this marker can be used to track the fate of all different subtypes of EVs (Figure 1C).”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    miRNA expression was normalized to U6 or UniSP6 spike-in RNA.

    “miRNA expression was normalized to U6 or UniSP6 spike-in RNA as listed in figure legends.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductown data

    qPCR data were normalized to β-Actin mRNA levels.

    “All qPCR reactions were done in triplicate and normalized to β-Actin mRNA levels.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationown data

    In the absence of a tumor, microglia can take up tumor cell-derived EVs injected into the striatum, leading to miR-21-dependent downregulation of Btg2.

    “However, these results suggest that in the absence of a tumor, microglia can take up tumor cell-derived EVs injected into the striatum, leading to miR-21-dependent downregulation of Btg2.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductown data

    RNA libraries included ERCC RNA Spike-In Mix.

    “RNA libraries were prepared with poly(A) selection using 3′-SMART CDS Primer II A within the SMARTer Ultra Low Input RNA Kit for Sequencing–v3 (Clontech Takara) following manufacturer’s protocol including ERCC RNA Spike-In Mix (Life Technologies).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisereasoning

    In miR-21-null mice, endogenous miR-21 is not expressed in stromal cells, so presence of miR-21 in stromal cells after tumor implantation is derived exclusively from implanted tumor cells.

    “In this model, endogenous miR-21 is not expressed in stromal cells, so the presence of miR-21 should be derived exclusively from the implanted tumor cells.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Ma et al., 2011

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • Classified as probably not a substantial claim.

    Study design and conductown data

    Equal amounts of protein were loaded for western blot analysis.

    “Protein concentration was determined using Pierce BCA protein assay (Thermo Fisher) and equal amounts were loaded and resolved on 10% SDS-PAGE gel (Thermo Fisher).”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    Differential expression analysis was subjected to statistical significance using Benjamini and Hochberg multiple testing adjusted p values.

    “Differential expression analysis as performed in DESeq2 was subjected to statistical significance using Benjamini and Hochberg multiple testing adjusted p values.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationown data

    Microglial proliferation is increased upon delivery of miR-21 and after downregulation of Btg2.

    “Overall, these results show that microglial proliferation is increased upon the delivery of miR-21 and after the downregulation of Btg2.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    A cut-off value of significance of multiple testing adjusted p value < 0.05 was used to include differentially expressed genes.

    “A cut-off value of significance of multiple testing adjusted p value < 0.05 was used to include differentially expressed genes.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    Non-specific binding of immunoglobulin to Fc receptors was blocked.

    “Non-specific binding of the immunoglobulin to the Fc receptors was blocked by incubating cells 10 min on ice in 0.5% BSA in DPBS (without Ca2+ or Mg2+) with 2 mM EDTA supplemented with TruStain fcX (anti-mouse Cd16/32, BioLegend, #101319, clone 93, 1:100).”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductown data

    Live cells were sorted for analysis.

    “DAPI was added to cells at final concentration of 1 μg/ml. Live cells were sorted using a BD FACSAria II SORP Cell Sorter.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    Equal molar individual libraries were pooled.

    “Equal molar individual libraries were pooled, and the pool concentration was determined using the KAPA SYBR® FAST Universal qPCR Kit.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    RNA concentration and integrity (RIN score) were determined using the Agilent 2100 Bioanalyzer Pico-chips.

    “The RNA concentration and integrity (RIN score) were determined using the Agilent 2100 Bioanalyzer Pico-chips (Agilent Technologies) following manufacturing protocol.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductown data

    GL261 cells were tested for mycoplasma contamination and found negative.

    “Cells were tested for mycoplasma contamination (Mycoplasma PCR Detection Kit, abm G238) and found negative.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Study design and conductreasoning

    The use of EVs isolated from GL261 grown in vitro allows study of uptake and effect without confounding action of other factors released by tumor cells.

    “By using EVs isolated from GL261, grown in vitro, we can study the uptake and effect of these EVs without confounding action of other factors released by the tumor cells.”
    Quote in the paperSubstantial claim
36 of 36

  • The paper relies on this without support.

    EV-mediated miRNA transfer had not previously been demonstrated in vivo using spontaneously released EVs.

    “Although EV-mediated miRNA transfer was previously either shown in vitro or after injection of arbitrary amounts of highly subselected EVs in vivo, this study demonstrates in vivo functional transfer of miRNA by spontaneously released EVs.”
1 of 1

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

Each contradiction between two passages listed here was confirmed by an independent check.

  • Pdcd4 is both included and excluded among the initially downregulated in vivo targets

    Minor

    The paper first says Pdcd4 was significantly downregulated after EV uptake in vivo. It later says that, of Pdcd4 and Btg2, only Btg2 was among the initially downregulated miR-21 targets in vivo.

1 of 1

Cited works that were retracted

Works this paper cites that were later retracted, from the retraction notices publishers deposit. Major when the notice came out before this paper was published.

  • Cites a retracted work: 10.1074/jbc.m116.772392

    Info

    The cited work was retracted on 2020-05-01 (notice 10.1074/jbc.w120.013725), not before this paper was published (2019-09).

    Cited work 10.1074/jbc.m116.772392 · retracted 2020-05-01 · notice 10.1074/jbc.w120.013725 · this paper published 2019-09

1 of 1

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Related

Authors
Abels, E. R., Maas, S. L. N., Nieland, L., Wei, Z., Cheah, P. S., Tai, E., Kolsteeg, C.-J., Dusoswa, S. A., Ting, D. T., Hickman, S., El Khoury, J., Krichevsky, A. M., Broekman, M. L. D., & Breakefield, X. O.
Affiliations
  • Harvard University (US)
  • Utrecht University (NL)
  • Brigham and Women's Hospital (US)
  • Universiti Putra Malaysia (MY)
  • Amsterdam University Medical Centers (NL)
  • Leiden University Medical Center (NL)
Corresponding author
  • Abels, Erik R.
  • Breakefield, Xandra O.
ORCID
Venue
Cell Reports
Publisher
Elsevier BV
Published
2019-09
Volume
28
Issue
12
Pages
3105-3119.e7
ISSN
2211-1247 (ISSN-L)
DOI
10.1016/j.celrep.2019.08.036
PMC
PMC6817978
OpenAlex
W2974646711
Semantic Scholar
023efccb5b74d12f75092f0aea6024ea7a7e5386
Cited by
199
References
108
Citations by year
2026: 14 · 2025: 13 · 2024: 28 · 2023: 26 · 2022: 36 · 2021: 44 · 2020: 35 · 2019: 3
FWCI
8.59
Type
journal article
Language
en
Open access
Licence
Locations
  • Cell Reports (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Pure Amsterdam UMC (publishedVersion, other-oa)
  • Amsterdam UMC (VU Amsterdam) - Institutional Repository (publishedVersion, other-oa)
  • Leiden Repository (Leiden University) (submittedVersion, cc-by)
  • PubMed Central (submittedVersion, cc-by-nc-nd)
  • Universiti Putra Malaysia Institutional Repository (Universiti Putra Malaysia) (submittedVersion)
  • Data Archiving and Networked Services (DANS) (submittedVersion)
  • Leiden Repository (Leiden University) (submittedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • Utrecht University Repository (Utrecht University) (submittedVersion, other-oa)
  • Utrecht University Repository (Utrecht University) (submittedVersion, cc-by)
  • Data Archiving and Networked Services (DANS) (submittedVersion, other-oa)
Funders
National Institutes of Health
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Extracellular vesicles in disease
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › MicroRNA in disease regulation
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
Keywords
glioblastoma, microglia, miR-21, extracellular vesicles, microglial reprogramming, tumor microenvironment, microRNA delivery, glioma
MeSH terms
Animals, Cell Communication, Glioblastoma, Mice, Transgenic, RNA, Neoplasm, Microglia, MicroRNAs, Cell Line, Tumor, Mice, Tumor Microenvironment, Cellular Reprogramming

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