Cited by 9Extracellular vesicles in diseaseCancer, Hypoxia, and MetabolismGlioma Diagnosis and Treatment

Exosomal miR-21-5p from glioma associated mesenchymal stem cells promotes the progression and glycolysis of glioblastoma via PDHA1

Open access
Zhang, Yanbin, Lv, Peng, Zhang, Qing, Xiang, Wei, Jiang, Xiaobing, Guo, Zijun, Zhang, Tao·2025·Scientific Reports

Abstract

Glioblastoma (GBM) is highly malignant and grows rapidly, and there is currently a lack of effective treatments. Metabolism provides the basis for the occurrence and development of GBM. Pyruvate dehydrogenase A1 (PDHA1) is a key component in both the tricarboxylic acid cycle and glycolysis, playing an important role in the metabolic processes related to cancer, but its role in GBM remains unclear. Glioma associated mesenchymal stem cells (GaMSC) play a significant role in the development of glioma. This study aims to explore the relationship between GaMSC derived exosomes (GAMSC-EXO) and PDHA1, as well as the effects and mechanisms on GBM glucose metabolism. In this study, human GaMSC-derived exosomes were isolated and identified. The role of GAMSC-EXO in GBM proliferation, migration, invasion and glucose metabolism was investigated. The upstream miRNA of PDHA1 was predicted and the relationship between miR-21-5p and PDHA1 in GAMSC-EXO and its effect on GBM glucose metabolism was investigated. We found that GAMSCs promote GBM cell proliferation, migration, invasion and glycolysis by releasing exosomes. After inhibiting GBM glycolysis, GBM proliferation, migration and invasion abilities were weakened. MiR-21-5p in exosomes was identified as the miRNA that affects the above biological behaviors. Mechanismly, miR-21-5p directly binds to the mRNA of PDHA1 and downregulates its transcription, thereby promoting GBM glycolysis. Together, this study demonstrated that exosomal miR-21-5p from GAMSC promoted GBM proliferation, migration, invasion, and glycolysis by targeting PDHA1, which provided novel insights into the metabolic interactions between GAMSCs and GBM cells, emphasizing the importance of exosome-mediated communication in tumor progression.

AI snapshot

Written from the paper’s full text.

TL;DR

Glioma-associated mesenchymal stem cell (GAMSC)-derived exosomes promote glioblastoma (GBM) proliferation, migration, invasion, and glycolysis. Exosomal miR-21-5p directly targets PDHA1 and downregulates it, linking GAMSC-to-GBM communication to metabolic reprogramming.

Key findings

  • GAMSCs were positive for CD73 (99.3%), CD90 (93.9%), and CD44 (91.6%), and negative for hematopoietic markers (5.2% negative cocktail); GAMSC-derived conditioned medium and exosomes increased GBM proliferation, migration, and invasion.
  • GAMSC-EXO enhanced glycolysis in GBM cells, increasing PKM2 expression, glucose utilization, lactate production, intracellular ATP, OCR, basal/maximal respiration, and ECAR; the glycolysis inhibitor 2-DG partially inhibited GAMSC-EXO-promoted proliferation and invasion.
  • miR-21-5p was identified as a direct repressor of PDHA1: luciferase activity was reduced by miR-21-5p mimics and increased by inhibitor with wild-type PDHA1 3′UTR, but no difference was seen with mutant PDHA1 reporters.
  • In vivo, GAMSC-EXO increased tumor fluorescence, shortened survival (Kaplan–Meier, P < 0.05), and increased PKM2 expression by IHC/IF; PDHA1 knockdown increased glucose utilization, lactate production, ATP, OCR, and ECAR in GBM cells.

Methods

  • U87 and U251 GBM cells and GAMSCs were cultured; GAMSCs were transfected with miR-21-5p mimics, inhibitor, or controls, and GBM cells with siPDHA1 or control.
  • Exosomes were isolated from GAMSC conditioned medium by differential centrifugation/ultracentrifugation and characterized by TEM, nanoparticle size, western blot (TSG101, CD81, calnexin), and PKH26 uptake.
  • Functional assays included colony formation, MTT, wound healing, Transwell, glucose/lactate/ATP measurements, OCR/ECAR, dual-luciferase reporter assays, RT-PCR, western blot, and an orthotopic nude mouse model with survival analysis and IHC/IF for PKM2.

Limitations

  • The paper states it only focused on the effect of GAMSC-EXO on GBM cell glycolysis and did not explain whether GAMSC-related changes in the tumor microenvironment (immunity, angiogenesis) are caused by GAMSC extracellular vesicles.
  • The paper states that effects of extracellular vesicles from other cell sources, and what drives these cell-to-cell interactions in GBM progression, require further exploration.
  • Evident from the text: some reported details are inconsistent or typographical (e.g., “miR-221 inhibitors” in the miR-21-5p transfection-efficiency description, and an MTT comparison sentence that appears to compare CM with CM), which limits clarity.

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

Integrity signals

Registry

Crossref · 10.1038/s41598-025-86580-0

Cites

36 of 36 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

  • Findingown data

    GAMSC-EXO promotes GBM cell migration.

    “The results of Transwell assay indicated that EXO could promote GBM cell migration and invasion (Fig. 3F and G).”
    • Also stated in: § GAMSC-EXO promotes GBM cell proliferation, migration and invasion · hedged
      “The results revealed that GAMSC-EXO could promotes GBM cell migration, invasion and proliferation.”
    Quote in the paperSubstantial claim
  • Findingown data

    GAMSC-EXO promotes glycolysis in GBM cells.

    “The results showed that GAMSC-EXO could promote the expression of PKM2 at both protein and gene levels (Fig. 4A and B).”
    • Also stated in: § GAMSC-EXO promotes glycolysis in GBM cells · hedged
      “GAMSC-EXO could promote the glucose utilization, lactate production and intracellular ATP levels in GBM cells.”
    • Also stated in: § GAMSC-EXO promotes glycolysis in GBM cells · hedged
      “Together, these results suggested that GAMSC-EXO enhanced glycolysis in GBM cells.”
    Quote in the paperSubstantial claim
  • Findingown data

    GAMSC-EXO promotes GBM cell proliferation.

    “The clone formation assay results indicated that the quantity of cell proliferation in the BM + EXO group was markedly increased in comparison to the BM group (Fig. 3D).”
    • Also stated in: § GAMSC-EXO promotes GBM cell proliferation, migration and invasion · plain
      “The MTT results showed that from 0 to 72 h, the value of BM + EXO group at 490 nm is significantly higher than that of CM group (Fig. 3E).”
    • Also stated in: § GAMSC-EXO promotes GBM cell proliferation, migration and invasion · hedged
      “The results revealed that GAMSC-EXO could promotes GBM cell migration, invasion and proliferation.”
    Quote in the paperSubstantial claim
  • Findingown data

    GAMSC-derived conditioned medium promotes GBM cell migration.

    “The results of Transwell assay indicated that CM could promote GBM cell migration and invasion (Fig. 2C and D).”
    • Also stated in: § GAMSC-derived conditioned medium promotes GBM cell proliferation, migration, and invasion · plain
      “In addition, the wound healing assay also verified that CM from GAMSC could promote GBM cell migration (Fig. 2E).”
    Quote in the paperSubstantial claim
  • Findingown data

    Inhibition of glycolysis with 2-DG inhibits GAMSC-EXO-induced GBM cell invasion.

    “the influence of GAMSC-EXO on enhancing the invasion of GBM cells could be inhibited by 2-DG (Figure s1C).”
    Quote in the paperSubstantial claim
  • May combine two claims. 3
  • May combine two claims.

    Findingown data

    The isolated exosomes from GAMSC conditioned medium are exosomes (express TSG101 and CD81, lack calnexin, round/elliptical).

    “The nanoparticle size profile and the transmission electron microscopy showed that the isolated exosomes were round or elliptical membranous vesicles with clear margins (Fig. 3A).”
    • Also stated in: § GAMSC-EXO promotes GBM cell proliferation, migration and invasion · plain
      “The western blot results showed that the exosomes expressed the marker proteins TSG101 and CD81 and lacked the endoplasmic reticulum protein calnexin (Fig. 3B).”
    Quote in the paperSubstantial claim
  • May combine two claims.

    Interpretationown data

    miR-21-5p directly binds the 3'UTR of PDHA1 and negatively regulates its mRNA levels in GBM cells.

    “This result indicated that miR-21-5p could directly bind the 3’UTR sequence of PDHA1 and negatively regulate its mRNA levels in GBM cells.”
    • Also stated in: § Identifying miR-21-5p from GAMSC-EXO as a direct repressor of PDHA1 · plain
      “miR-21-5p was identified as a direct repressor of PDHA1 in GAMSC-EXO.”
    Quote in the paperSubstantial claim
  • May combine two claims.

    Interpretationown data

    Exosomal miR-21-5p from GAMSC promotes GBM proliferation, migration, invasion, and glycolysis by targeting PDHA1.

    “Together, this study demonstrated that exosomal miR-21-5p from GAMSC promoted GBM proliferation, migration, invasion, and glycolysis by targeting PDHA1”
    • Also stated in: § Discussion · boosted
      “Together, this study demonstrated that GAMSCs provide miR-21-5p to GBM by secreting exosomes, thereby reducing the expression level of PDHA1 in GBM, promoting GBM glycolysis and cancer cell phenotypes such as proliferation and invasion.”
    Quote in the paperSubstantial claim
3 of 3
  • The paper relies on this without support.

    The role and mechanism of PDHA1 in GBM remain unclear.

    “but its role in GBM remains unclear.”
    “But its role and mechanism in GBM remain unclear.”
  • The paper relies on this without support.

    The mode of action by which GAMSC affects GBM malignancy is unclear.

    “Although the effect of GAMSC on the malignancy of GBM has been reported, its mode of action is still unclear and needs further exploration.”
2 of 2

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.

  • Conditioned-medium group is compared with itself

    Minor

    The results say the CM group's MTT value was significantly higher than the CM group's own value. The figure caption instead identifies BM as the comparison group.

  • Fig. 7 transfection reagent is identified as both miR-21 and miR-221

    Minor

    The results describe transfecting GAMSC with miR-21-5p mimics and inhibitors, but the Fig. 7E caption calls them miR-221 mimics and inhibitors. This leaves the identity of the reagents used for that result inconsistent.

  • Differentiation stains are assigned to different outcomes

    Minor

    The results assign Alizarin Red S to osteogenic differentiation and Oil Red O to adipogenic differentiation, while the Fig. 1 caption assigns them to lipogenic and osteogenic differentiation, respectively.

3 of 3

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: 10.18632/oncotarget.10782

    Info

    The cited work was retracted on 2025-11-06 (notice 10.18632/oncotarget.28777), not before this paper was published (2025-01-17).

    Cited work 10.18632/oncotarget.10782 · retracted 2025-11-06 · notice 10.18632/oncotarget.28777 · this paper published 2025-01-17

1 of 1

Cites

1 retracted

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Authors
Zhang, Y., Lv, P., Zhang, Q., Xiang, W., Jiang, X., Guo, Z., & Zhang, T.
Affiliations
  • Huazhong University of Science and Technology (CN)
  • Wuhan Union Hospital (CN)
  • Wuhan University (CN)
Corresponding author
  • Jiang, Xiaobing
  • Guo, Zijun
  • Zhang, Tao
Venue
Scientific Reports
Published
2025-01-17
Volume
15
Issue
1
Pages
2320-2320
ISSN
2045-2322 (ISSN-L)
OpenAlex
W4406597812
Cited by
9
References
36
Citations by year
2026: 5 · 2025: 4
FWCI
2.25
Type
journal article
Language
en
Open access
Locations
  • Scientific Reports (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
  • PubMed Central (submittedVersion, cc-by-nc-nd)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
National Natural Science Foundation of China (82273210, 82403222, 82200972)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Extracellular vesicles in disease
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
  • Health Sciences › Medicine › Genetics › Glioma Diagnosis and Treatment
Keywords
glioblastoma, exosomes, miR-21-5p, PDHA1, glycolysis, tumor glucose metabolism, tumor cell proliferation, cell migration and invasion, exosome-mediated intercellular communication, tumor microenvironment
MeSH terms
Animals, Brain Neoplasms, Cell Movement, Glioblastoma, Glioma, Glucose, Glycolysis, Humans, Gene Expression Regulation, Neoplastic, Disease Progression, Pyruvate Dehydrogenase (Lipoamide), MicroRNAs, Cell Line, Tumor, Cell Proliferation, Mice, Exosomes, Mesenchymal Stem Cells

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Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-21.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-21.

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