Glioma-Associated Mesenchymal Stromal/Stem Cells Derived Exosomal miR-191 Promotes the Proneural-to-Mesenchymal Transition in Glioblastoma Cells via PTEN/PI3K/AKT Signaling

Background: The proneural-to-mesenchymal transition (PMT) represents a crucial phenotypic transformation in glioblastoma. Glioma-associated mesenchymal stromal/stem cells (GaMSCs) play a significant role in diverse biological processes of gliomas. However, the impact of exosomes released from GaMSCs (GaMSCs-Exos) on the PMT of glioblastoma remains inadequately understood. This study aimed to explore the effects and mechanisms of GaMSCs-derived exosomal miRNA-191-5p on the PMT of glioblastoma.

Methods and results: Conditioned medium from three independently established GaMSCs lines (GaMSCs-CM) significantly enhanced the tumorigenicity of glioma cells. Further analysis demonstrated that GaMSC-Exos, isolated from GaMSCs-CM, promoted both the tumorigenicity and PMT of glioma cells, both in vitro and in vivo. Exosomal miR-191-5p derived from GaMSCs was identified as the principal mediator. Overexpression and inhibition of miR-191-5p affected the tumorigenicity and PMT of glioma cells, in both laboratory and animal models. Bioinformatics analyses and luciferase reporter assays confirmed that miR-191-5p targets PTEN. Additionally, rescue experiments indicated that increased PTEN expression could reverse the effects of miR-191-5p overexpression on tumorigenicity and PMT through modulation of the PI3K/Akt signaling pathway.

Conclusion: Our findings highlight the role of GaMSC-Exos in mediating the intercellular transfer of miRNA-191-5p, which facilitates the PMT of glioma. The process underlying the enhanced aggressiveness and PMT is driven by miR-191-5p, promoting glioma progression by targeting PTEN and activating the PI3K/Akt signaling pathway.