BMSCs promote apoptosis in glioma cells by inhibiting STAT3 phosphorylation

Abstract: Background: Bone marrow mesenchymal stem cells (BMSCs) show promise in glioma therapy, but the underlying mechanisms remain unclear. Signal transducer and activator of transcription 3 (STAT3) is a key oncogenic driver in glioma; however, whether BMSCs exert anti-glioma effects through STAT3 modulation requires further investigation. Objectives: To investigate whether BMSCs promote glioma cell apoptosis by inhibiting STAT3 phosphorylation and to validate the causal role of STAT3 using a specific agonist. Methods: C6 glioma-bearing rats were randomized into control, model, BMSC, positive control (MS-275) and STAT3 agonist (Colivelin) groups. BMSCs (1×10⁷ cells) were injected via the tail vein on days 14 and 17. Tumor growth, apoptosis, glial fibrillary acidic protein (GFAP) expression, basic fibroblast growth factor (bFGF)/vascular endothelial growth factor (VEGF) mRNA levels and STAT3/phosphorylated STAT3 (p-STAT3) expression were assessed by magnetic resonance imaging (MRI), histology, terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining, flow cytometry, immunohistochemistry, reverse transcription-polymerase chain reaction (RT-PCR) and Western blotting. In-vitro validation was performed using BMSC-conditioned medium and the STAT3 inhibitor Stattic in C6 cells. Results: BMSC transplantation significantly reduced the tumor area and Ki-67 proliferation index, increased the number of apoptotic cells and the apoptotic rate (P < 0.01) and decreased p-STAT3 levels and the p-STAT3/STAT3 ratio (P < 0.01) without altering total STAT3 expression. Colivelin reversed BMSC-induced apoptosis. bFGF and VEGF mRNA levels were increased in the BMSC group (P < 0.01). In-vitro, BMSC-conditioned medium suppressed STAT3 phosphorylation and induced apoptosis, effects that were enhanced by Stattic. Conclusion: BMSCs promote apoptosis in glioma cells by inhibiting STAT3 phosphorylation. The reversal of these effects by a STAT3 agonist confirms the causal role of STAT3 inhibition. These findings identify STAT3 as a key therapeutic target for BMSC-based glioma therapy.