Glioma Stem Cells-Derived Exosomes Promote the Angiogenic Ability of Endothelial Cells Through miR-21/VEGF Signal

Glioma stem cells (GSCs) play an important role in glioblastoma prognosis. Exosomes (EXs) mediate cell communication by delivering microRNAs (miRs). Glioblastoma has a high level of miR-21 which could upregulate vascular endothelial growth factor (VEGF) expression. We hypothesized GSC-EXs can promote the angiogenic ability of endothelial cells (ECs) through miR-21/VEGF signal. GSCs were isolated from U-251 cells with stem cell marker CD133. GSCs transfected without or with scramble or miR-21 mimics were used to produce GSC- ^EXs con, GSC-EXs ^sc and GSC-EXs ^miR-21 . Human brain ECs were co-cultured with vehicle, GSC-EXs ^con , GSC-EXs ^sc or GSC-EXs ^miR-21 plus VEGF siRNAs (siRNA ^VEGF ). After 24 hours, the angiogenic abilities of ECs were evaluated. The levels of miR-21, VEGF and p-Flk1/VEGFR2 were determined. Results showed: 1) Over 90% of purified GSCs expressed CD133; 2) The levels of miR-21 and VEGF in GSCs and GSC-EXs were up-regulated by miR-21 mimic transfection; 3) Compared to GSC-EXs ^con or GSC-EXs ^sc , GSC-EXs ^miR-21 were more effective in elevating the levels of miR-21 and VEGF, and the ratio of p-Flk1/VEGFR2 in ECs; 4) GSC-EXsmiR-21 were more effective in promoting the angiogenic ability of ECs than GSC-EXs ^con or GSC-EXs ^sc , which were remarkably reduced by siRNA ^VEGF pretreatment. In conclusion, GSC-EXs can promote the angiogenic ability of ECs by stimulating miR-21/VEGF/VEGFR2 signal pathway.