Peng Lv,1,2,* Yanbin Zhang,1,3,* Zhen Zhao,1,* Wenjie Wu,1,* Yan Zhou,1 Zhen Liu,1 Haofei Wang,1 Xiaobing Jiang,1 Sumeng Li,4 Pengfei Yan,1 Xing Huang,1 Wei Xiang,1 Peng Fu1 

1Department of Neurosurgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, People’s Republic of China; 2Department of Rehabilitation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, People’s Republic of China; 3Department of Plastic Surgery, Hubei Provincial Hospital of TCM, Wuhan, 430061, People’s Republic of China; 4Department of Infectious Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, People’s Republic of China

*These authors contributed equally to this work

Correspondence: Peng Fu, Department of Neurosurgery, Union Hospital, Jiefang Avenue No. 1277, Wuhan, Hubei, 430022, People’s Republic of China, Tel +86 27 85350819, Email pfu@hust.edu.cn Wei Xiang, Department of Neurosurgery, Union Hospital, Jiefang Avenue No. 1277, Wuhan, Hubei, 430022, People’s Republic of China, Tel +86 27 85350819, Email xiangwei20@hotmail.com

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.

Keywords: glioma-associated mesenchymal stromal/stem cells, exosomes, proneural to mesenchymal transition, miR-191-5p