Mesenchymal stem cells as natural biofactories for exosomes carrying miR-124a in the treatment of gliomas

• Published in: Neuro-oncology (Charlottesville, Va.) Va.), 2018-02, Vol.20 (3), p.380-390
• Main Authors: Lang, Frederick M, Hossain, Anwar, Gumin, Joy, Momin, Eric N, Shimizu, Yuzaburo, Ledbetter, Dan, Shahar, Tal, Yamashita, Shinji, Parker Kerrigan, Brittany, Fueyo, Juan, Sawaya, Raymond, Lang, Frederick F
• Format: Article
• Language: English
• Subjects: Animals; Apoptosis; Basic and Translational Investigations; Cell Proliferation; Exosomes - genetics; Glioma - genetics; Glioma - pathology; Glioma - prevention & control; Humans; Male; Mesenchymal Stem Cell Transplantation; Mesenchymal Stem Cells - cytology; Mesenchymal Stem Cells - metabolism; Mice; Mice, Nude; MicroRNAs - genetics; Tumor Cells, Cultured; Xenograft Model Antitumor Assays
• ISSN: 1522-8517; 1523-5866
• DOI: 10.1093/neuonc/nox152

MicroRNAs (miRs) are promising new therapeutics for glioblastoma. However, which miRs are most effective against glioblastomas and how these miRs should be delivered are major unanswered problems. To identify potent antiglioma miRs, we selected 8 miRs based on a literature search and screened them against a panel of glioma stem cell (GSC) lines, representing all of the glioblastoma subtypes defined by The Cancer Genome Atlas. To address delivery, we tested the hypothesis that ex vivo cultured bone marrow-derived mesenchymal stem cells (MSCs) can package miRs into exosomes and that these engineered exosomes can systemically deliver antiglioma miRs to glioblastomas. Of the screened miRs, we identified miR-124a as the most effective antiglioma agent against GSCs. We then transduced MSCs with lentivirus vectors containing miR-124a and isolated vesicles from the medium. Electron microscopy, western blotting, and Nanosight proved that the isolated vesicles were exosomes. Quantitative PCR documented that these exosomes contained high levels of miR-124a, which was not present in control exosomes. In vitro treatment of GSCs with exosomes containing miR-124a (Exo-miR124) resulted in a significant reduction in viability and clonogenicity of GSCs compared with controls. In vivo treatment of mice harboring intracranial GSC267 with systemically delivered Exo-miR124 resulted in 50% of animals living long term. No evidence of tumor was present on histological analysis of the survivors. Mechanistic studies showed that miR-124a acts by silencing Forkhead box (FOX)A2, resulting in aberrant intracellular lipid accumulation. MSCs can be used as natural biofactories to produce Exo-miR124, which is an effective antiglioma agent worthy of further clinical evaluation.