Glioblastoma-Associated Microglia Reprogramming Is Mediated by Functional Transfer of Extracellular miR-21

• Published in: Cell reports (Cambridge) Vol. 28; no. 12; pp. 3105 - 3119.e7
• Main Authors: Abels, Erik R., Maas, Sybren L.N., Nieland, Lisa, Wei, Zhiyun, Cheah, Pike See, Tai, Eric, Kolsteeg, Christy-Joy, Dusoswa, Sophie A., Ting, David T., Hickman, Suzanne, El Khoury, Joseph, Krichevsky, Anna M., Broekman, Marike L.D., Breakefield, Xandra O.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 17.09.2019; Elsevier
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2019.08.036

Gliomas are primary, diffusely infiltrating brain tumors. Microglia are innate immune cells in the CNS and make up a substantial portion of the tumor mass. Glioma cells shape their microenvironment, communicating with and reprogramming surrounding cells, resulting in enhanced angiogenesis, immune suppression, and remodeling of the extracellular matrix. Glioma cells communicate with microglia, in part by releasing extracellular vesicles (EVs). Mouse glioma cells stably expressing a palmitoylated GFP to label EVs were implanted intracranially into syngeneic miR-21-null mice. Here, we demonstrate functional delivery of miR-21, regulating specific downstream mRNA targets in microglia after uptake of tumor-derived EVs. These findings attest to EV-dependent microRNA delivery as studied in an in vivo-based model and provide insight into the reprograming of microglial cells by tumor cells to create a favorable microenvironment for cancer progression. [Display omitted] •Extracellular vesicles (EVs) shed by glioma cells are taken up by microglia in vivo•miR-21 is functionally transferred from glioma to microglia through EVs in vivo•miR-21 mRNA targets in microglia are downregulated upon EV uptake•Microglia proliferation is increased after miR-21 target Btg2 downregulation Abels et al. show miR-21 transfer from glioma to microglia by palmitoylated GFP-labeled extracellular vesicles in vivo. This transfer results in miR-21 target-specific mRNA downregulation. Following downregulation of Btg2, proliferation in microglia is increased, suggesting reprogramming of microglia in the tumor microenvironment through extracellular vesicles shed by glioma cells.