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

Erik R Abels; Sybren L N Maas; Lisa Nieland; Zhiyun Wei; Pike See Cheah; Eric Tai; Christy-Joy Kolsteeg; Sophie A Dusoswa; David T Ting; Suzanne Hickman; Joseph El Khoury; Anna M Krichevsky; Marike L D Broekman; Xandra O Breakefield

doi:10.1016/j.celrep.2019.08.036

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

Cell Rep. 2019 Sep 17;28(12):3105-3119.e7. doi: 10.1016/j.celrep.2019.08.036.

Authors

Affiliations

¹ Departments of Neurology and Radiology, Massachusetts General Hospital, and NeuroDiscovery Center, Harvard Medical School, Boston, MA 02129, USA. Electronic address: eabels@mgh.harvard.edu.
² Department of Neurosurgery, UMC Utrecht Brain Center, University Medical Center, Utrecht University, 3584 CX Utrecht, the Netherlands.
³ Departments of Neurology and Radiology, Massachusetts General Hospital, and NeuroDiscovery Center, Harvard Medical School, Boston, MA 02129, USA.
⁴ Department of Neurology, Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
⁵ Departments of Neurology and Radiology, Massachusetts General Hospital, and NeuroDiscovery Center, Harvard Medical School, Boston, MA 02129, USA; Department of Human Anatomy, Faculty of Medicine and Health Sciences, Universiti Putra Malaysia, Serdang, Selangor 43400, Malaysia.
⁶ Cancer Center, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.
⁷ Department of Molecular Cell Biology and Immunology, Amsterdam Infection & Immunology Institute and Cancer Center Amsterdam, Amsterdam UMC, 1081 HZ Amsterdam, the Netherlands.
⁸ Center for Immunology & Inflammatory Diseases, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02129, USA.
⁹ Department of Neurosurgery, Leiden University Medical Center, 2300 RC Leiden, the Netherlands; Department of Neurosurgery, Haaglanden Medical Center, 2512 VA The Hague, the Netherlands.
¹⁰ Departments of Neurology and Radiology, Massachusetts General Hospital, and NeuroDiscovery Center, Harvard Medical School, Boston, MA 02129, USA. Electronic address: breakefield@hms.harvard.edu.

Abstract

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.

Publication types

Research Support, N.I.H., Extramural

MeSH terms

Animals
Cell Communication*
Cell Line, Tumor
Cellular Reprogramming*
Glioblastoma / genetics
Glioblastoma / metabolism*
Glioblastoma / pathology
Mice
Mice, Transgenic
MicroRNAs / genetics
MicroRNAs / metabolism*
Microglia / metabolism*
Microglia / pathology
RNA, Neoplasm / genetics
RNA, Neoplasm / metabolism*
Tumor Microenvironment*

Substances

MIRN21 microRNA, mouse
MicroRNAs
RNA, Neoplasm

Abstract

Publication types

MeSH terms

Substances

Grants and funding