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

Abels ER 1 , Maas SLN 2 , Nieland L 3 , Wei Z 4 , Cheah PS 5 , Tai E 6 Show all authors , Kolsteeg CJ 3 , Dusoswa SA 7 , Ting DT 6 , Hickman S 8 , El Khoury J 8 , Krichevsky AM 4 , Broekman MLD 9 , Breakefield XO 10

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
Cell Rep, 2019 09 17;28(12):3105-3119.e7.
PMID: 31533034 DOI: 10.1016/j.celrep.2019.08.036

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.

* Title and MeSH Headings from MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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