Glioblastoma-Associated Microglia Reprogramming Is Mediated by Functional Transfer of Extracellular miR-21
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.
(2019) Cell Reports, volume 28, issue 12, pp. 3105 - 3119.e7
(Article)
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
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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.
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Keywords: General Biochemistry,Genetics and Molecular Biology, Journal Article
ISSN: 2211-1247
Publisher: Cell Press
Note: Funding Information: This publication is part of the NIH Extracellular RNA Communication Consortium paper package and was supported by the NIH Common Fund’s exRNA Communication Program. We thank the Massachusetts General Hospital, Department of Pathology Flow and Image Cytometry Research Core, specifically Rachel Servis and Dr. Ravi Mylvaganam for their help and execution of the flow cytometry experiments. All members of the Breakefield laboratory who suggested ideas during laboratory meetings are very much appreciated. We also thank Dr. Thorsten Mempel for providing the H2B.mRFP plasmid. We thank Ms. Suzanne McDavitt for skilled editorial assistance. The Breakefield laboratory acknowledges grant support from NIH NCI CA179563 , CA069246 , and CA232103 . The Krichevsky laboratory acknowledges grant support from NIH grants U19 CA179563 , R01 CA215072 , and R21 NS098051 . Grant U19 CA179563 was supported by the NIH Common Fund, through the Office of Strategic Coordination/Office of the NIH Director. The MGH Vector Core was supported by NIH NINDS grant P30 NS045776 . The MGH Department of Pathology Flow and Image Cytometry Research Core obtained support from the NIH Shared Instrumentation Program with grants 1S10OD012027-01A1 , 1S10OD016372-01 , 1S10RR020936-01 , and 1S10RR023440-01A1 . Graphical illustrations in figures are derived from Servier Medical Art by Servier ( https://smart.servier.com/ ) licensed under a Creative Commons Attribution 3.0 Unported License ( https://creativecommons.org/licenses/by/3.0/ ). Funding Information: This publication is part of the NIH Extracellular RNA Communication Consortium paper package and was supported by the NIH Common Fund's exRNA Communication Program. We thank the Massachusetts General Hospital, Department of Pathology Flow and Image Cytometry Research Core, specifically Rachel Servis and Dr. Ravi Mylvaganam for their help and execution of the flow cytometry experiments. All members of the Breakefield laboratory who suggested ideas during laboratory meetings are very much appreciated. We also thank Dr. Thorsten Mempel for providing the H2B.mRFP plasmid. We thank Ms. Suzanne McDavitt for skilled editorial assistance. The Breakefield laboratory acknowledges grant support from NIH NCI CA179563, CA069246, and CA232103. The Krichevsky laboratory acknowledges grant support from NIH grants U19 CA179563, R01 CA215072, and R21 NS098051. Grant U19 CA179563 was supported by the NIH Common Fund, through the Office of Strategic Coordination/Office of the NIH Director. The MGH Vector Core was supported by NIH NINDS grant P30 NS045776. The MGH Department of Pathology Flow and Image Cytometry Research Core obtained support from the NIH Shared Instrumentation Program with grants 1S10OD012027-01A1, 1S10OD016372-01, 1S10RR020936-01, and 1S10RR023440-01A1. Graphical illustrations in figures are derived from Servier Medical Art by Servier (https://smart.servier.com/) licensed under a Creative Commons Attribution 3.0 Unported License (https://creativecommons.org/licenses/by/3.0/). E.R.A. S.L.N.M. X.O.B. M.L.D.B. and A.M.K. conceived the study. E.R.A. S.L.N.M. and X.O.B. designed the experiments. E.R.A. Z.W. L.N. P.S.C. and C.-J.K. performed and analyzed experiments. S.A.D. assisted during animal experiments. D.T.T. and E.T. assisted and performed RNA sequencing (RNA-seq) experiments. S.L.N.M. and E.T. performed the computational and statistical analysis of RNA-seq data. S.H. and J.E.K. provided advice on microglial isolation. X.O.B. M.L.D.B. and A.M.K. supervised the project. E.R.A. prepared figures. E.R.A. wrote the manuscript. All authors edited or commented on the manuscript. The authors declare no competing interests. Publisher Copyright: © 2019 The Authors
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