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Author Notes:

Correspondence: gutmannd@wustl.edu; David.Gutmann@mdc-berlin.de

Verena Haage, Marcus Semtner and Ramon Oliveira Vidal; equal contribution as first authors.

Sascha Sauer, Helmut Kettenmann and David H. Gutmann; equal contribution as senior authors.

VH performed cell isolation and qRT-PCR experiments; ROV, and DPH performed the RNA and protein bioinformatic analyses; WWP, ZC, DH, VM, AL, JW, and EM provided new RNA datasets; PM, MS, SS, HK, and DHG supervised the studies and conceived the project; VH, MS, HK and DHG wrote the manuscript. All authors read and approved the final manuscript.

We thank Regina Piske, Maren Wendt, Nadine Scharek, and Michaela Seeger-Zografakis for technical assistance.

We thank the FACS facility and the proteomics facility of the Max Delbrück Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany for technical assistance.

The authors declare that they have no competing interests.

Subjects:

Research Funding:

The work was supported by the NeuroCure Cluster of Excellence, a Berlin Institute of Health/Einstein fellowship grant to D.H.G. and H.K.

D.H.G. is an Alexander von Humboldt Fellow.

Keywords:

  • Science & Technology
  • Life Sciences & Biomedicine
  • Neurosciences
  • Neurosciences & Neurology
  • Microglia
  • Monocytes
  • Glioma
  • CNS
  • RNA sequencing
  • Microarray
  • Macrophages
  • FRACTALKINE RECEPTOR CX(3)CR1
  • RESIDENT MICROGLIA
  • MACROPHAGES
  • MOUSE
  • CELLS
  • NEURODEGENERATION
  • MONOCYTES
  • ONTOGENY
  • CCR2

Comprehensive gene expression meta-analysis identifies signature genes that distinguish microglia from peripheral monocytes/macrophages in health and glioma

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Journal Title:

Acta Neuropathologica Communications

Volume:

Volume 7, Number 1

Publisher:

, Pages 20-20

Type of Work:

Article | Final Publisher PDF

Abstract:

Monocytes/macrophages have begun to emerge as key cellular modulators of brain homeostasis and central nervous system (CNS) disease. In the healthy brain, resident microglia are the predominant macrophage cell population; however, under conditions of blood-brain barrier leakage, peripheral monocytes/macrophages can infiltrate the brain and participate in CNS disease pathogenesis. Distinguishing these two populations is often challenging, owing to a paucity of universally accepted and reliable markers. To identify discriminatory marker sets for microglia and peripheral monocytes/macrophages, we employed a large meta-analytic approach using five published murine transcriptional datasets. Following hierarchical clustering, we filtered the top differentially expressed genes (DEGs) through a brain cell type-specific sequencing database, which led to the identification of eight microglia and eight peripheral monocyte/macrophage markers. We then validated their differential expression, leveraging a published single cell RNA sequencing dataset and quantitative RT-PCR using freshly isolated microglia and peripheral monocytes/macrophages from two different mouse strains. We further verified the translation of these DEGs at the protein level. As top microglia DEGs, we identified P2ry12, Tmem119, Slc2a5 and Fcrls, whereas Emilin2, Gda, Hp and Sell emerged as the best DEGs for identifying peripheral monocytes/macrophages. Lastly, we evaluated their utility in discriminating monocyte/macrophage populations in the setting of brain pathology (glioma), and found that these DEG sets distinguished glioma-associated microglia from macrophages in both RCAS and GL261 mouse models of glioblastoma. Taken together, this unbiased bioinformatic approach facilitated the discovery of a robust set of microglia and peripheral monocyte/macrophage expression markers to discriminate these monocyte populations in both health and disease.

Copyright information:

© The Author(s). 2019

This is an Open Access work distributed under the terms of the Creative Commons Attribution 4.0 International License (https://creativecommons.org/licenses/by/4.0/).
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