Human glioblastoma-associated microglia/monocytes express a distinct RNA profile compared to human control and murine samples.
Glioblastoma (GBM) is the most aggressive brain tumor in adults. It is strongly infiltrated by microglia and peripheral monocytes that support tumor growth. In the present study we used RNA sequencing to compare the expression profile of CD11b(+) human glioblastoma-associated microglia/monocytes (hGAMs) to CD11b(+) microglia isolated from non-tumor samples. Hierarchical clustering and principal component analysis showed a clear separation of the two sample groups and we identified 334 significantly regulated genes in hGAMs. In comparison to human control microglia hGAMs upregulated genes associated with mitotic cell cycle, cell migration, cell adhesion, and extracellular matrix organization. We validated the expression of several genes associated with extracellular matrix organization in samples of human control microglia, hGAMs, and the hGAMs-depleted fraction via qPCR. The comparison to murine GAMs (mGAMs) showed that both cell populations share a significant fraction of upregulated transcripts compared with their respective controls. These genes were mostly related to mitotic cell cycle. However, in contrast to murine cells, human GAMs did not upregulate genes associated to immune activation. Comparison of human and murine GAMs expression data to several data sets of in vitro-activated human macrophages and murine microglia showed that, in contrast to mGAMs, hGAMs share a smaller overlap to these data sets in general and in particular to cells activated by proinflammatory stimulation with LPS + INFγ or TNFα. Our findings provide new insights into the biology of human glioblastoma-associated microglia/monocytes and give detailed information about the validity of murine experimental models. GLIA 2016 GLIA 2016;64:1416-1436.
Department of Cellular Neurosciences, Max-Delbrueck-Center for Molecular Medicine in the Helmholtz Society, Berlin, Germany.|Department of Human Biology, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
Frank
F
Szulzewsky
Department of Human Biology, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
Sonali
S
Arora
Department of Psychiatry, Brain Center Rudolf Magnus, University Medical Center Utrecht, Utrecht, the Netherlands.
Lot
L
de Witte
Department of Genomics and Immunoregulation, Life and Medical Sciences Institute University of Bonn, Bonn, Germany.
Thomas
T
Ulas
Department of Cellular Neurosciences, Max-Delbrueck-Center for Molecular Medicine in the Helmholtz Society, Berlin, Germany.|Department of Neurosurgery, Helios Clinics, Berlin, Germany.
Darko
D
Markovic
Department of Genomics and Immunoregulation, Life and Medical Sciences Institute University of Bonn, Bonn, Germany.|Platform for Single Cell Genomics and Epigenomics at the German Center for Neurodegenerative Diseases and the University of Bonn, Bonn, Germany.
Joachim L
JL
Schultze
Department of Human Biology, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
Eric C
EC
Holland
Department of Cellular Neurosciences, Max-Delbrueck-Center for Molecular Medicine in the Helmholtz Society, Berlin, Germany.|Department of Neurosurgery, University Medical Center Schleswig-Holstein (UKSH), Kiel, Germany.
Michael
M
Synowitz
Department of Cellular Neurosciences, Max-Delbrueck-Center for Molecular Medicine in the Helmholtz Society, Berlin, Germany.
Susanne A
SA
Wolf
Department of Cellular Neurosciences, Max-Delbrueck-Center for Molecular Medicine in the Helmholtz Society, Berlin, Germany.
Helmut
H
Kettenmann
D000818:Animals; D001932:Brain Neoplasms / Q000378:metabolism*; D039481:CD11b Antigen / Q000378:metabolism; D019295:Computational Biology; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D005909:Glioblastoma / Q000378:metabolism*; D006801:Humans; D051379:Mice; D017628:Microglia / Q000378:metabolism*; D009000:Monocytes / Q000378:metabolism*; D060888:Real-Time Polymerase Chain Reaction; D017423:Sequence Analysis, RNA; D059467:Transcriptome
D039481:CD11b Antigen; C509295:ITGAM protein, human
RNA sequencing; glioblastoma; glioma; macrophage; microglia; monocyte