Mapping microglia states in the human brain through the integration of high-dimensional techniques

Sankowski, Roman; Böttcher, Chotima; Masuda, Takahiro; Geirsdóttir, Laufey; Sagar,; Sindram, Elena; Seredenina, Tamara; Muhs, Andreas; Scheiwe, Christian; Shah, Mukesch; Heiland, Dieter Henrik; Schnell, Oliver; Grün, Dominic; Priller, Josef; Prinz, Marco

doi:10.1038/s41593-019-0532-y

Cited by 349 publications

(434 citation statements)

References 63 publications

(140 reference statements)

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“…S1H, J, S2B). This expression pattern has been recently reported in early postnatal mouse brain, and shown to be associated with proliferative zones (13) and white matter (4,26,27). This cluster was found across all stages of development and all brain regions ( Fig 1D-E).…”

Section: Introductionsupporting

confidence: 83%

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Human microglia upregulate cytokine signatures and accelerate maturation of neural networks

Schmunk

et al. 2020

Preprint

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Microglia are the resident macrophages of the brain that emerge in early development and play vital role disease states, as well as in normal development. Many fundamental questions about microglia diversity and function during human brain development remain unanswered, as we currently lack cellular-resolution datasets focusing on microglia in developing primary tissue, or experimental strategies for interrogating their function. Here, we report an integrative analysis of microglia throughout human brain development, which reveals molecular signatures of stepwise maturation, as well as human-specific cytokine-associated subtype that emerges around the onset of neurogenesis. To demonstrate the utility of this atlas, we have compared microglia across several culture models, including cultured primary microglia, pluripotent stem cell-derived microglia. We identify gene expression signatures differentially recruited and attenuated across experimental models, which will accelerate functional characterization of microglia across perturbations, species, and disease conditions. Finally, we identify a role for human microglia in development of synchronized network activity using a xenotransplantation model of human microglia into cerebral organoids.

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Section: Introductionsupporting

confidence: 83%

“…We also identified cluster 4 that was enriched for genes involved in cytokine signaling, CCL2, CCL4, CCL4L2, TNF and IL1B (4,28), and human immunodeficiency virus entry cofactor CXCR4 (29) ( Fig. 1B-G,figs.…”

Section: Introductionmentioning

confidence: 97%

Human microglia upregulate cytokine signatures and accelerate maturation of neural networks

Schmunk

et al. 2020

Preprint

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“…In IDH-wildtype gliomas, it has been very recently shown that TAMs acquire a disease-associated signature related to aging microglia programs, including downregulation of the microglia homeostatic genes and upregulation of inflammatory, metabolic and interferon-associated genes. Various TAM clusters, including subsets enriched for positive regulation of vasculature development or antigen processing via MHC class I, have been identified [78] (Figure 1). Taken together, TAMs heterogeneity in glioma is currently emerging and should be taken into account when designing therapeutic approaches based on specific GBM features.…”

Section: Single-cell Analyses Of Microglia and Macrophages In Glioblamentioning

confidence: 99%

Revealing and Harnessing Tumour-Associated Microglia/Macrophage Heterogeneity in Glioblastoma

Pires‐Afonso

Niclou

Michelucci

2020

IJMS

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Cancer heterogeneity and progression are subject to complex interactions between neoplastic cells and their microenvironment, including the immune system. Although glioblastomas (GBMs) are classified as ‘cold tumours’ with very little lymphocyte infiltration, they can contain up to 30–40% of tumour-associated macrophages, reported to contribute to a supportive microenvironment that facilitates tumour proliferation, survival and migration. In GBM, tumour-associated macrophages comprise either resident parenchymal microglia, perivascular macrophages or peripheral monocyte-derived cells. They are recruited by GBMs and in turn release growth factors and cytokines that affect the tumour. Notably, tumour-associated microglia/macrophages (TAMs) acquire different expression programs, which shape the tumour microenvironment and contribute to GBM molecular subtyping. Further, emerging evidence highlights that TAM programs may adapt to specific tumour features and landscapes. Here, we review key evidence describing TAM transcriptional and functional heterogeneity in GBM. We propose that unravelling the intricate complexity and diversity of the myeloid compartment as well as understanding how different TAM subsets may affect tumour progression will possibly pave the way to new immune therapeutic avenues for GBM patients.

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“…Characteristic gene expression markers were employed to assign cellular identities to each cluster of myeloid populations in blood (Figure 5A) and CSF (Figure 5B). Recent studies identified myeloid cells within the CSF using scRNA-seq that resembled microglia 11,[32][33][34] , which are characterized by the expression of signature genes including CX3CR1, CSF1R, SLC2A5, MARCKS, and P2RY13 [35][36][37] .…”

Section: And Csf By Transcriptomic Profilingmentioning

confidence: 99%

CD11c⁺CD88⁺CD317⁺myeloid cells are critical mediators of persistent CNS autoimmunity

Manouchehri

Hussain

Cravens

et al. 2020

Preprint

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BackgroundNatalizumab, a humanized monoclonal antibody (mAb) against α4-integrin, reduces the number of dendritic cells (DC) in cerebral perivascular spaces in multiple sclerosis (MS). Selective deletion of α4-integrin in CD11c+ cells should curtail their migration to the CNS and ameliorate experimental autoimmune encephalomyelitis (EAE).MethodsWe generated CD11c.Cre+/-ITGA4fl/fl C57/Bl6 mice to selectively delete α4-integrin in CD11c+ cells. Active immunization and adoptive transfer EAE models were employed. Multi-parameter flow cytometry was utilized to immunophenotype leukocytes. Single-cell RNA sequencing (scRNA-seq) was used to profile individual cells.Resultsα4-integrin expression by CD11c+ cells was significantly reduced in primary and secondary lymphoid organs in CD11c.Cre+/-ITGA4fl/fl mice. In active EAE, a delayed disease onset was observed in CD11c.Cre+/-ITGA4fl/fl mice, during which CD11c+CD88+ cells were sequestered in the blood. Upon EAE onset, CD11c+CD88+ cells accumulated in the CNS and expressed CD317+. In adoptive transfer experiments, CD11c.Cre+/-ITGA4fl/fl mice had ameliorated clinical disease associated with diminished numbers of CNS CD11c+CD88+CD317+ cells. The transcription profile of CD11c+CD88+CD317+ cells placed them within previously defined microglia-like cells in human CSF. We show that activated, but not naïve microglia expressed CD11c, CD88, and CD317. Finally, anti-CD317 treatment prior to clinical EAE substantially enhanced recovery.ConclusionCD11c+CD88+CD317+ cells in the CNS promote inflammatory damage. Transcriptional analysis identifies CD11c+CD88+CD317+ cells as a unique myeloid subset in human CSF. The disease-propagating effects of these cells can be antagonized using anti-CD317 mAb.

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Mapping microglia states in the human brain through the integration of high-dimensional techniques

Cited by 349 publications

References 63 publications

Human microglia upregulate cytokine signatures and accelerate maturation of neural networks

Human microglia upregulate cytokine signatures and accelerate maturation of neural networks

Revealing and Harnessing Tumour-Associated Microglia/Macrophage Heterogeneity in Glioblastoma

CD11c⁺CD88⁺CD317⁺myeloid cells are critical mediators of persistent CNS autoimmunity

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Mapping microglia states in the human brain through the integration of high-dimensional techniques

Cited by 349 publications

References 63 publications

Human microglia upregulate cytokine signatures and accelerate maturation of neural networks

Human microglia upregulate cytokine signatures and accelerate maturation of neural networks

Revealing and Harnessing Tumour-Associated Microglia/Macrophage Heterogeneity in Glioblastoma

CD11c+CD88+CD317+myeloid cells are critical mediators of persistent CNS autoimmunity

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CD11c⁺CD88⁺CD317⁺myeloid cells are critical mediators of persistent CNS autoimmunity