Single‐cell transcriptomics reveals distinct inflammation‐induced microglia signatures

Sousa, Carole; Golebiewska, Anna; Poovathingal, Suresh; Kaoma, Tony; Pires‐Afonso, Yolanda; Martina, Silvia; Coowar, Djalil; Azuaje, Francisco; Skupin, Alexander; Balling, Rudi; Biber, Knut; Niclou, Simone P.; Michelucci, Alessandro

doi:10.15252/embr.201846171

Cited by 223 publications

(244 citation statements)

References 75 publications

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“…Also, a large overlap between cells and nuclei was observed both after PBS and LPS stimulation (Figure b). Upon LPS stimulation, microglia shift from a homeostatic to an activated state resulting in an activated microglia subpopulation (Sousa et al, ). To confirm the induction of a subset of activated microglia, we determined the expression of homeostatic and activated microglia marker genes reported previously (Keren‐Shaul et al, ; Sousa et al, ).…”

Section: Resultsmentioning

confidence: 99%

Transcriptional profiling of microglia; current state of the art and future perspectives

Gerrits

Heng

Boddeke

et al. 2019

Glia

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Microglia are the tissue macrophages of the central nervous system (CNS) and the first to respond to CNS dysfunction and disease. Gene expression profiling of microglia during development, under homeostatic conditions, and in the diseased CNS provided insight in microglia functions and changes thereof. Single‐cell sequencing studies further contributed to our understanding of microglia heterogeneity in relation to age, sex, and CNS disease. Recently, single nucleus gene expression profiling was performed on (frozen) CNS tissue. Transcriptomic profiling of CNS tissues by (single) nucleus RNA‐sequencing has the advantage that it can be applied to archived and well‐stratified frozen specimens. Here, we give an overview of the significant advances recently made in microglia transcriptional profiling. In addition, we present matched cellular and nuclear microglia RNA‐seq datasets we generated from mouse and human CNS tissue to compare cellular versus nuclear transcriptomes from fresh and frozen samples. We demonstrate that microglia can be similarly profiled with cell and nucleus profiling, and importantly also with nuclei isolated from frozen tissue. Nuclear microglia transcriptomes are a reliable proxy for cellular transcriptomes. Importantly, lipopolysaccharide‐induced changes in gene expression were conserved in the nuclear transcriptome. In addition, heterogeneity in microglia observed in fresh samples was similarly detected in frozen nuclei of the same donor. Together, these results show that microglia nuclear RNAs obtained from frozen CNS tissue are a reliable proxy for microglia gene expression and cellular heterogeneity and may prove an effective strategy to study of the role of microglia in neuropathology.

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Section: Resultsmentioning

confidence: 99%

Transcriptional profiling of microglia; current state of the art and future perspectives

Gerrits

Heng

Boddeke

et al. 2019

Glia

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show abstract

“…Microglia play vital roles in brain health and diseases. Depending on their cellular state, microglia exert distinct functions in different disease contexts (Sousa et al, ) and even in different stages of the same disease (Hamelin et al, ; Keren‐Shaul et al, ). Understanding the mechanisms of the transition between different microglia cellular states is essential for developing therapeutic approaches against neurodegenerative diseases.…”

Section: Discussionmentioning

confidence: 99%

NG2 glia are required for maintaining microglia homeostatic state

Liu

Aguzzi

2019

Glia

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Microglia play vital roles in the health and diseases of the central nervous system. Loss of microglia homeostatic state is a key feature of brain aging and neurodegeneration. However, the mechanisms underlying the maintenance of distinct microglia cellular states are largely unclear. Here, we show that NG2 glia, also known as oligodendrocyte precursor cells, are essential for maintaining the homeostatic microglia state. We developed a highly efficient and selective NG2 glia depletion method using small‐molecule inhibitors of platelet‐derived growth factor (PDGF) signaling in cultured brain slices. We found that loss of NG2 glia abolished the homeostatic microglia signature without affecting the disease‐associated microglia profiles. Similar findings were also observed in vivo by genetically depleting NG2 glia or conditionally inhibiting NG2 glia PDGF signaling in the adult mouse brain. These data suggest that NG2 glia exert a crucial influence onto microglia cellular states that are relevant to brain aging and neurodegenerative diseases. In addition, our results provide a powerful, convenient, and selective tool for the investigation of NG2 glia function.

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“…They first emerge during the first postnatal week, peaking at P5 and gradually decreasing as animals age, being barely detectable in the healthy adult CNS (33-35, 42, 80, 81) to increase again in aging or disease (33,73,81,85,89). Importantly, none of the studies that have investigated induction of inflammation by means of lipopolysaccharide, poly(I:C), or other immune challenges could recapitulate the robust CD11c+ signature found in steady state and disease and injury contexts (86,88,90,124,155,156). Below, we present factors that participate in controlling the induction of this population (Figure 4).…”

Section: Emergence Of Cd11c+ Microgliamentioning

confidence: 99%

Protective Microglial Subset in Development, Aging, and Disease: Lessons From Transcriptomic Studies

2020

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Microglial heterogeneity has been the topic of much discussion in the scientific community. Elucidation of their plasticity and adaptability to disease states triggered early efforts to characterize microglial subsets. Over time, their phenotypes, and later on their homeostatic signature, were revealed, through the use of increasingly advanced transcriptomic techniques. Recently, an increasing number of these "microglial signatures" have been reported in various homeostatic and disease contexts. Remarkably, many of these states show similar overlapping microglial gene expression patterns, both in homeostasis and in disease or injury. In this review, we integrate information from these studies, and we propose a unique subset, for which we introduce a core signature, based on our own research and reports from the literature. We describe that this subset is found in development and in normal aging as well as in diverse diseases. We discuss the functions of this subset as well as how it is induced.

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Single‐cell transcriptomics reveals distinct inflammation‐induced microglia signatures

Cited by 223 publications

References 75 publications

Transcriptional profiling of microglia; current state of the art and future perspectives

Transcriptional profiling of microglia; current state of the art and future perspectives

NG2 glia are required for maintaining microglia homeostatic state

Protective Microglial Subset in Development, Aging, and Disease: Lessons From Transcriptomic Studies

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