High-Resolution Transcriptomic and Proteomic Profiling of Heterogeneity of Brain-Derived Microglia in Multiple Sclerosis

Miedema, Anneke; Wijering, Marion Heleen Cathérine; Eggen, Bart J. L.; Kooistra, Susanne M.

doi:10.3389/fnmol.2020.583811

Cited by 18 publications

(10 citation statements)

References 166 publications

(273 reference statements)

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“…Together, this ensures that a positive signal within the cell truly represents a specific transcript of the decoded gene. Concerning sensitivity, Miedema et al reported smFISH to be one of the most sensitive spatial RNA detection methods and highly suitable for low abundance genes 46 , considering it to be the gold standard of spatial in-situ methods.…”

Section: Discussionmentioning

confidence: 99%

Highly resolved spatial transcriptomics for detection of rare events in cells

Groiss

Pabst

Faber³

et al. 2021

Preprint

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Single-cell spatial transcriptomics technologies leveraged the potential to transcriptionally landscape sophisticated reactions in cells. Current methods to delineate such complex interplay lack the flexibility in rapid target adaptation and are particularly restricted in detecting rare transcripts. We developed a multiplex single-cell RNA In-situ hybridization technique, called ‘Molecular Cartography’ (MC) that can be easily tailored to specific applications and, by providing unprecedented sensitivity, specificity and resolution, is particularly suitable in tracing rare events at a subcellular level. Using a SARS-CoV-2 infection model, MC allows the discernment of single events in host-pathogen interactions, dissects primary from secondary responses, and illustrates differences in antiviral signaling pathways affected by SARS-CoV-2, simultaneously in various cell types.

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Section: Discussionmentioning

confidence: 99%

Highly resolved spatial transcriptomics for detection of rare events in cells

Groiss

Pabst

Faber³

et al. 2021

Preprint

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“…Recent technological advances permitting analysis at the single-cell level (reviewed in Papalexi and Satija, 2018) have not only allowed for this distinction, but have also provided greater insight into the mechanisms underlying the vast cellular plasticity and heterogeneity of CNS-resident microglia (Masuda et al, 2019;Böttcher et al, 2020). These studies, which are reviewed extensively in Miedema et al (2020), provide additional evidence that discrete microglial subsets perform multiple, unique functions and contribute to MS/EAE disease pathogenesis through the temporal regulation of disease-and context-specific gene expression programs (Masuda et al, 2019;Böttcher et al, 2020).…”

Section: Microgliamentioning

confidence: 99%

Neuroinflammation in Autoimmune Disease and Primary Brain Tumors: The Quest for Striking the Right Balance

Mitchell

Shireman

Potchanant

et al. 2021

Front. Cell. Neurosci.

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According to classical dogma, the central nervous system (CNS) is defined as an immune privileged space. The basis of this theory was rooted in an incomplete understanding of the CNS microenvironment, however, recent advances such as the identification of resident dendritic cells (DC) in the brain and the presence of CNS lymphatics have deepened our understanding of the neuro-immune axis and revolutionized the field of neuroimmunology. It is now understood that many pathological conditions induce an immune response in the CNS, and that in many ways, the CNS is an immunologically distinct organ. Hyperactivity of neuro-immune axis can lead to primary neuroinflammatory diseases such as multiple sclerosis and antibody-mediated encephalitis, whereas immunosuppressive mechanisms promote the development and survival of primary brain tumors. On the therapeutic front, attempts are being made to target CNS pathologies using various forms of immunotherapy. One of the most actively investigated areas of CNS immunotherapy is for the treatment of glioblastoma (GBM), the most common primary brain tumor in adults. In this review, we provide an up to date overview of the neuro-immune axis in steady state and discuss the mechanisms underlying neuroinflammation in autoimmune neuroinflammatory disease as well as in the development and progression of brain tumors. In addition, we detail the current understanding of the interactions that characterize the primary brain tumor microenvironment and the implications of the neuro-immune axis on the development of successful therapeutic strategies for the treatment of CNS malignancies.

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“…Microglia are highly dependent on environmental signals to maintain their polarization. Given that such signals may vary across brain regions, it is notable that immune profiling of human brain microglia by single-cell proteomics revealed remarkable regional heterogeneity ( 185 ). Myeloid cells strategically located in close proximity to fenestrated blood vessels in the MBH may be able to sense metabolic factors including circulating lipids.…”

Section: Concluding Remarks and Future Perspectivesmentioning

confidence: 99%

Microglial Lipid Biology in the Hypothalamic Regulation of Metabolic Homeostasis

2021

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In mammals, myeloid cells help maintain the homeostasis of peripheral metabolic tissues, and their immunologic dysregulation contributes to the progression of obesity and associated metabolic disease. There is accumulating evidence that innate immune cells also serve as functional regulators within the mediobasal hypothalamus (MBH), a critical brain region controlling both energy and glucose homeostasis. Specifically, microglia, the resident parenchymal myeloid cells of the CNS, play important roles in brain physiology and pathology. Recent studies have revealed an expanding array of microglial functions beyond their established roles as immune sentinels, including roles in brain development, circuit refinement, and synaptic organization. We showed that microglia modulate MBH function by transmitting information resulting from excess nutrient consumption. For instance, microglia can sense the excessive consumption of saturated fats and instruct neurons within the MBH accordingly, leading to responsive alterations in energy balance. Interestingly, the recent emergence of high-resolution single-cell techniques has enabled specific microglial populations and phenotypes to be profiled in unprecedented detail. Such techniques have highlighted specific subsets of microglia notable for their capacity to regulate the expression of lipid metabolic genes, including lipoprotein lipase (LPL), apolipoprotein E (APOE) and Triggering Receptor Expressed on Myeloid Cells 2 (TREM2). The discovery of this transcriptional signature highlights microglial lipid metabolism as a determinant of brain health and disease pathogenesis, with intriguing implications for the treatment of brain disorders and potentially metabolic disease. Here we review our current understanding of how changes in microglial lipid metabolism could influence the hypothalamic control of systemic metabolism.

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High-Resolution Transcriptomic and Proteomic Profiling of Heterogeneity of Brain-Derived Microglia in Multiple Sclerosis

Cited by 18 publications

References 166 publications

Highly resolved spatial transcriptomics for detection of rare events in cells

Highly resolved spatial transcriptomics for detection of rare events in cells

Neuroinflammation in Autoimmune Disease and Primary Brain Tumors: The Quest for Striking the Right Balance

Microglial Lipid Biology in the Hypothalamic Regulation of Metabolic Homeostasis

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