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Spatial Transcriptomics correlated Electron Microscopy [MERFISH]

ABSTRACT: Current spatial transcriptomics methods provide molecular and spatial information but no morphological readout. Here, we present STEM - a method that correlates multiplexed error-robust FISH with electron microscopy from neighboring tissue sections of the same sample. STEM links transcriptional and spatial organization of single cells with ultrastructural morphology of the tissue in vivo. Using STEM to characterize demyelinated white-matter lesions allowed us to link morphology of myelin-laden foamy microglia to transcriptional signature. Moreover, we revealed that interferon-response microglia have unique morphology and are enriched near CD8 T-cells.

ORGANISM(S): Mus musculus synthetic construct

PROVIDER: GSE202623 | GEO | 2023/06/21

REPOSITORIES: GEO

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Spatial Transcriptomics correlated Electron Microscopy [scRNA-Seq]

Project description:Current spatial transcriptomics methods identify cell types and states in a spatial context but lack morphological information. Electron microscopy, in contrast, provides structural details at nanometer resolution without decoding the diverse cellular states and identity. STEM address this limitation by correlating multiplexed error-robust FISH with electron microscopy from adjacent tissue sections. Using STEM to characterize demyelinated lesions in mice, we were able to bridge spatially resolved transcriptional data with morphological information on cell identities. This approach allowed us to link the morphology of foamy microglia and interferon-response microglia with their transcriptional signatures.

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Spatial Transcriptomics correlated Electron Microscopy

Project description:This SuperSeries is composed of the SubSeries listed below.

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Gene expression profiling of myelin-phagocytosing macrophages

Project description:Multiple sclerosis is a chronic, inflammatory, demyelinating disease of the central nervous system in which macrophages and microglia play a central role. During active multiple sclerosis foamy macrophages and microglia, containing degenerated myelin, are abundantly found in demyelinated areas. Recent studies have described an altered macrophage phenotype after myelin internalization. However, by which mechanisms myelin affects the phenotype of macrophages and how this phenotype can influence lesion progression is unclear. Here we demonstrate, by using genome wide gene expression analysis, that myelin-phagocytosing macrophages have an enhanced expression of genes in pathways involved in migration, phagocytosis and inflammation. More interestingly, we show that myelin internalization induces the expression of genes involved in liver X receptor signaling and cholesterol efflux. In vitro validation shows that myelin-phagocytosing macrophages indeed have an increased capacity to dispose intracellular cholesterol. Additionally, myelin suppresses the production of pro-inflammatory mediators, like nitric oxide and IL-6, by macrophages in a similar manner as a liver X receptor agonist. Our data show that myelin modulates the phenotype of macrophages by nuclear receptor activation, which may subsequently affect lesion progression in multiple sclerosis. Rat peritoneal macrophages were left untreated (n=5) or treated with isolated myelin (n=5) for 3 days. Both untreated and myelin-treated macrophages were subsequently stimulated with IFNM-RM-/ and IL1-M-NM-2 for 9 hours.

2012-08-20 | E-GEOD-34811 | biostudies-arrayexpress

PI3K signaling promotes formation of lipid-laden foamy macrophages at the spinal cord injury site

Project description:After spinal cord injury (SCI), infiltrating macrophages undergo excessive phagocytosis of myelin and cellular debris, forming lipid-laden foamy macrophages. To understand their role in the cellular pathology of SCI, investigation of foamy macrophage phenotype in vitro revealed a unique inflammatory profile, increased reactive oxygen species (ROS) production, and mitochondrialdysfunction. Bioinformatic analysis identified PI3K as a regulator of inflammation in foamy macrophages, and pharmacological inhibition of this pathway decreased lipid content and inflammatory cytokine and ROS production in these cells. Macrophage-specific inhibition of PI3K using liposomes significantly decreased foamy macrophages at the injury site after a mid-thoracic contusive SCI in mice. RNA sequencing and in vitro analysis of foamy macrophages revealed increased autophagy after PI3K inhibition as a potential mechanism for reduced cellular lipid accumulation. Together, our data suggest that formation of pro-inflammatory foamy macrophages after SCI is due to activation of PI3K signaling that leads to decreased autophagy.

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Macrophage Scavenger Receptor 1 mediates lipid-induced inflammation in non-alcoholic fatty liver disease

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Multiplexed imaging of high-density libraries of RNAs with MERFISH and expansion microscopy.

Project description: Not available

| S-EPMC5859009 | biostudies-literature

Spatiotemporal trajectory analysis and validation of microglia activation in traumatic brain injury

Project description:Spatial transcriptomics (ST) is an innovative technology that holds tremendous potential for transforming the field of tissue biology research. By simultaneously capturing multiple types of spatial data, including gene expression values, spatial distance information, and tissue morphology, ST enables a comprehensive understanding of biological samples. However, the effective integration of these diverse data types remains a challenge. In this study, we present stLearn, a collection of three computational-statistical algorithms specifically designed to exploit the combined power of gene expression, spatial distance, and tissue morphology data. Our aim is to unlock novel insights into tissue maintenance, development, and disease. The first algorithm, known as pseudo-time-space (PSTS), employs a spatial-graph-based approach to uncover the spatial relationships between cells' transcriptional states in dynamic tissue contexts. To demonstrate the effectiveness of stLearn, we utilize traumatic brain injury datasets to investigate the spatio-temporal dynamics of microglia activation. By applying the PSTS algorithm to a well-established mouse model of acquired brain injury, we successfully reconstruct the spatial trajectory of microglia activation following insult, thereby validating this key component of stLearn.

2023-07-03 | GSE236171 | GEO

Gene expression profiling of myelin-phagocytosing macrophages

2012-08-20 | GSE34811 | GEO

Single-cell RNA-seq of rat microglia in monoculture and in coculture with neurons and astrocytes

Project description:Microglia, brain resident macrophages, require instruction from the central nervous system microenvironment to maintain their identity, morphology, and to regulate inflammatory responses. We investigated the heterogeneity of response of microglia to the presence of neurons and astrocytes by performing single-cell sequencing of microglia in both monoculture, and in coculture with neurons and astrocytes.

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