scholarly journals Microglia Diversity in Healthy and Diseased Brain: Insights from Single‐Cell Omics

2021 ◽  
Vol 22 (6) ◽  
pp. 3027
Author(s):  
Natalia Ochocka ◽  
Bozena Kaminska
Keyword(s):  
Single Cell ◽  
Immune Cells ◽  
Current State ◽  
Pathological Conditions ◽  
Cell Technologies ◽  
The Central Nervous System ◽  
Health And Disease ◽  
Definition Of ◽  
Context Specific ◽  
Peripheral Cells

Microglia are the resident immune cells of the central nervous system (CNS) that have distinct ontogeny from other tissue macrophages and play a pivotal role in health and disease. Microglia rapidly react to the changes in their microenvironment. This plasticity is attributed to the ability of microglia to adapt a context-specific phenotype. Numerous gene expression profiling studies of immunosorted CNS immune cells did not permit a clear dissection of their phenotypes, particularly in diseases when peripheral cells of the immune system come to play. Only recent advances in single-cell technologies allowed studying microglia at high resolution and revealed a spectrum of discrete states both under homeostatic and pathological conditions. Single-cell technologies such as single-cell RNA sequencing (scRNA-seq) and mass cytometry (Cytometry by Time-Of-Flight, CyTOF) enabled determining entire transcriptomes or the simultaneous quantification of >30 cellular parameters of thousands of individual cells. Single-cell omics studies demonstrated the unforeseen heterogeneity of microglia and immune infiltrates in brain pathologies: neurodegenerative disorders, stroke, depression, and brain tumors. We summarize the findings from those studies and the current state of knowledge of functional diversity of microglia under physiological and pathological conditions. A precise definition of microglia functions and phenotypes may be essential to design future immune-modulating therapies.

Immunology in the Era of Single-Cell Technologies

2020 ◽  
Vol 38 (1) ◽  
pp. 727-757 ◽  
Author(s):  
Mirjana Efremova ◽  
Roser Vento-Tormo ◽  
Jong-Eun Park ◽  
Sarah A. Teichmann ◽  
Kylie R. James
Keyword(s):  
Immune System ◽  
Single Cell ◽  
Immune Cells ◽  
The Body ◽  
Cell Technologies ◽  
Genomics And Proteomics ◽  
Health And Disease ◽  
The Many

Immune cells are characterized by diversity, specificity, plasticity, and adaptability—properties that enable them to contribute to homeostasis and respond specifically and dynamically to the many threats encountered by the body. Single-cell technologies, including the assessment of transcriptomics, genomics, and proteomics at the level of individual cells, are ideally suited to studying these properties of immune cells. In this review we discuss the benefits of adopting single-cell approaches in studying underappreciated qualities of immune cells and highlight examples where these technologies have been critical to advancing our understanding of the immune system in health and disease.

scholarly journals NCMP-05. DECODING THE IMMUNE SYSTEM RESPONSE TO LEPTOMENINGEAL METASTASIS

2020 ◽  
Vol 22 (Supplement_2) ◽  
pp. ii124-ii124
Author(s):  
Jan Remsik ◽  
Xinran Tong ◽  
Ugur Sener ◽  
Danille Isakov ◽  
Yudan Chi ◽  
...  
Keyword(s):  
Immune System ◽  
Immune Cells ◽  
Leptomeningeal Metastasis ◽  
System Response ◽  
Idle State ◽  
The Central Nervous System ◽  
Health And Disease ◽  
Immune System Response ◽  
Therapeutic Protocols ◽  
Brain And Spinal Cord

Abstract For decades, the central nervous system was considered to be an immune privileged organ with limited access to systemic immunity. However, the leptomeninges, the cerebrospinal fluid (CSF)-filled anatomical structure that protects the brain and spinal cord, represent a relatively immune-rich environment. Despite the presence of immune cells, complications in the CSF, such as infectious meningitis and a neurological development of cancer known as leptomeningeal metastasis, are difficult to treat and are frequently fatal. We show that immune cells entering the CSF are held in an ‘idle’ state that limits their cytotoxic arsenal and antigen presentation machinery. To understand this underappreciated neuroanatomic niche, we used unique mouse models and rare patient samples to characterize its cellular composition and critical signaling events in health and disease at a single-cell resolution. Revealing the mediators of CSF immune response will allow us to re-evaluate current therapeutic protocols and employ rational combinations with immunotherapies, therefore turning the patient’s own immune system into an active weapon against pathogens and cancer.

Investigating the tumor immune infiltrate for populations that predict immune-related adverse events (irAEs) in patients receiving PD-1 inhibitors.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 3116-3116
Author(s):  
Steven Michael Blum ◽  
Neal Smith ◽  
Moshe Sade-Feldman ◽  
Dennie T. Frederick ◽  
Russell William Jenkins ◽  
...  
Keyword(s):  
T Cell ◽  
Adverse Events ◽  
Single Cell ◽  
Immune Cells ◽  
Checkpoint Inhibitors ◽  
Advanced Melanoma ◽  
Cell Populations ◽  
Data Set ◽  
Systemic Immunosuppression ◽  
Definition Of

3116 Background: The mechanistic relationship between clinical benefit and immune-related adverse events (irAEs) in response to immune checkpoint inhibitors (ICIs) remains unclear, with several clinical studies reporting that irAEs are biomarkers of responses. Single-cell RNA sequencing (scRNAseq) analysis of tumors from patients with advanced melanoma before and after treatment with ICIs have identified immune cells that correlate with response to ICIs. We sought to evaluate if these populations were also associated with irAEs. Methods: A published scRNAseq data set generated with the Smart-Seq2 protocol (Sade-Feldman M, et al. Cell 2018.) was re-analyzed, stratified by two definitions of irAEs: (1) toxicity requiring systemic immunosuppression (prednisone > 10mg/day) or (2) systemic immunosuppression and/or endocrinopathy. Unbiased single-cell analysis was performed, followed by sub-clustering of T cell populations. The percentage of cells in each cluster was determined on a per sample basis. Results: 13,184 immune cells from 39 samples collected from 25 patients were re-analyzed. 27 samples were from patients who did not respond to ICIs, while 12 samples came from responding patients. 21 samples came from patients who required immunosuppression, 5 samples from patients with isolated thyroiditis, and 13 samples from patients who met neither irAE criteria. Unsupervised scRNAseq analyses focused on ICI efficacy re-capitulated published associations between response and populations that included B-cells (p < 0.01) and TCF7 expressing T-cells (p < 0.01). While these cell populations were not associated with either definition of toxicity, we observed a non-Treg CD4 expressing T cell population (0.8-10.5% cells/sample) that positively correlated with either definition of toxicity (p < 0.05) but not efficacy. Conclusions: In a patient cohort with advanced melanoma, tumor-infiltrating immune cell populations associated with response to ICI therapy were not associated with irAEs. This suggests that biomarkers of ICI response may not function as biomarkers of irAEs, and ongoing analysis will seek to validate this result. Understanding the differences between ICI response and irAEs may identify new therapeutic targets for maximizing efficacy while mitigating toxicity.

scholarly journals Microglia Heterogeneity in Alzheimer’s Disease: Insights From Single-Cell Technologies

2021 ◽  
Vol 13 ◽  
Author(s):  
Hansen Wang
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Single Cell ◽  
Current Knowledge ◽  
Cell Mass ◽  
Risk Genes ◽  
Functional Studies ◽  
Cell Technologies ◽  
The Central Nervous System ◽  
The Brain

Microglia are resident immune cells in the central nervous system and play critical roles in brain immunity, development, and homeostasis. The pathology of Alzheimer’s disease (AD) triggers activation of microglia. Microglia express many AD risk genes, suggesting that their response to AD pathology can affect disease progression. Microglia have long been considered a homogenous cell population. The diversity of microglia has gained great interest in recent years due to the emergence of novel single-cell technologies, such as single-cell/nucleus RNA sequencing and single-cell mass cytometry by time-of-flight. This review summarizes the current knowledge about the diversity/heterogeneity of microglia and distinct microglia states in the brain of both AD mouse models and patients, as revealed by single-cell technologies. It also discusses the future developments for application of single-cell technologies and the integration of these technologies with functional studies to further dissect microglia biology in AD. Defining the functional correlates of distinct microglia states will shed new light on the pathological roles of microglia and might uncover new relevant therapeutic targets for AD.

scholarly journals Cross-tissue single-cell transcriptomics reveals organizing principles of fibroblasts in health and disease

2021 ◽  
Author(s):  
Matthew B. Buechler ◽  
Rachana N. Pradhan ◽  
Aslihan Karabacak Calviello ◽  
Soren Muller ◽  
Richard Bourgon ◽  
...  
Keyword(s):  
Steady State ◽  
Single Cell ◽  
Human Cancer ◽  
Fibroblast Cell ◽  
Tissue Type ◽  
Perturbed State ◽  
Health And Disease ◽  
Definition Of ◽  
Lineage Structure ◽  
Organizing Principles

AbstractFibroblasts are non-hematopoietic structural cells that define the architecture of organs, support the homeostasis of tissue-resident cells and play key roles in fibrosis, cancer, autoimmunity and wound healing. Recent studies have described fibroblast heterogeneity within individual tissues. However, the field lacks a definition of fibroblasts at single-cell resolution across tissues in healthy and diseased organs. Here, we integrated single-cell RNA transcriptomic data from ~150,000 fibroblast cells derived from 16 steady- and 11 perturbed-state mouse organs into fibroblast atlases. These data revealed two universal fibroblast cell subtypes, marked by expression of Pi16 or Col15a1, in all tissues; it also revealed discrete subsets of five specialized fibroblast subtypes in steady-state tissues and three activated fibroblast subtypes in perturbed or diseased tissues. These subsets were transcriptionally shaped by microenvironmental context rather than tissue-type alone. Inference of fibroblast lineage structure from the murine steady-state and perturbed-state fibroblast atlases suggested that specialized and activated subtypes are developmentally related to universal tissue-resident fibroblasts. Analysis of human samples revealed that fibroblast subtypes found in mice are conserved between species, including universal fibroblasts and activated phenotypes associated with pathogenicity in human cancer, fibrosis, arthritis and inflammation. In sum, a cross-species and pan-tissue approach to transcriptomics at single-cell resolution enabled us to define the organizing principles of the fibroblast lineage in health and disease.

scholarly journals Single-cell transcriptomics to explore the immune system in health and disease

Science ◽  
2017 ◽  
Vol 358 (6359) ◽  
pp. 58-63 ◽  
Author(s):  
Michael J. T. Stubbington ◽  
Orit Rozenblatt-Rosen ◽  
Aviv Regev ◽  
Sarah A. Teichmann
Keyword(s):  
Immune System ◽  
Single Cell ◽  
Immune Cells ◽  
Cell Types ◽  
Massively Parallel ◽  
Antigen Receptors ◽  
Adaptive Immune ◽  
Adaptive Immune Cells ◽  
Health And Disease ◽  
Multiple Cell

The immune system varies in cell types, states, and locations. The complex networks, interactions, and responses of immune cells produce diverse cellular ecosystems composed of multiple cell types, accompanied by genetic diversity in antigen receptors. Within this ecosystem, innate and adaptive immune cells maintain and protect tissue function, integrity, and homeostasis upon changes in functional demands and diverse insults. Characterizing this inherent complexity requires studies at single-cell resolution. Recent advances such as massively parallel single-cell RNA sequencing and sophisticated computational methods are catalyzing a revolution in our understanding of immunology. Here we provide an overview of the state of single-cell genomics methods and an outlook on the use of single-cell techniques to decipher the adaptive and innate components of immunity.

scholarly journals Advances in single cell technologies in immunology

BioTechniques ◽  
2020 ◽  
Vol 69 (3) ◽  
pp. 226-236
Author(s):  
Jane Ru Choi
Keyword(s):  
Single Cell ◽  
Immune Cells ◽  
Immune Cell ◽  
Single Cell Level ◽  
Future Perspectives ◽  
Biological Mechanisms ◽  
Cell Level ◽  
Cell Responses ◽  
Physiological Processes ◽  
Cell Technologies

The immune system is composed of heterogeneous populations of immune cells that regulate physiological processes and protect organisms against diseases. Single cell technologies have been used to assess immune cell responses at the single cell level, which are crucial for identifying the causes of diseases and elucidating underlying biological mechanisms to facilitate medical therapy. In the present review we first discuss the most recent advances in the development of single cell technologies to investigate cell signaling, cell–cell interactions and cell migration. Each technology's advantages and limitations and its applications in immunology are subsequently reviewed. The latest progress toward commercialization, the remaining challenges and future perspectives for single cell technologies in immunology are also briefly discussed.

scholarly journals Functional immune cell–astrocyte interactions

2021 ◽  
Vol 218 (9) ◽  
Author(s):  
Liliana M. Sanmarco ◽  
Carolina M. Polonio ◽  
Michael A. Wheeler ◽  
Francisco J. Quintana
Keyword(s):  
Multiple Sclerosis ◽  
Immune Cells ◽  
Immune Cell ◽  
Neurological Diseases ◽  
Cell Types ◽  
Special Focus ◽  
Potential Value ◽  
The Central Nervous System ◽  
Health And Disease ◽  
Peripheral Immune Cells

Astrocytes are abundant glial cells in the central nervous system (CNS) that control multiple aspects of health and disease. Through their interactions with components of the blood–brain barrier (BBB), astrocytes not only regulate BBB function, they also sense molecules produced by peripheral immune cells, including cytokines. Here, we review the interactions between immune cells and astrocytes and their roles in health and neurological diseases, with a special focus on multiple sclerosis (MS). We highlight known pathways that participate in astrocyte crosstalk with microglia, NK cells, T cells, and other cell types; their contribution to the pathogenesis of neurological diseases; and their potential value as therapeutic targets.

scholarly journals Blood-Based Biomarkers of Neuroinflammation in Alzheimer’s Disease: A Central Role for Periphery?

Diagnostics ◽  
2021 ◽  
Vol 11 (9) ◽  
pp. 1525
Author(s):  
Federica Angiulli ◽  
Elisa Conti ◽  
Chiara Paola Zoia ◽  
Fulvio Da Re ◽  
Ildebrando Appollonio ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Immune Cells ◽  
Treatment Effectiveness ◽  
Neurodegenerative Disorder ◽  
Central Feature ◽  
The Central Nervous System ◽  
Peripheral Immune Cells ◽  
Peripheral Cells ◽  
The Brain

Neuroinflammation represents a central feature in the development of Alzheimer’s disease (AD). The resident innate immune cells of the brain are the principal players in neuroinflammation, and their activation leads to a defensive response aimed at promoting β-amyloid (Aβ) clearance. However, it is now widely accepted that the peripheral immune system—by virtue of a dysfunctional blood–brain barrier (BBB)—is involved in the pathogenesis and progression of AD; microglial and astrocytic activation leads to the release of chemokines able to recruit peripheral immune cells into the central nervous system (CNS); at the same time, cytokines released by peripheral cells are able to cross the BBB and act upon glial cells, modifying their phenotype. To successfully fight this neurodegenerative disorder, accurate and sensitive biomarkers are required to be used for implementing an early diagnosis, monitoring the disease progression and treatment effectiveness. Interestingly, as a result of the bidirectional communication between the brain and the periphery, the blood compartment ends up reflecting several pathological changes occurring in the AD brain and can represent an accessible source for such biomarkers. In this review, we provide an overview on some of the most promising peripheral biomarkers of neuroinflammation, discussing their pathogenic role in AD.

scholarly journals A Novel Tmem119-tdTomato Reporter Mouse Model for Studying Microglia in the Central Nervous System

2019 ◽  
Author(s):  
Chunsheng Ruan ◽  
Linlin Sun ◽  
Alexandra Kroshilina ◽  
Lien Beckers ◽  
Philip L. De Jager ◽  
...  
Keyword(s):  
Central Nervous System ◽  
Flow Cytometry ◽  
Nervous System ◽  
Mouse Model ◽  
Immune Cells ◽  
Exon 2 ◽  
Reporter Mouse ◽  
The Central Nervous System ◽  
Health And Disease

AbstractMicroglia are resident immune cells of the central nervous system (CNS). The exact role of microglia in the physiopathology of CNS disorders is not clear due to lack of tools to discriminate between CNS resident and infiltrated innate immune cells. Here, we present a novel reporter mouse model targeting a microglia-specific marker (TMEM119) for studying the function of microglia in health and disease. By placing a reporter cassette (GSG-3xFlag-P2A-tdTomato) between the coding sequence of exon 2 and 3’UTR of the Tmem119 gene using CRISPR/Cas9 technology, we generated a Tmem119-tdTomato knock-in mouse strain. Gene expression assay showed no difference of endogenous Tmem119 mRNA level in the CNS of Tmem119tdTomato/+ relative to control Wild-type mice. The cells expressing tdTomato-were recognized by immunofluorescence staining using commercially available anti-TMEM119 antibodies. Using immunofluorescence and flow cytometry techniques, tdTomato+ cells were detected throughout the CNS, but not in peripheral tissues of adult Tmem119tdTomato/+ mice. In addition, aging does not seem to influence TMEM119 expression as tdTomato+ cells were detectable in the CNS of older mice (300 and 540 days old). Further immunofluorescence characterization shows that the tdTomato+ cells were highly colocalized with Iba1+ cells (microglia and macrophages) in the brain, but not with NeuN- (neurons), GFAP- (astrocytes) or Olig2- (oligodendrocytes) labeled cells. Moreover, flow cytometry analysis of brain tissues of adult mice demonstrates that the majority of microglial CD45lowCD11b+ cells (96.6%) are tdTomato positive. Functionally, using a laser-induced injury model, we measured time-lapse activation of tdTomato-labeled microglia by transcranial two-photon microscopy in live Tmem119tdTomato/+ mice. Taken together, the Tmem119-tdTomato reporter mouse model will serve as a valuable tool to specifically study the role of microglia in health and disease.

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