Microglia and macrophages in brain homeostasis and disease

Nature reviews. Immunology, Journal Year: 2017, Volume and Issue: 18(4), P. 225 - 242

Published: Nov. 20, 2017

Language: Английский

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Microglia Biology: One Century of Evolving Concepts

Cell, Journal Year: 2019, Volume and Issue: 179(2), P. 292 - 311

Published: Oct. 1, 2019

Language: Английский

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Microglia innately develop within cerebral organoids

Nature Communications, Journal Year: 2018, Volume and Issue: 9(1)

Published: Oct. 3, 2018

Cerebral organoids are 3D stem cell-derived models that can be utilized to study the human brain. The current consensus is cerebral consist of cells derived from neuroectodermal lineage. This limits their value and applicability, as mesodermal-derived microglia important players in neural development disease. Remarkably, here we show innately develop within a organoid model display characteristic ramified morphology. transcriptome response inflammatory stimulation these organoid-grown closely mimic adult acutely isolated post mortem brain tissue. In addition, mediate phagocytosis synaptic material detected inside them. all, our characterizes microglia-containing represents valuable tool for studying interplay between microglia, macroglia, neurons

Language: Английский

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Modeling Alzheimer’s disease with iPSC-derived brain cells

Molecular Psychiatry, Journal Year: 2019, Volume and Issue: 25(1), P. 148 - 167

Published: Aug. 7, 2019

Alzheimer’s disease is a devastating neurodegenerative disorder with no cure. Countless promising therapeutics have shown efficacy in rodent models yet failed to benefit human patients. While hope remains that earlier intervention existing will improve outcomes, it becoming increasingly clear new approaches understand and combat the pathophysiology of are needed. Human induced pluripotent stem cell (iPSC) technologies changed face preclinical research iPSC-derived types being utilized study an array conditions, including disease. All major brain can now be differentiated from iPSCs, while complex co-culture systems developed facilitate neuroscience research. Many cellular functions perturbed recapitulated using cells vitro, platforms beginning yield insights into interactions occur between during neurodegeneration. Further, iPSC-based genome editing tools critical understanding roles numerous genes mutations found modify risk past decade. still their relative infancy, these developing hold considerable promise push forward efforts other disorders.

Language: Английский

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Development and validation of a simplified method to generate human microglia from pluripotent stem cells

Molecular Neurodegeneration, Journal Year: 2018, Volume and Issue: 13(1)

Published: Dec. 1, 2018

Microglia, the principle immune cells of brain, play important roles in neuronal development, homeostatic function and neurodegenerative disease. Recent genetic studies have further highlighted importance microglia neurodegeneration with identification disease risk polymorphisms many microglial genes. To better understand role these genes biology disease, we, others, developed methods to differentiate from human induced pluripotent stem (iPSCs). While development has begun enable new biology, labs little prior cell experience sometimes found it challenging adopt complex protocols. Therefore, we now a greatly simplified approach generate large numbers highly pure microglia. iPSCs are first differentiated toward mesodermal, hematopoietic lineage using commercially available media. Highly populations non-adherent CD43+ progenitors then simply transferred media that includes three key cytokines (M-CSF, IL-34, TGFβ-1) promote differentiation This updated avoids requirement for hypoxic incubation, formulation, FACS sorting, or co-culture, thereby significantly simplifying generation. confirm resulting equivalent previously iPSC-microglia, performed RNA-sequencing, functional testing, transplantation studies. Our findings reveal generated via this method virtually identical iPS-microglia produced our published approach. also determine whether small molecule activator TGFβ signaling (IDE1) can be used replace recombinant TGFβ1, reducing costs, examined growth kinetics transcriptome IDE1. These data demonstrate indeed alternative approach, although transcriptional differences do occur should considered. We anticipate protocol will interested labs, including those flow cytometry experience, study iPS-microglia. By combining other advances such as CRISPR-gene editing xenotransplantation, field continue improve understanding their homeostasis,

Language: Английский

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Microglia in Alzheimer Disease: Well-Known Targets and New Opportunities

Frontiers in Aging Neuroscience, Journal Year: 2019, Volume and Issue: 11

Published: Aug. 30, 2019

Microglia are the resident macrophages of central nervous system. They play key roles in brain development and physiology during life aging. Equipped with a variety molecular sensors through various functions they can fulfil, critically involved maintaining brain's homeostasis. In Alzheimer disease (AD), microglia reaction was initially thought to be incidental triggered by amyloid deposits dystrophic neurites. However, recent genome-wide association studies have established that majority AD risk loci found or near genes highly sometimes uniquely expressed microglia. This leads concept being early steps identified them as important potential therapeutic targets. Whether is beneficial, detrimental both progression still unclear subject intense debate. this review, we presenting state-of-knowledge report intended highlight microglial pathways shown progression. We first address acquisition new alteration their homeostatic reactive Second, propose summary parameters currently emerging field need considered identify relevant Finally, discuss many obstacles designing efficient strategies for present innovative technologies may foster our understanding pathology. Ultimately, work aims fly over make general reliable current knowledge regarding microglia's involvement research opportunities field.

Language: Английский

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The pro-remyelination properties of microglia in the central nervous system

Nature Reviews Neurology, Journal Year: 2019, Volume and Issue: 15(8), P. 447 - 458

Published: June 29, 2019

Language: Английский

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Microglia: Agents of the CNS Pro-Inflammatory Response

Cells, Journal Year: 2020, Volume and Issue: 9(7), P. 1717 - 1717

Published: July 17, 2020

The pro-inflammatory immune response driven by microglia is a key contributor to the pathogenesis of several neurodegenerative diseases. Though research spans over century, last two decades have increased our understanding exponentially. Here, we discuss phenotypic transformation from homeostatic towards reactive microglia, initiated specific ligand binding pattern recognition receptors including toll-like receptor-4 (TLR4) or triggering expressed on myeloid cells-2 (TREM2), as well signaling pathways triggered such caspase-mediated response. Additionally, new disciplines epigenetics and immunometabolism provided us with more holistic view how changes in DNA methylation, microRNAs, metabolome may influence This review aimed current knowledge different angles, recent highlights role exosomes spreading neuroinflammation emerging techniques positron emission tomography (PET) scanning use human generated induced pluripotent stem cells (iPSCs). Finally, also thoughts impact

Language: Английский

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Phagocytosis in the Brain: Homeostasis and Disease

Frontiers in Immunology, Journal Year: 2019, Volume and Issue: 10

Published: April 16, 2019

Microglia are resident macrophages of the central nervous system and significantly contribute to overall brain function by participating in phagocytosis during development, homeostasis, diseased states. Phagocytosis is a highly complex process that specialized for uptake removal opsonized non-opsonized targets, such as pathogens, apoptotic cells, cellular debris. While role mediating classical innate adaptive immune responses has been known decades, it now appreciated also critical throughout early neural initiating repair mechanisms. As such, modulating phagocytic processes provided unexplored avenues with intent developing novel therapeutics promote regeneration CNS. Here, we review functional consequences plays both healthy CNS, summarize how contributes pathophysiological mechanisms involved injury repair.

Language: Английский

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The Kaleidoscope of Microglial Phenotypes

Frontiers in Immunology, Journal Year: 2018, Volume and Issue: 9

Published: July 31, 2018

Gene expression analysis of microglia, the tissue-resident macrophages central nervous system, has led to identification homeostatic as well neurodegenerative disease-specific core gene signatures microglia phenotypes, driven by epigenetic mechanisms. Upon alterations in neural microenvironment, for instance during disease, can switch phenotypes- generally referred “microglia activation. Phenotypical switches due environmental changes be imagined different colorful crystal formations (microglia phenotypes) that change upon rotation (environmental changes) a kaleidoscope. In this review, we will discuss phenotypes relation neurodevelopment, homeostasis and diseases, based on transcriptome studies complexity microglial signature associated with multiple diseases.

Language: Английский

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