A Combination of Ontogeny and CNS Environment Establishes Microglial Identity

Neuron, Journal Year: 2018, Volume and Issue: 98(6), P. 1170 - 1183.e8

Published: June 1, 2018

Language: Английский

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A transcriptomic atlas of aged human microglia

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

Published: Feb. 1, 2018

With a rapidly aging global human population, finding cure for late onset neurodegenerative diseases has become an urgent enterprise. However, these efforts are hindered by the lack of understanding what constitutes phenotype aged microglia-the cell type that been strongly implicated genetic studies in pathogenesis age-related disease. Here, we establish set genes is preferentially expressed microglia brain. This HuMi_Aged gene captures unique phenotype, which confirm at protein level. Furthermore, find this to be enriched susceptibility Alzheimer's disease and multiple sclerosis, increased with advancing age, reduced protective APOEε2 haplotype. APOEε4 no effect. These findings existence aging-related microglial brain its involvement pathological processes associated aging.

Language: Английский

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Determinants of Resident Tissue Macrophage Identity and Function

Immunity, Journal Year: 2020, Volume and Issue: 52(6), P. 957 - 970

Published: June 1, 2020

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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Microglia and Central Nervous System–Associated Macrophages—From Origin to Disease Modulation

Annual Review of Immunology, Journal Year: 2021, Volume and Issue: 39(1), P. 251 - 277

Published: Feb. 9, 2021

The immune system of the central nervous (CNS) consists primarily innate cells. These are highly specialized macrophages found either in parenchyma, called microglia, or at CNS interfaces, such as leptomeningeal, perivascular, and choroid plexus macrophages. While they were thought phagocytes, their function extends well beyond simple removal cell debris during development diseases. Brain-resident cells to be plastic, long-lived, host an outstanding number risk genes for multiple pathologies. As a result, now considered most suitable targets modulating Additionally, recent single-cell technologies enhanced our molecular understanding origins, fates, interactomes, functional statesduring health perturbation. Here, we review current state challenges myeloid biology treatment options related

Language: Английский

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Microglia and Monocytes/Macrophages Polarization Reveal Novel Therapeutic Mechanism against Stroke

International Journal of Molecular Sciences, Journal Year: 2017, Volume and Issue: 18(10), P. 2135 - 2135

Published: Oct. 13, 2017

Stroke is a leading cause of morbidity and mortality worldwide, consists two types, ischemic hemorrhagic. Currently, there no effective treatment to increase the survival rate or improve quality life after hemorrhagic stroke in subacute chronic phases. Therefore, it necessary establish therapeutic strategies facilitate functional recovery patients with during both Cell-based therapies, using microglia monocytes/macrophages preconditioned by optimal stimuli and/or any therapies targeting these cells, might be an ideal strategy for managing stroke. Microglia polarize classic pro-inflammatory type (M1-like) alternative protective (M2-like) condition. M2-like against three reasons. First, monocytes/monocytes secrete remodeling factors, thus prompting neuronal network via tissue (including neuronal) vascular remodeling. Second, cells could migrate injured hemisphere through blood–brain barrier choroid–plexus. Third, mitigate extent inflammation-induced injuries suitable timing intervention. Although future translational studies are required, attractive based on their functions.

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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Development of a Chimeric Model to Study and Manipulate Human Microglia In Vivo

Neuron, Journal Year: 2019, Volume and Issue: 103(6), P. 1016 - 1033.e10

Published: July 30, 2019

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 complexity of tau in Alzheimer’s disease

Neuroscience Letters, Journal Year: 2019, Volume and Issue: 705, P. 183 - 194

Published: April 25, 2019

Language: Английский

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