Identification of region-specific astrocyte subtypes at single cell resolution

Nature Communications, Год журнала: 2020, Номер 11(1)

Опубликована: Март 5, 2020

Abstract Astrocytes, a major cell type found throughout the central nervous system, have general roles in modulation of synapse formation and synaptic transmission, blood–brain barrier formation, regulation blood flow, as well metabolic support other brain resident cells. Crucially, emerging evidence shows specific adaptations astrocyte-encoded functions regions, such spinal cord cerebellum. To investigate true extent astrocyte molecular diversity across forebrain we used single-cell RNA sequencing. Our analysis identifies five transcriptomically distinct subtypes adult mouse cortex hippocampus. Validation our data situ reveals spatial positioning defined subtypes, reflecting distribution morphologically physiologically populations. findings are for specialized between within regions. The available through an online database ( https://holt-sc.glialab.org/ ), providing resource on which to base explorations local function brain.

Язык: Английский

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Astrocyte Reactivity: Subtypes, States, and Functions in CNS Innate Immunity

Trends in Immunology, Год журнала: 2020, Номер 41(9), С. 758 - 770

Опубликована: Авг. 17, 2020

Astrocytes are neural parenchymal cells that ubiquitously tile the central nervous system (CNS). In addition to playing essential roles in healthy tissue, astrocytes exhibit an evolutionarily ancient response all CNS insults, referred as astrocyte reactivity. Long regarded passive and homogeneous, reactivity is being revealed a heterogeneous functionally powerful component of mammalian innate immunity. Nevertheless, concepts about what comprises it does incomplete sometimes controversial. This review discusses goal differentiating reactive subtypes states based on composite pictures molecular expression, cell morphology, cellular interactions, proliferative state, normal functions, disease-induced dysfunctions. A working model conceptual framework presented for characterizing diversity

Язык: Английский

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Neuroinfection may contribute to pathophysiology and clinical manifestations of COVID‐19

Acta Physiologica, Год журнала: 2020, Номер 229(3)

Опубликована: Март 29, 2020

The new coronavirus, classified as severe acute respiratory syndrome (SARS)-CoV-2 that emerged in Hubei province China, causes a coronavirus disease, which was termed COVID-19 by WHO on 11 February 2020. claimed more than 65 000 lives around the world 5th of April It is not first infects humans; pathogenic viruses cause human diseases (human coronaviruses, HCoV) include 6 other members designated SARS-CoV, middle east (MERS)-CoV, HCoV-HKU1, HCoV-NL63, HCoV-OC43 and HCoV-229E. clinical presentation mainly manifested malignant pneumonia; although many patients present neurological symptoms, such vomiting, dizziness, headache delirium.1 Human coronaviruses were identified mid-1960s; they named for crown-like spikes their surface. SARS-CoV-2 virus belongs to β-coronavirus, also MERS-CoV, SARS-CoV-1, NCoV-OC43 HCoV-HKU1. primary target cells are epithelial gastrointestinal tract, contain angiotensin converting enzyme 2 (ACE2), utilized enter cell; it is, however, hard believe penetration viral agent into organism limited only these tissues.2 Clinical pre-clinical data from studies with suggest wider tissue invasiveness an evident neurotropism, may result complex scenarios. Can central nervous system (CNS) infect neural cells? And if yes, how CNS damage contributes pathophysiology COVID-19, its signs, symptoms progression well sequelae. In words, had significant could presence be pathophysiologically relevant? has been demonstrated especially β-coronaviruses belongs, do limit tract frequently invade CNS. This propensity convincingly documented MERS-CoV responsible porcine haemagglutinating encephalomyelitis (HEV 67N).3-5 Previous findings demonstrate ACE2 represents key, but exclusive, site entry cell. expressed brain, being particularly brain stem regions regulation cardiovascular function including subfornical organ, paraventricular nucleus, nucleus tractus solitarius, rostral ventrolateral medulla; expression found both neurones glia.6, 7 Non-ACE2 pathways infection cannot excluded; marked liver, organ lower levels ACE compared CNS, strongly supports assumption cell routes can vary.8 Be this all may, have reported2 SARS-CoV-1 tissues obtained infected patients.9 intranasal administration SARS-CoV-110 or MERS-COV11 resulted rapid invasion particles possibly through olfactory bulb via trans-synaptic route. pathway when enters peripheral nerves spreads synaptic contacts well-documented several CoVs.12 brainstem, hosts neuronal circuit medulla, severely types viruses, contribute degradation failure centres. When nasal infecting charges delivered extremely low doses, colonized, absent lungs,11 corroborating potent neurotropism coronarovirus strains. testifies property ignored complete understanding impact organism. Although direct evidence currently lacking, high identity between suggests, latter strain ability clearly family belong. β-coronavirus NCoV-OC43, upper disorder, lines culture; encephalitis associated apoptosis necrosis mice.13 At least two cases encephalitis/encepahlomyelitis caused reported.14, 15 About 12% children hospitalised at Children's Hospital Chenzhou, China May 2014 2015 anti-CoV antibodies serum cerebrospinal fluid.16 considerable interest distribution shown cerebrum, cerebellum.17 These parts exhibit distinct ratios neuroglia; neocortex number non-neuronal (most represented neuroglia) almost four times larger neurones, whereas cerebellum account ~90% cells.18 Upon because forms neuroglial become reactive, representing most classic neuropathological scenario ongoing neuroinflammation. Therefore, possible triggers reactive astrogliosis activation microglia. framework, learned Tick-borne (TBEV) Zika (ZIKV), predicts strong role astrocytes microglia orchestrating response neuroinfection spread brain. One fundamental events pathogen crossing blood-brain barrier (BBB). Astrocytes form parenchymal portion BBB endfeet, extensively plaster (~98% coverage) intracranial blood vessels. grey mater occupy separate territorial domains integrate elements vasculature forming neurovascular unit.19 Both TBEV ZIKV belong Flaviviridae family, endocytosis20, 21 thus instigating neuroinfection. Internalization mediated clathrin-dependent endocytosis known West Nile virus, Dengue Hepatitis C Bovine Viral Diarrhoea virus.21 Whether SARS-Co-V2 astroglial remains studied, interneuronal transfer another HEV67 utilises endocytotic/exocytotic pathway.4 rodent no detrimental effect viability hence likely represent reservoir where further re-infection occur. Once within cell, traffic different compartments. astroglia uses endosomal cytoplasm.22 virus-loaded vesicles exhibits directional mobility, driven protein motors carrying along cytoskeletal elements, microtubules, actin intermediate filaments. On hand, non-directional characterized randomness free diffusion. As time, there series virus-infected cells, leading increased per astrocytes, pronounced increase particle mobility.22 Similar infiltration TBEV, recently confirmed mechanism microglia.23 Among susceptible released progeny tolerated higher loads neurones.20 occurrence affect chemosensing centre damaging ventilatory lung function. Further support hypothesis route organism, provided observations early profound anosmia subjects (Ear, Nose Throat surgery society, ENT UK; https://www.entuk.org/sites/default/files/files/LossofsenseofsmellasmarkerofCOVID.pdf). Another aspect SARS CoV2 substantial systemic inflammatory storm massive release cytokines, chemokines, inflammation signals subsequent break BBB, instigates amplifies neuroinflammatory process. Numerous preclinical consistently inflammation, regardless nature, bacterial, toxic, compromises injures glia limitans, activates Toll-like receptors residing innate immunity, ultimately promoting neuroinflammation disturb homeostasis death.24 process functional explain experience according even who overcome pneumonia, onset cognitive impairment behavioural changes observed. Delirium deficits abnormalities situation conditions prolonged hypoxia induces persistent uncontrolled neuroinflammation—responsible, turn, hippocampus cortical areas functions alterations.25 Elderly recovering pneumonia often delirium attention memory persist over time require treatment, remarkably demanding. commonly provoked inflammation. Elevated concentrations pro-interleukins S100B, (recognized index disruption), observed during elderly patients.26 Neuroinflammation appears obligatory component neurodegenerative disorders27 implicated psychiatric pathologies psychosis schizophrenia, autism spectrum affective disorders name few.28 There association depressive syndromes infections rising risk episodes ~60%.28 animal models, injections cytokines sickness behaviour29; very similar "flu-like syndrome" anhedonia, anorexia, fever, fatigue, pain, sleep disturbances, confusion. Furthermore, accompanying long-lasting hypoxia, arguably affects neurocognitive alterations. To conclude: neurotropic, exception; routes, notably inoculation though using pathways. Coronaviruses express ACE2, endocytotic (similar those ZIKA viruses) excluded. Coronavirueses predominantly nuclei cardio-respiratory control; injuries exacerbate lead failure. Direct together accompanies promote neuropsychiatric developments impairments chronic. aspects attack must therefore considered designing therapeutic strategies rehabilitation paradigms aimed victims SARS-CoV-2. No conflict declare.

Язык: Английский

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Astrocyte Heterogeneity: Impact to Brain Aging and Disease

Frontiers in Aging Neuroscience, Год журнала: 2019, Номер 11

Опубликована: Март 19, 2019

Astrocytes, one of the largest glial cell population in Central Nervous System, play key function several events brain development and function, such as synapse formation control neurotransmitters release uptake, production trophic factors neuronal survival. Initially described a homogenous population, evidences have pointed that astrocytes are highly heterogeneous, both morphologically functionally, within same region, across different regions. Recent findings suggest heterogeneity expression profile proteins involved astrocyte may predict selective vulnerability regions to specific diseases, well age-related cognitive decline. However, molecular mechanisms underlying these changes, either aging disease scarce. Neuroinflammation, hallmark neurodegenerative diseases aging, is reported dubious impact on activation, cells pro- anti-inflammatory cytokines chemokines, anti-oxidants, free radicals, neurotrophic factors. Despite emerging evidence supporting reactive duality their phenotype, neurotoxic or neuroprotective properties, depending age stimuli, cellular interplays regional still matter discussion. In this review, we will summarize recent phenotypes, likely for during neural diseases. We focus molecules triggered by Finally, discuss new how modulation phenotype could synaptic deficits dysfunction present pathological states.

Язык: Английский

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Interaction between Aβ and Tau in the Pathogenesis of Alzheimer's Disease

International Journal of Biological Sciences, Год журнала: 2021, Номер 17(9), С. 2181 - 2192

Опубликована: Янв. 1, 2021

Extracellular neuritic plaques composed of amyloid‑β (Aβ) protein and intracellular neurofibrillary tangles containing phosphorylated tau are the two hallmark proteins Alzheimer's disease (AD), separate neurotoxicity these in AD has been extensively studied. However, interventions that target Aβ or individually have not yielded substantial breakthroughs. The interest interactions between is increasing, but related drug investigations their infancy. This review discusses how accelerates phosphorylation possible mechanisms pathways by which mediates toxicity. also describes synergistic effects on microglial cells astrocytes. Studies suggest coexistence to mechanism facilitates propagation aggregation plaques. mediate cognitive dysfunction patients with AD. In summary, this summarizes recent data interplay promote a better understanding roles pathological process provide new insights into against

Язык: Английский

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Emerging importance of satellite glia in nervous system function and dysfunction

Nature reviews. Neuroscience, Год журнала: 2020, Номер 21(9), С. 485 - 498

Опубликована: Июль 22, 2020

Satellite glial cells (SGCs) closely envelop cell bodies of neurons in sensory, sympathetic and parasympathetic ganglia. This unique organization is not found elsewhere the nervous system. SGCs sensory ganglia are activated by numerous types nerve injury inflammation. The activation includes upregulation fibrillary acidic protein, stronger gap junction-mediated SGC-SGC neuron-SGC coupling, increased sensitivity to ATP, downregulation Kir4.1 potassium channels cytokine synthesis release. There evidence that these changes contribute chronic pain augmenting neuronal activity consistent various rodent models likely also human pain. Therefore, understanding resulting abnormal interactions with could provide a mechanistic approach might be exploited therapeutically alleviation prevention We describe how altered four common pain: systemic inflammation (sickness behaviour), post-surgical pain, diabetic neuropathic post-herpetic

Язык: Английский

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The role of astrocytes in oxidative stress of central nervous system: A mixed blessing

Cell Proliferation, Год журнала: 2020, Номер 53(3)

Опубликована: Фев. 8, 2020

Abstract Central nervous system (CNS) maintains a high level of metabolism, which leads to the generation large amounts free radicals, and it is also one most vulnerable organs oxidative stress. Emerging evidences have shown that, as key homeostatic cells in CNS, astrocytes are deeply involved multiple aspects CNS function including stress regulation. Besides, redox can turn affect morphology function. The complex roles indicate that their correct performance crucial for normal functioning its dysfunction may result occurrence progression various neurological disorders. To date, influence rarely reviewed. Therefore, this review we sum up regulation corresponding mechanisms under both different pathological conditions.

Язык: Английский

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Role of astroglial toll-like receptors (TLRs) in central nervous system infections, injury and neurodegenerative diseases

Brain Behavior and Immunity, Год журнала: 2020, Номер 91, С. 740 - 755

Опубликована: Окт. 8, 2020

Central nervous system (CNS) innate immunity plays essential roles in infections, neurodegenerative diseases, and brain or spinal cord injuries. Astrocytes microglia are the principal cells that mediate CNS. Pattern recognition receptors (PRRs), expressed by astrocytes microglia, sense pathogen-derived endogenous ligands released damaged initiate immune response. Toll-like (TLRs) a well-characterized family of PRRs. The contribution microglial TLR signaling to CNS pathology has been extensively investigated. Even though assume wide variety key functions, information about role astroglial TLRs disease injuries is limited. Because display heterogeneity exhibit phenotypic plasticity depending on effectors present local milieu, they can exert both detrimental beneficial effects. modulators these paradoxical properties. goal current review highlight played diseases. We discuss host defense as well dissemination viral bacterial infections examine link between pathogenesis diseases evidence showing pivotal influence sterile inflammation injury. Finally, we define research questions areas warrant further investigations context astrocytes, TLRs, dysfunction.

Язык: Английский

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Enteric glial biology, intercellular signalling and roles in gastrointestinal disease

Nature Reviews Gastroenterology & Hepatology, Год журнала: 2021, Номер 18(8), С. 571 - 587

Опубликована: Март 17, 2021

Язык: Английский

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Astrocyte senescence: Evidence and significance

Aging Cell, Год журнала: 2019, Номер 18(3)

Опубликована: Фев. 27, 2019

Astrocytes participate in numerous aspects of central nervous system (CNS) physiology ranging from ion balance to metabolism, and disruption their physiological roles can therefore be a contributor CNS dysfunction pathology. Cellular senescence, one the mechanisms aging, has been proposed as component age dependency neurodegenerative disorders. Cumulative evidence supports an integral role astrocytes initiation progression disease cognitive decline with aging. The loss astrocyte function or gain neuroinflammatory result cellular senescence could have profound implications for aging brain disorders, we propose term "astrosenescence" describe this phenotype. This review summarizes current pertaining early evidence, vitro characterization relationship age-related disease. We discuss significance targeting senescent novel approach toward therapies age-associated

Язык: Английский

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