Abstract

Signalling between cells of the neurovascularunit, or neurovascular coupling, is essential to match local blood flow withneuronal activity. Pericytes interact with endothelial cells and extendprocesses that wrap capillaries, covering up to 90% of their surface area1,2.Pericytes are candidates to regulate microcirculatory blood flow because theyare strategically positioned along capillaries, contain contractile proteinsand respond rapidly to neuronal stimulation3,4, but whether they synchronizemicrovascular dynamics and neurovascular coupling within a capillary networkwas unknown. Here we identify nanotube-like processes that connect two bonafide pericytes on separate capillary systems, forming a functional network inthe mouse retina, which we named interpericyte tunnelling nanotubes (IP-TNTs).We provide evidence that these (i) have an open-ended proximal side and aclosed-ended terminal (end-foot) that connects with distal pericyte processesvia gap junctions, (ii) carry organelles including mitochondria, which cantravel along these processes, and (iii) serve as a conduit for intercellularCa2+ waves, thus mediating communication between pericytes. Using two-photonmicroscope live imaging, we demonstrate that retinal pericytes rely on IP-TNTsto control local neurovascular coupling and coordinate light-evoked responsesbetween adjacent capillaries. IP-TNT damage following ablation or ischaemiadisrupts intercellular Ca2+ waves, impairing blood flow regulation andneurovascular coupling. Notably, pharmacological blockade of Ca2+ influxpreserves IP-TNTs, rescues light-evoked capillary responses and restores bloodflow after reperfusion. Our study thus defines IP-TNTs and characterizes theircritical role in regulating neurovascular coupling in the living retina underboth physiological and pathological conditions.

參考文獻(xiàn)：Interpericyte tunnelling nanotubes regulateneurovascular coupling. Nature. 2020 Sep;585(7823):91-95.

2.Nature—外周中樞交互再獲突破！！生理性血-腦間蛋白轉(zhuǎn)運(yùn)隨著衰老過(guò)程中BBB跨細(xì)胞運(yùn)輸功能的下降而下降

Abstract

The vascular interface of the brain, known asthe blood-brain barrier (BBB), is understood to maintain brain function in partvia its low transcellular permeability1-3. Yet, recent studies havedemonstrated that brain ageing is sensitive to circulatory proteins4,5. Thus,it is unclear whether permeability to individually injected exogenoustracers-as is standard in BBB studies-fully represents blood-to-braintransport. Here we label hundreds of proteins constituting the mouse bloodplaSMa proteome, and upon their systemic administration, study the BBB with itsphysiological ligand. We find that plaSMa proteins readily permeate the healthybrain parenchyma, with transport maintained by BBB-specific transcriptionalprogrammes. Unlike IgG antibody, plaSMa protein uptake diminishes in the agedbrain, driven by an age-related shift in transport from ligand-specificreceptor-mediated to non-specific caveolar transcytosis. This age-related shiftoccurs alongside a specific loss of pericyte coverage. Pharmacologicalinhibition of the age-upregulated phosphatase ALPL, a predicted negativeregulator of transport, enhances brain uptake of therapeutically relevanttransferrin, transferrin receptor antibody and plaSMa. These findings revealthe extent of physiological protein transcytosis to the healthy brain, amechaniSM of widespread BBB dysfunction with age and a strategy for enhanceddrug delivery.

參考文獻(xiàn)：Physiological blood-brain transport isimpaired with age by a shift in transcytosis. Nature. 2020Jul;583(7816):425-430

3.Nature—重磅！！研究發(fā)現(xiàn)caveolae是介導(dǎo)神經(jīng)血管偶聯(lián)的關(guān)鍵小動(dòng)脈內(nèi)皮細(xì)胞結(jié)構(gòu)

Abstract

Proper brain function depends on neurovascularcoupling: neural activity rapidly increases local blood flow to meetmoment-to-moment changes in regional brain energy demand1. Neurovascularcoupling is the basis for functional brain imaging2, and impaired neurovascularcoupling is implicated in neurodegeneration1. The underlying molecular andcellular mechaniSMs of neurovascular coupling remain poorly understood. Theconventional view is that neurons or astrocytes release vasodilatory factorsthat act directly on SMooth muscle cells (SMCs) to induce arterial dilation andincrease local blood flow1. Here, using two-photon microscopy to image neuralactivity and vascular dynamics simultaneously in the barrel cortex of awakemice under whisker stimulation, we found that arteriolar endothelial cells(aECs) have an active role in mediating neurovascular coupling. We found thataECs, unlike other vascular segments of endothelial cells in the centralnervous system, have abundant caveolae. Acute genetic perturbations thateliminated caveolae in aECs, but not in neighbouring SMCs, impairedneurovascular coupling. Notably, caveolae function in aECs is independent ofthe endothelial NO synthase (eNOS)-mediated NO pathway. Ablation of bothcaveolae and eNOS completely abolished neurovascular coupling, whereas thesingle mutants exhibited partial impairment, revealing that thecaveolae-mediated pathway in aECs is a major contributor to neurovascularcoupling. Our findings indicate that vasodilation is largely mediated byendothelial cells that actively relay Signals from the central nervous systemto SMCs via a caveolae-dependent pathway.

參考文獻(xiàn)：Caveolae in CNS arterioles mediateneurovascular coupling. Nature. 2020 Mar;579(7797):106-110.

4.Science—改寫(xiě)醫(yī)學(xué)教科書(shū)的重磅突破！！腦梗死腦水腫是由腦脊液的滲入引起的，而非來(lái)自血管滲入

Abstract

Stroke affects millions each year. Poststrokebrain edema predicts the severity of eventual stroke damage, yet our concept ofhow edema develops is incomplete and treatment options remain limited. In earlystages, fluid accumulation occurs owing to a net gain of ions, widely thoughtto enter from the vascular compartment. Here, we used magnetic resonanceimaging, radiolabeled tracers, and multiphoton imaging in rodents to showinstead that cerebrospinal fluid surrounding the brain enters the tissue withinminutes of an ischemic insult along perivascular flow channels. This processwas initiated by ischemic spreading depolarizations along with subsequentvasoconstriction, which in turn enlarged the perivascular spaces and doubledglymphatic inflow speeds. Thus, our understanding of poststroke edema needs tobe revised, and these findings could provide a conceptual basis for developmentof alternative treatment strategies.

參考文獻(xiàn)：Cerebrospinal fluid influx drives acuteischemic tissue swelling. Science. 2020 Mar 13;367(6483):eaax7171.

5.Cell—科學(xué)家發(fā)布小鼠內(nèi)皮細(xì)胞單細(xì)胞轉(zhuǎn)錄組圖譜

Abstract

The heterogeneity of endothelial cells (ECs)across tissues remains incompletely inventoried. We constructed an atlas of>32,000 single-EC transcriptomes from 11 mouse tissues and identified 78 ECsubclusters, including Aqp7+ intestinal capillaries and angiogenic ECs inhealthy tissues. ECs from brain/testis, liver/spleen, SMall intestine/colon,and skeletal muscle/heart pairwise expressed partially overlapping markergenes. Arterial, venous, and lymphatic ECs shared more markers in more tissuesthan did heterogeneous capillary ECs. ECs from different vascular beds(arteries, capillaries, veins, lymphatics) exhibited transcriptome similarityacross tissues, but the tissue (rather than the vessel) type contributed to theEC heterogeneity. Metabolic transcriptome analysis revealed a similartissue-grouping phenomenon of ECs and heterogeneous metabolic gene signaturesin ECs between tissues and between vascular beds within a single tissue in atissue-type-dependent pattern. The EC atlas taxonomy enabled identification ofEC subclusters in public scRNA-seq datasets and provides a powerful discoverytool and resource value.

參考文獻(xiàn)：Single-Cell Transcriptome Atlas of MurineEndothelial Cells. Cell. 2020 Feb 20;180(4):764-779.e20.

6.Science—腦類(lèi)器官研究再獲突破！！脈絡(luò)叢類(lèi)器官可以產(chǎn)生腦脊液且具有“分子篩”樣屏障功能

Abstract

Cerebrospinal fluid (CSF) is a vital liquid,providing nutrients and Signaling molecules and clearing out toxic by-productsfrom the brain. The CSF is produced by the choroid plexus (ChP), a protectiveepithelial barrier that also prevents free entry of toxic molecules or drugsfrom the blood. Here, we establish human ChP organoids with a selective barrierand CSF-like fluid secretion in self-contained compartments. We show that thisin vitro barrier exhibits the same selectivity to SMall molecules as the ChP invivo and that ChP-CSF organoids can predict central nervous system (CNS)permeability of new compounds. The transcriptomic and proteomic signatures ofChP-CSF organoids reveal a high degree of similarity to the ChP in vivo.Finally, the intersection of single-cell transcriptomics and proteomic analysisuncovers key human CSF components produced by previously unidentifiedspecialized epithelial subtypes.

參考文獻(xiàn)：Human CNS barrier-forming organoids withcerebrospinal fluid production. Science. 2020 Jul 10;369(6500):eaaz5626.

7.Cell—科學(xué)家找到改善中樞神經(jīng)系統(tǒng)水腫的新方法??！AQP4的細(xì)胞內(nèi)轉(zhuǎn)運(yùn)是關(guān)鍵靶點(diǎn)

Abstract

Swelling of the brain or spinal cord (CNSedema) affects millions of people every year. All potential pharmacologicalinterventions have failed in clinical trials, meaning that symptom managementis the only treatment option. The water channel protein aquaporin-4 (AQP4) isexpressed in astrocytes and mediates water flux across the blood-brain andblood-spinal cord barriers. Here we show that AQP4 cell-surface abundanceincreases in response to hypoxia-induced cell swelling in acalmodulin-dependent manner. Calmodulin directly binds the AQP4 carboxylterminus, causing a specific conformational change and driving AQP4cell-surface localization. Inhibition of calmodulin in a rat spinal cord injurymodel with the licensed drug trifluoperazine inhibited AQP4 localization to theblood-spinal cord barrier, ablated CNS edema, and led to accelerated functionalrecovery compared with untreated animals. We propose that targeting themechaniSM of calmodulin-mediated cell-surface localization of AQP4 is a viablestrategy for development of CNS edema therapies.

參考文獻(xiàn)：Targeting Aquaporin-4 Subcellular Localizationto Treat Central Nervous System Edema. Cell. 2020 May 14;181(4):784-799.e19.

8.Nature—APOE4通過(guò)引起血腦屏障損傷進(jìn)而導(dǎo)致認(rèn)知功能下降

Abstract

Vascular contributions to dementia andAlzheimer's disease are increasingly recognized1-6. Recent studies have suggestedthat breakdown of the blood-brain barrier (BBB) is an early biomarker of humancognitive dysfunction7, including the early clinical stages of Alzheimer'sdisease5,8-10. The E4 variant of apolipoprotein E (APOE4), the mainsusceptibility gene for Alzheimer's disease11-14, leads to acceleratedbreakdown of the BBB and degeneration of brain capillary pericytes15-19, whichmaintain BBB integrity20-22. It is unclear, however, whether thecerebrovascular effects of APOE4 contribute to cognitive impairment. Here weshow that individuals bearing APOE4 (with the ε3/ε4 or ε4/ε4 alleles) aredistinguished from those without APOE4 (ε3/ε3) by breakdown of the BBB in thehippocampus and medial temporal lobe. This finding is apparent in cognitivelyunimpaired APOE4 carriers and more severe in those with cognitive impairment,but is not related to amyloid-β or tau pathology measured in cerebrospinalfluid or by positron emission tomography23. High baseline levels of the BBBpericyte injury biomarker soluble PDGFRβ7,8 in the cerebrospinal fluidpredicted future cognitive decline in APOE4 carriers but not in non-carriers,even after controlling for amyloid-β and tau status, and were correlated withincreased activity of the BBB-degrading cyclophilin A-matrix metalloproteinase-9pathway19 in cerebrospinal fluid. Our findings suggest that breakdown of theBBB contributes to APOE4-associated cognitive decline independently ofAlzheimer's disease pathology, and might be a therapeutic target in APOE4carriers.

參考文獻(xiàn)：APOE4 leads to blood-brain barrier dysfunctionpredicting cognitive decline. Nature. 2020 May;581(7806):71-76.

9.Cell—TubeMap技術(shù)來(lái)了！?。∥覀兊谝淮稳绱饲逦目吹叫∈蟠竽X的所有血管

Abstract

The cerebral vasculature is a dense network ofarteries, capillaries, and veins. Quantifying variations of the vascularorganization across individuals, brain regions, or disease models ischallenging. We used immunolabeling and tissue clearing to image the vascularnetwork of adult mouse brains and developed a pipeline to segmentterabyte-sized multichannel images from light sheet microscopy, enabling theconstruction, analysis, and visualization of vascular graphs composed of over100 million vessel segments. We generated datasets from over 20 mouse brains,with labeled arteries, veins, and capillaries according to their anatomicalregions. We characterized the organization of the vascular network across brainregions, highlighting local adaptations and functional correlates. We propose aclassification of cortical regions based on the vascular topology. Finally, weanalysed brain-wide rearrangements of the vasculature in animal models ofcongenital deafness and ischemic stroke, revealing that vascular plasticity andremodeling adopt diverging rules in different models.

參考文獻(xiàn)：Mapping the Fine-Scale Organization andPlasticity of the Brain Vasculature. Cell. 2020 Feb 20;180(4):780-795.e25.

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10. Nature—腫瘤細(xì)胞通過(guò)激活TLR3-SLIT2軸驅(qū)動(dòng)腫瘤腦轉(zhuǎn)移

Abstract

Blood vessels support tumours by providingnutrients and oxygen, while also acting as conduits for the dissemination ofcancer1. Here we use mouse models of breast and lung cancer to investigatewhether endothelial cells also have active 'instructive' roles in thedissemination of cancer. We purified genetically tagged endothelial ribosomesand their associated transcripts from highly and poorly metastatic tumours.Deep sequencing revealed that metastatic tumours induced expression of the axon-guidancegene Slit2 in endothelium, establishing differential expression between theendothelial (high Slit2 expression) and tumoural (low Slit2 expression)compartments. Endothelial-derived SLIT2 protein and its receptor ROBO1 promotedthe migration of cancer cells towards endothelial cells and intravasation.Deleting endothelial Slit2 suppressed metastatic dissemination in mouse modelsof breast and lung cancer. Conversely, deletion of tumoural Slit2 enhancedmetastatic progression. We identified double-stranded RNA derived from tumourcells as an upstream Signal that induces expression of endothelial SLIT2 byacting on the RNA-sensing receptor TLR3. Accordingly, a set of endogenousretroviral element RNAs were upregulated in metastatic cells and detectedextracellularly. Thus, cancer cells co-opt innate RNA sensing to induce achemotactic Signalling pathway in endothelium that drives intravasation andmetastasis. These findings reveal that endothelial cells have a directinstructive role in driving metastatic dissemination, and demonstrate that asingle gene (Slit2) can promote or suppress cancer progression depending on itscellular source.

參考文獻(xiàn)：Tumoural activation of TLR3-SLIT2 axis inendothelium drives metastasis. Nature. 2020 Oct;586(7828):299-304.