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A fluoro-Nissl dye identifies pericytes as distinct vascular mural cells during in vivo brain imaging.

ABSTRACT: Pericytes and smooth muscle cells are integral components of the brain microvasculature. However, no techniques exist to unambiguously identify these cell types, greatly limiting their investigation in vivo. Here we show that the fluorescent Nissl dye NeuroTrace 500/525 labels brain pericytes with specificity, allowing high-resolution optical imaging in the live mouse. We demonstrate that capillary pericytes are a population of mural cells with distinct morphological, molecular and functional features that do not overlap with precapillary or arteriolar smooth muscle actin-expressing cells. The remarkable specificity for dye uptake suggests that pericytes have molecular transport mechanisms not present in other brain cells. We demonstrate feasibility of longitudinal pericyte imaging during microvascular development and aging and in models of brain ischemia and Alzheimer's disease. The ability to easily label pericytes in any mouse model opens the possibility of a broad range of investigations of mural cells in vascular development, neurovascular coupling and neuropathology.

SUBMITTER: Damisah EC

PROVIDER: S-EPMC5550770 | biostudies-literature | 2017 Jul

REPOSITORIES: biostudies-literature

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A fluoro-Nissl dye identifies pericytes as distinct vascular mural cells during in vivo brain imaging.

Damisah Eyiyemisi C EC Hill Robert A RA Tong Lei L Murray Katie N KN Grutzendler Jaime J

Nature neuroscience 20170515 7

Pericytes and smooth muscle cells are integral components of the brain microvasculature. However, no techniques exist to unambiguously identify these cell types, greatly limiting their investigation in vivo. Here we show that the fluorescent Nissl dye NeuroTrace 500/525 labels brain pericytes with specificity, allowing high-resolution optical imaging in the live mouse. We demonstrate that capillary pericytes are a population of mural cells with distinct morphological, molecular and functional fe ...[more]

PMID: 28504673

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Project description:Pericytes are unique, multi-functional mural cells localized at the abluminal side of the perivascular space in microvessels. Originally discovered in 19th century, pericytes had drawn less attention until decades ago mainly due to lack of specific markers. Recently, however, a growing body of evidence has revealed that pericytes play various important roles: development and maintenance of blood-brain barrier (BBB), regulation of the neurovascular system (e.g., vascular stability, vessel formation, cerebral blood flow, etc.), trafficking of inflammatory cells, clearance of toxic waste products from the brain, and acquisition of stem cell-like properties. In the neurovascular unit, pericytes perform these functions through coordinated crosstalk with neighboring cells including endothelial, glial, and neuronal cells. Dysfunction of pericytes contribute to a wide variety of diseases that lead to cognitive impairments such as cerebral small vessel disease (SVD), acute stroke, Alzheimer's disease (AD), and other neurological disorders. For instance, in SVDs, pericyte degeneration leads to microvessel instability and demyelination while in stroke, pericyte constriction after ischemia causes a no-reflow phenomenon in brain capillaries. In AD, which shares some common risk factors with vascular dementia, reduction in pericyte coverage and subsequent microvascular impairments are observed in association with white matter attenuation and contribute to impaired cognition. Pericyte loss causes BBB-breakdown, which stagnates amyloid ? clearance and the leakage of neurotoxic molecules into the brain parenchyma. In this review, we first summarize the characteristics of brain microvessel pericytes, and their roles in the central nervous system. Then, we focus on how dysfunctional pericytes contribute to the pathogenesis of vascular cognitive impairment including cerebral 'small vessel' and 'large vessel' diseases, as well as AD. Finally, we discuss therapeutic implications for these disorders by targeting pericytes.

Project description:Many pathological conditions of the brain are associated with structural abnormalities within the neurovascular system and linked to pericyte (PC) loss and/or dysfunction. Since crosstalk between endothelial cells (ECs) and PCs greatly impacts the function of the blood-brain barrier (BBB), effects of PCs on endothelial integrity and function have been investigated extensively. However, the impact of ECs on the function and activity of PCs remains largely unknown. Hence, using co-cultures of human brain vascular PCs with human cerebral microvascular ECs on opposite sides of porous Transwell inserts which facilitates direct EC-PC contact and improves EC barrier function, we analyzed EC-driven transcriptomic changes in PCs using microarrays and changes in cytokines/chemokines using proteome arrays. Gene expression analysis (GEA) in PCs co-cultured with ECs versus PCs cultured alone showed significant upregulation of 1'334 genes and downregulation of 964 genes. GEA in co-cultured PCs revealed increased expression of five prominent PC markers as well as soluble factors, such as transforming growth factor beta, fibroblast growth factor, angiopoietin 1, brain-derived neurotrophic factor, all of which are involved in EC-PC crosstalk and BBB induction. Pathway enrichment analysis of modulated genes showed a strong impact on many inflammatory and extracellular matrix (ECM) pathways including interferon and interleukin signaling, TGF-β and interleukin-1 regulation of ECM, as well as on the mRNA processing pathway. Interestingly, while co-culture induced the mRNA expression of many chemokines and cytokines, including several CCL- and CXC-motif ligands and interleukins, we observed a decreased expression of the same inflammatory mediators on the protein level. Importantly, in PCs, ECs significantly induced interferon associated proteins (IFIT1, IFI44L, IF127, IFIT3, IFI6, IFI44) with anti-viral actions; downregulated prostaglandin E receptor 2 (prevent COX-2 mediated BBB damage); upregulated fibulin-3 and connective tissue growth factor essential for BBB integrity; and multiple ECMs (collagens and integrins) that inhibit cell migration. Our findings suggest that via direct contact, ECs prime PCs to induce molecules to promote BBB integrity and cell survival during infection and inflammatory insult. Taken together, we provide first evidence that interaction with ECs though porous membranes induces major changes in the transcriptomic and proteomic profile of PCs. ECs influence genes involved in diverse aspects of PC function including PC maturation, cell survival, anti-viral defense, blood flow regulation, immuno-modulation and ECM deposition.

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A fluoro-Nissl dye identifies pericytes as distinct vascular mural cells during in vivo brain imaging.

Publications

A fluoro-Nissl dye identifies pericytes as distinct vascular mural cells during in vivo brain imaging.

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