Extracellular vesicles: mediators and biomarkers of pathology along CNS barriers

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Abstract

Extracellular vesicles (EVs) are heterogeneous, nano-sized vesicles that are shed into the blood and other body fluids, which disperse a variety of bioactive molecules (e.g., protein, mRNA, miRNA, DNA and lipids) to cellular targets over long and short distances. EVs are thought to be produced by nearly every cell type, however this review will focus specifically on EVs that originate from cells at the interface of CNS barriers. Highlighted topics include, EV biogenesis, the production of EVs in response to neuroinflammation, role in intercellular communication and their utility as a therapeutic platform. In this review, novel concepts regarding the use of EVs as biomarkers for BBB status and as facilitators for immune neuroinvasion are also discussed. Future directions and prospective are covered along with important unanswered questions in the field of CNS endothelial EV biology.

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Most cited references 112

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Extracellular vesicle isolation and characterization: toward clinical application.

Rong Xu, David W. Greening, Hong-Jian Zhu … (2016)

Two broad categories of extracellular vesicles (EVs), exosomes and shed microvesicles (sMVs), which differ in size distribution as well as protein and RNA profiles, have been described. EVs are known to play key roles in cell-cell communication, acting proximally as well as systemically. This Review discusses the nature of EV subtypes, strategies for isolating EVs from both cell-culture media and body fluids, and procedures for quantifying EVs. We also discuss proteins selectively enriched in exosomes and sMVs that have the potential for use as markers to discriminate between EV subtypes, as well as various applications of EVs in clinical diagnosis.

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Blockade of exosome generation with GW4869 dampens the sepsis-induced inflammation and cardiac dysfunction.

Kobina Essandoh, Liwang Yang, Xiaohong Wang … (2015)

Sepsis is an infection-induced severe inflammatory disorder that leads to multiple organ failure. Amongst organs affected, myocardial depression is believed to be a major contributor to septic death. While it has been identified that large amounts of circulating pro-inflammatory cytokines are culprit for triggering cardiac dysfunction in sepsis, the underlying mechanisms remain obscure. Additionally, recent studies have shown that exosomes released from bacteria-infected macrophages are pro-inflammatory. Hence, we examined in this study whether blocking the generation of exosomes would be protective against sepsis-induced inflammatory response and cardiac dysfunction. To this end, we pre-treated RAW264.7 macrophages with GW4869, an inhibitor of exosome biogenesis/release, followed by endotoxin (LPS) challenge. In vivo, we injected wild-type (WT) mice with GW4869 for 1h prior to endotoxin treatment or cecal ligation/puncture (CLP) surgery. We observed that pre-treatment with GW4869 significantly impaired release of both exosomes and pro-inflammatory cytokines (TNF-α, IL-1β, IL-6) in RAW264.7 macrophages. At 12h after LPS treatment or CLP surgery, WT mice pre-treated with GW4869 displayed lower amounts of exosomes and pro-inflammatory cytokines in the serum than control PBS-injected mice. Accordingly, GW4869 treatment diminished the sepsis-induced cardiac inflammation, attenuated myocardial depression and prolonged survival. Together, our findings indicate that blockade of exosome generation in sepsis dampens the sepsis-triggered inflammatory response and thereby, improves cardiac function and survival.

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Differential fates of biomolecules delivered to target cells via extracellular vesicles.

Masamitsu Kanada, Michael Bachmann, Jonathan W Hardy … (2015)

Extracellular vesicles (EVs), specifically exosomes and microvesicles (MVs), are presumed to play key roles in cell-cell communication via transfer of biomolecules between cells. The biogenesis of these two types of EVs differs as they originate from either the endosomal (exosomes) or plasma (MVs) membranes. To elucidate the primary means through which EVs mediate intercellular communication, we characterized their ability to encapsulate and deliver different types of macromolecules from transiently transfected cells. Both EV types encapsulated reporter proteins and mRNA but only MVs transferred the reporter function to recipient cells. De novo reporter protein expression in recipient cells resulted only from plasmid DNA (pDNA) after delivery via MVs. Reporter mRNA was delivered to recipient cells by both EV types, but was rapidly degraded without being translated. MVs also mediated delivery of functional pDNA encoding Cre recombinase in vivo to tissues in transgenic Cre-lox reporter mice. Within the parameters of this study, MVs delivered functional pDNA, but not RNA, whereas exosomes from the same source did not deliver functional nucleic acids. These results have significant implications for understanding the role of EVs in cellular communication and for development of EVs as delivery tools. Moreover, studies using EVs from transiently transfected cells may be confounded by a predominance of pDNA transfer.

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Author and article information

Contributors

Servio H. Ramirez: servio.ramirez@temple.edu

Allison M. Andrews: allison.andrews@temple.edu

Debayon Paul: Paul@uchc.edu

Joel S. Pachter: pachter@uchc.edu

Journal

Journal ID (nlm-ta): Fluids Barriers CNS

Journal ID (iso-abbrev): Fluids Barriers CNS

Title: Fluids and Barriers of the CNS

Publisher: BioMed Central (London )

ISSN (Electronic): 2045-8118

Publication date (Electronic): 1 July 2018

Publication date PMC-release: 1 July 2018

Publication date Collection: 2018

Volume: 15

Electronic Location Identifier: 19

Affiliations

[1 ]ISNI 0000 0001 2248 3398, GRID grid.264727.2, Department of Pathology and Laboratory Medicine, , The Lewis Katz School of Medicine at Temple University, ; 3500 N Broad St, Philadelphia, PA 19140 USA

[2 ]Shriners Hospital Pediatric Research Center, Philadelphia, PA 19140 USA

[3 ]ISNI 0000 0001 2248 3398, GRID grid.264727.2, Center for Substance Abuse Research, , The Lewis Katz School of Medicine at Temple University, ; Philadelphia, PA 19140 USA

[4 ]ISNI 0000000419370394, GRID grid.208078.5, Department of Immunology, Blood-Brain Barrier Laboratory & Laser Capture Microdissection Core, , UConn Health, ; 263 Farmington Ave., Farmington, CT 06070 USA

Article

Publisher ID: 104

DOI: 10.1186/s12987-018-0104-7

PMC ID: 6026502

PubMed ID: 29960602

SO-VID: d697eccb-3670-4e6d-baaa-0333d78d6bf3

License:

Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

History

Date received : 5 March 2018

Date accepted : 28 May 2018

Funding

Funded by: FundRef http://dx.doi.org/10.13039/100000002, National Institutes of Health;

Award ID: P30 DA013429-16

Award ID: R01 NS086570-01

Award ID: F32 DA041282-02

Award ID: R01 NS099855-01

Award Recipient : Servio H. Ramirez Allison M. Andrews Joel S. Pachter

Funded by: FundRef http://dx.doi.org/10.13039/100000890, National Multiple Sclerosis Society;

Award ID: RG-1702-27045

Award Recipient : Joel S. Pachter

Custom metadata

ScienceOpen disciplines: Neurology

Keywords: brain endothelial cells,blood brain barrier,extracellular vesicles,microvesicles,exosomes,neuroinflammation

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ScienceOpen disciplines: Neurology

Keywords: brain endothelial cells, blood brain barrier, extracellular vesicles, microvesicles, exosomes, neuroinflammation

Extracellular vesicles: mediators and biomarkers of pathology along CNS barriers

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Journal of Circulating Biomarkers

Most cited references 112

Extracellular vesicle isolation and characterization: toward clinical application.

Blockade of exosome generation with GW4869 dampens the sepsis-induced inflammation and cardiac dysfunction.

Differential fates of biomolecules delivered to target cells via extracellular vesicles.

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