Extracellular vesicles: biomarkers and regulators of vascular function during extracorporeal circulation

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Abstract

Extracellular vesicles (EVs) are generated at increased rates from parenchymal and circulating blood cells during exposure of the circulation to abnormal flow conditions and foreign materials associated with extracorporeal circuits (ExCors). This review describes types of EVs produced in different ExCors and extracorporeal life support (ECLS) systems including cardiopulmonary bypass circuits, extracorporeal membrane oxygenation (ECMO), extracorporeal carbon dioxide removal (ECCO ₂R), apheresis, dialysis and ventricular assist devices. Roles of EVs not only as biomarkers of adverse events during ExCor/ECLS use, but also as mediators of vascular dysfunction are explored. Manipulation of the number or subtypes of circulating EVs may prove a means of improving vascular function for individuals requiring ExCor/ECLS support. Strategies for therapeutic manipulation of EVs during ExCor/ECLS use are discussed such as accelerating their clearance, preventing their genesis or pharmacologic options to reduce or select which and how many EVs circulate. Strategies to reduce or select for specific types of EVs may prove beneficial in preventing or treating other EV-related diseases such as cancer.

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Microparticles in hemostasis and thrombosis.

A Phillip Owens, Nigel Mackman (2011)

Blood contains microparticles (MPs) derived from a variety of cell types, including platelets, monocytes, and endothelial cells. In addition, tumors release MPs into the circulation. MPs are formed from membrane blebs that are released from the cell surface by proteolytic cleavage of the cytoskeleton. All MPs are procoagulant because they provide a membrane surface for the assembly of components of the coagulation protease cascade. Importantly, procoagulant activity is increased by the presence of anionic phospholipids, particularly phosphatidylserine (PS), and the procoagulant protein tissue factor (TF), which is the major cellular activator of the clotting cascade. High levels of platelet-derived PS(+) MPs are present in healthy individuals, whereas the number of TF(+), PS(+) MPs is undetectable or very low. However, levels of PS(+), TF(+) MPs are readily detected in a variety of diseases, and monocytes appear to be the primary cellular source. In cancer, PS(+), TF(+) MPs are derived from tumors and may serve as a useful biomarker to identify patients at risk for venous thrombosis. This review will summarize our current knowledge of the role of procoagulant MPs in hemostasis and thrombosis.

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Exosome removal as a therapeutic adjuvant in cancer

Annette Marleau, Chien-Shing Chen, James Joyce … (2012)

Exosome secretion is a notable feature of malignancy owing to the roles of these nanoparticles in cancer growth, immune suppression, tumor angiogenesis and therapeutic resistance. Exosomes are 30–100 nm membrane vesicles released by many cells types during normal physiological processes. Tumors aberrantly secrete large quantities of exosomes that transport oncoproteins and immune suppressive molecules to support tumor growth and metastasis. The role of exosomes in intercellular signaling is exemplified by human epidermal growth factor receptor type 2 (HER2) over-expressing breast cancer, where exosomes with the HER2 oncoprotein stimulate tumor growth and interfere with the activity of the therapeutic antibody Herceptin®. Since numerous observations from experimental model systems point toward an important clinical impact of exosomes in cancer, several pharmacological strategies have been proposed for targeting their malignant activities. We also propose a novel device strategy involving extracorporeal hemofiltration of exosomes from the entire circulatory system using an affinity plasmapheresis platform known as the Aethlon ADAPT™ (adaptive dialysis-like affinity platform technology) system, which would overcome the risks of toxicity and drug interactions posed by pharmacological approaches. This technology allows affinity agents, including exosome-binding lectins and antibodies, to be immobilized in the outer-capillary space of plasma filtration membranes that integrate into existing kidney dialysis systems. Device therapies that evolve from this platform allow rapid extracorporeal capture and selective retention of target particles < 200 nm from the entire circulatory system. This strategy is supported by clinical experience in hepatitis C virus-infected patients using an ADAPT™ device, the Hemopurifier®, to reduce the systemic load of virions having similar sizes and glycosylated surfaces as cancer exosomes. This review discusses the possible therapeutic approaches for targeting immune suppressive exosomes in cancer patients, and the anticipated significance of these strategies for reversing immune dysfunction and improving responses to standard of care treatments.

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Exosome-dependent trafficking of HSP70: a novel secretory pathway for cellular stress proteins.

Graeme I. Lancaster, Mark A. Febbraio (2005)

The heat shock proteins (HSPs) are a family of intracellular proteins found in all eukaryotes and prokaryotes. Their functions are well characterized and are central to maintaining cellular homeostasis and in promoting cell survival in response to stressful cellular conditions. However, several studies provide evidence that specific members of the HSP family might be secreted via an unidentified exocytotic pathway. Here we show that exosomes, small membrane vesicles that are secreted by numerous cell types, contribute to the release of HSP70 from human peripheral blood mononuclear cells (PBMCs) in both basal and stress-induced (heat shock at 40 or 43 degrees C for 1 h) states. HSP70 release from PBMCs is independent of the common secretory pathway because Brefeldin A, an inhibitor of the classical protein transport pathway, did not block HSP70 release. Furthermore, we show that HSP70 release from PBMCs does not occur via a lipid raft-dependent pathway, because treatment with methyl-beta-cyclodextrin, a raft-disrupting drug, had no affect on HSP70 release. To examine whether exosomes contributed to HSP70 release from PBMCs, exosomes were purified from PBMC cultures, and exosomal number and HSP70 content were determined. We demonstrate that although heat shock does not influence the exosomal secretory rate, the HSP70 content of exosomes isolated from heat shocked PBMCs is significantly higher than control. These data identify a novel secretory pathway by which HSP70 can be actively released from cells in both the basal and stress-induced state.

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Author and article information

Journal

Journal ID (nlm-ta): Oncotarget

Journal ID (iso-abbrev): Oncotarget

Journal ID (publisher-id): Oncotarget

Journal ID (publisher-id): ImpactJ

Title: Oncotarget

Publisher: Impact Journals LLC

ISSN (Electronic): 1949-2553

Publication date Collection: 14 December 2018

Publication date (Electronic): 14 December 2018

Volume: 9

Issue: 98

Pages: 37229-37251

Affiliations

¹ Keenan Research Centre for Biomedical Science, St Michael's Hospital, Toronto, ON, Canada

² Department of Physiology, University of Toronto, Toronto, ON, Canada

³ Department of Anesthesia, University of Toronto, Toronto, ON, Canada

⁴ Department of Anesthesia and Pain Medicine, SickKids, Toronto, ON, Canada

⁵ Department of Surgery, University of Toronto, Toronto, ON, Canada

⁶ Institute of Physiology, Charité-Universitätsmedizin Berlin, Berlin, Germany

⁷ German Heart Institute, Berlin, Germany

Author notes

Correspondence to: Wolfgang M. Kuebler, wolfgang.kuebler@ 123456charite.de

Article

Publisher ID: 26433

DOI: 10.18632/oncotarget.26433

PMC ID: 6324688

SO-VID: 1b85e2d8-221c-4e20-80bd-98c3d24a32cd

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This article is distributed under the terms of the Creative Commons Attribution License (CC-BY), which permits unrestricted use and redistribution provided that the original author and source are credited.

Extracellular vesicles: biomarkers and regulators of vascular function during extracorporeal circulation

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Abstract

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Most cited references 117

Microparticles in hemostasis and thrombosis.

Exosome removal as a therapeutic adjuvant in cancer

Exosome-dependent trafficking of HSP70: a novel secretory pathway for cellular stress proteins.

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