Redefining Tissue Crosstalk via Shotgun Proteomic Analyses of Plasma Extracellular Vesicles

Whitham, Martin; Febbraio, Mark A.

doi:10.1002/pmic.201800154

Cited by 17 publications

(25 citation statements)

References 45 publications

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“…These EVs contain a vast array of signaling proteins and other molecules which can target specific organs, including the brain (see Figure 1 ). Therefore, EVs released during exercise may be one mechanism by which regular physical activity can slow or prevent the progression of neurodegenerative diseases such as AD [ 14 , 15 ], the focus of this review.…”

Section: Introductionmentioning

confidence: 99%

The Protective Effect of Exercise in Neurodegenerative Diseases: The Potential Role of Extracellular Vesicles

Fuller

Whitham

Mathivanan

et al. 2020

Cells

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Physical activity has systemic effects on the body, affecting almost every organ. It is important not only for general health and wellbeing, but also in the prevention of diseases. The mechanisms behind the therapeutic effects of physical activity are not completely understood; however, studies indicate these benefits are not confined to simply managing energy balance and body weight. They also include systemic factors which are released into the circulation during exercise and which appear to underlie the myriad of benefits exercise can elicit. It was shown that along with a number of classical cytokines, active tissues also engage in inter-tissue communication via extracellular vesicles (EVs), specifically exosomes and other small EVs, which are able to deliver biomolecules to cells and alter their metabolism. Thus, EVs may play a role in the acute and systemic adaptations that take place during and after physical activity, and may be therapeutically useful in the treatment of a range of diseases, including metabolic disorders such as type 2 diabetes and obesity; and the focus of this review, neurological disorders such as Alzheimer’s disease.

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Section: Introductionmentioning

confidence: 99%

The Protective Effect of Exercise in Neurodegenerative Diseases: The Potential Role of Extracellular Vesicles

Fuller

Whitham

Mathivanan

et al. 2020

Cells

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“…In separate studies, Ratajczak, Valadi, and Skog each showed that EVs contain RNA, and that EV-derived RNAs were transferable to recipient cells (Ratajczak et al, 2006;Valadi et al, 2007;Skog et al, 2008). Interestingly, Valadi et al found no clear correlation between EV expression and parent cell (Valadi et al, 2007) which is contradictory with later studies (Wei et al, 2017). The combination of the 2006 Nobel Prize being awarded to Fire and Mello for their discovery of RNA interference (Fire et al, 1998), and Valadi et al establishing the presence of small RNAs including micro-RNAs within EVs (Valadi et al, 2007;Skog et al, 2008) together pushed EV research into the spotlight.…”

Section: Historical Backgroundmentioning

confidence: 93%

“…The advantages of EV-focused MS analysis have been made clear through a number of studies including the identification of GPC1 as a marker of pancreatic cancer-derived EVs, genetic renal disease markers in urinary EVs, and novel myokines secreted during exercise in mammals (Gonzales et al, 2009 ; Melo et al, 2015 ; Whitham et al, 2018 ). Namely, EV separation and concentration prior to MS improves biomolecule discovery and identification by depleting highly abundant proteins and thereby sidestepping the dynamic range problem inherent within MS (Whitham and Febbraio, 2019 ). By separating EVs into density gradient fractions and then performing MS, for instance, one group was able to more sensitively uncover the heterogeneity among the protein content of EV subsets (Kowal et al, 2016 ).…”

Section: Experimental Approachesmentioning

confidence: 99%

“…During exercise, organism-wide signaling cascades involved with the physical stress response are mediated by a variety of myokines and regulatory RNAs. It is thought that exercise-induced adaptations are largely mediated by this extracellular milieu (Adams and Bamman, 2012 ; Shah et al, 2017b ; Whitham and Febbraio, 2019 ). EV secretion is upregulated during exercise and correlated with novel myokines (Whitham et al, 2018 ).…”

Section: Extracellular Vesicle Physiology and Biomedical Relevancementioning

confidence: 99%

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Characterizing Extracellular Vesicles and Their Diverse RNA Contents

2020

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Cells release nanometer-scale, lipid bilayer-enclosed biomolecular packages (extracellular vesicles; EVs) into their surrounding environment. EVs are hypothesized to be intercellular communication agents that regulate physiological states by transporting biomolecules between near and distant cells. The research community has consistently advocated for the importance of RNA contents in EVs by demonstrating that: (1) EV-related RNA contents can be detected in a liquid biopsy, (2) disease states significantly alter EV-related RNA contents, and (3) sensitive and specific liquid biopsies can be implemented in precision medicine settings by measuring EV-derived RNA contents. Furthermore, EVs have medical potential beyond diagnostics. Both natural and engineered EVs are being investigated for therapeutic applications such as regenerative medicine and as drug delivery agents. This review focuses specifically on EV characterization, analysis of their RNA content, and their functional implications. The NIH extracellular RNA communication (ERC) program has catapulted human EV research from an RNA profiling standpoint by standardizing the pipeline for working with EV transcriptomics data, and creating a centralized database for the scientific community. There are currently thousands of RNA-sequencing profiles hosted on the Extracellular RNA Atlas alone (Murillo et al., 2019 ), encompassing a variety of human biofluid types and health conditions. While a number of significant discoveries have been made through these studies individually, integrative analyses of these data have thus far been limited. A primary focus of the ERC program over the next five years is to bring higher resolution tools to the EV research community so that investigators can isolate and analyze EV sub-populations, and ultimately single EVs sourced from discrete cell types, tissues, and complex biofluids. Higher resolution techniques will be essential for evaluating the roles of circulating EVs at a level which impacts clinical decision making. We expect that advances in microfluidic technologies will drive near-term innovation and discoveries about the diverse RNA contents of EVs. Long-term translation of EV-based RNA profiling into a mainstay medical diagnostic tool will depend upon identifying robust patterns of circulating genetic material that correlate with a change in health status.

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“…Specifically, current studies have highlighted that Filter-Assisted Sample Preparation (FASP) has improved performance of biological MS data [16, 118]. Moreover the high resolution MS analyzers, i.e., hybrid mass spectrometers, such as quadrupole time-of-flight (Q-Tof) and ion-trap like Orbitraps, show major advantages like excellent mass accuracy, high resolving power and fast duty cycles, thus they have become the most used for analyzing complex samples, as biological fluids, cells lysate or EVs [119].…”

Section: Mass Spectrometry (Ms)-based Analysis Of Extracellular Vementioning

confidence: 99%

Extracellular Vesicles and Their Potential Use in Monitoring Cancer Progression and Therapy: The Contribution of Proteomics

Cufaro

Pieragostino

Lanuti

et al. 2019

Journal of Oncology

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Extracellular Vesicles (EVs) are small membrane-enclosed particles released by cells and able to vehiculate information between them. The term EVs categorizes many and different vesicles based on their biogenesis and release pathway, such as exosomes (Exo), ectosomes, or shedding microvesicles (SMVs), apoptotic blebs (ABs), and other EVs subsets, generating a heterogeneous group of components able to redistribute their cargo into the entire organism. Moreover EVs are becoming increasingly important in monitoring cancer progression and therapy, since they are able to carry specific disease biomarkers such as Glypican-1, colon cancer-associated transcript 2, CD63, CD24, and many others. The importance of their biological role together with their heterogeneity prompted researchers to adopt and standardize purification methods able to isolate EVs for characterizing their cargo. In this way, mass spectrometry (MS)-based proteomics approaches are emerging as promising tool for the identification and quantification of EVs protein cargoes, but this technique resulted to be deeply influenced by the low quality of the isolation techniques. This review presents the state-of-the-art of EVs isolation, purification, and characterization for omics studies, with a particular focus to their potential use in monitoring cancer progression and therapy.

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Redefining Tissue Crosstalk via Shotgun Proteomic Analyses of Plasma Extracellular Vesicles

Cited by 17 publications

References 45 publications

The Protective Effect of Exercise in Neurodegenerative Diseases: The Potential Role of Extracellular Vesicles

The Protective Effect of Exercise in Neurodegenerative Diseases: The Potential Role of Extracellular Vesicles

Characterizing Extracellular Vesicles and Their Diverse RNA Contents

Extracellular Vesicles and Their Potential Use in Monitoring Cancer Progression and Therapy: The Contribution of Proteomics

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