In sickness and in health: The functional role of extracellular vesicles in physiology and pathology in vivo

Yates, Abi G.; Pink, Ryan C.; Erdbrügger, Uta; Siljander, Pia; Dellar, Elizabeth R.; Pantazi, Paschalia; Akbar, Naveed; Cooke, William R.; Vatish, Manu; Dias‐Neto, Emmanuel; Anthony, Daniel C.; Couch, Yvonne

doi:10.1002/jev2.12190

Cited by 91 publications

(96 citation statements)

References 183 publications

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“…Additionally, gene ontology enrichment of dysregulated proteins in the skin dataset also pointed towards ‘Extracellular vesicle-mediated signaling in recipient cells’ (Table 3). Extracellular vesicles could play an important role in neurodegeneration as they have been implicated as one route for the spread of misfolded proteins, for instance in Parkinson’s disease, and they also contain other cargo such as miRNAs [44]. In HD, our human tissue data indicate that the expression of the HD mutation affects the homeostasis of extracellular vesicles similar to what has been observed before [45].…”

Section: Discussionsupporting

confidence: 74%

Abnormal molecular signatures of inflammation, energy metabolism and vesicle biology in human Huntington disease peripheral tissues

Neueder

Kojer

Hering

et al. 2022

Preprint

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Background: A major challenge in neurodegenerative diseases concerns identifying biological disease signatures that track with disease progression or respond to an intervention. Several clinical trials in Huntington disease (HD), an inherited, progressive neurodegenerative disease, are currently ongoing. Therefore, we examined whether peripheral tissues can serve as a source of readily accessible biological signatures at the RNA and protein level in HD patients. Results: We generated large, high-quality human datasets from skeletal muscle, skin and adipose tissue to probe molecular changes in human premanifest and early manifest HD patients - those most likely involved in clinical trials. In-depth single nucleotide polymorphism data across the HTT gene will facilitate the use of the generated primary- and iPSC cell lines in allele-specific targeting approaches. The analysis of the transcriptomics and proteomics data shows robust, stage-dependent dysregulation. Gene ontology analysis confirmed the involvement of inflammation and energy metabolism in peripheral HD pathogenesis. Furthermore, we observed changes in the homeostasis of extracellular vesicles, where we found consistent changes of genes and proteins involved in this process. Conclusions: Our 'omics data document the involvement of inflammation, energy metabolism and extracellular vesicle homeostasis. This demonstrates the potential to identify biological signatures from peripheral tissues in HD suitable as biomarkers in clinical trials. Together with the primary cell lines established from peripheral tissues and a large panel of iPSC lines that can serve as human models of HD, the generated data are a valuable and unique resource to advance the current understanding of molecular mechanisms driving HD pathogenesis.

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Section: Discussionsupporting

confidence: 74%

Abnormal molecular signatures of inflammation, energy metabolism and vesicle biology in human Huntington disease peripheral tissues

Neueder

Kojer

Hering

et al. 2022

Preprint

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“…As for sources of EVs, approximately 96% (n = 49) of the 51 articles used human patient or human-origin cells. Four used samples from animal models: nonhuman primate (Kumar et al, 2021), rat (Dagur et al, 2020), and mouse (Shi et al, 2014;Yuyama et al, 2019). Both articles that used mouse models also used human samples (serum).…”

Section:  Sources Of Evs For Lcam Studiesmentioning

confidence: 99%

“…Plasma (n = 31) was used more frequently than serum (n = 10). Of the 40 articles that used blood derivatives, several used other fluids/tissue, such as CSF (Cressatti et al, 2021;Norman et al, 2021), brain tissue (Dagur et al, 2020;Yuyama et al, 2019), urine (Cressatti et al, 2021), ascites fluid (Keller et al, 2009), and saliva (Cressatti et al, 2021) (Table 2). One article each used saliva (Rani et al, 2019), urine (Trnka et al, 2012, and ascites fluid (Gutwein et al, 2005) as the sole EV source (Table 2).…”

Section:  Sources Of Evs For Lcam Studiesmentioning

confidence: 99%

“…Extracellular vesicles (EVs) are a heterogeneous group of membrane‐bound particles that are released by all studied cell types (Cocozza, Grisard, Martin‐Jaular, Mathieu, & Théry, 2020; Van Niel, D'Angelo, & Raposo, 2018; Yáñez‐Mó et al., 2015; Yates et al., 2022). Most abundant in the 30–150 nm diameter range, EVs function in waste removal and cell‐cell communication by transporting nucleic acids, lipids, proteins, and other molecules (Harding, Heuser, & Stahl, 1983; Johnstone, 1992; Mateescu et al., 2017; Russell et al., 2019).…”

Section: Introductionmentioning

confidence: 99%

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L1CAM‐associated extracellular vesicles: A systematic review of nomenclature, sources, separation, and characterization

Gomes

Witwer

2022

J of Extracellular Bio

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When released into biological fluids like blood or saliva, brain extracellular vesicles (EVs) might provide a window into otherwise inaccessible tissue, contributing useful biomarkers of neurodegenerative and other central nervous system (CNS) diseases. To enrich for brain EVs in the periphery, however, cell-specific EV surface markers are needed. The protein that has been used most frequently to obtain EVs of putative neuronal origin is the transmembrane L1 cell adhesion molecule (L1CAM/CD171). In this systematic review, we examine the existing literature on L1CAM and EVs, including investigations of both neurodegenerative disease and cancer through the lens of the minimal information for studies of EVs (MISEV), specifically in the domains of nomenclature usage, EV sources, and EV separation and characterization. Although numerous studies have reported L1CAM-associated biomarker signatures that correlate with disease, interpretation of these results is complicated since L1CAM expression is not restricted to neurons and is also upregulated during cancer progression. A recent study has suggested that L1CAM epitopes are present in biofluids mostly or entirely as cleaved, soluble protein. Our findings on practices and trends in L1CAM-mediated EV separation, enrichment, and characterization yield insights that may assist with interpreting results, evaluating rigor, and suggesting avenues for further exploration.

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“…Additionally, hyaluronan induces the secretion of extracellular vesicles (EVs) ( 8 ) and accumulates on their surface, forming a thick coating on EVs ( 9 ). EVs are plasma membrane-derived particles produced by all cell types into the extracellular space and body fluids, regulating both normal physiology and pathological conditions ( 10 ). Tumor derived EVs affect the formation of tumor microenvironments and mediate cellular interactions during cancer progression ( 11 ).…”

Section: Introductionmentioning

confidence: 99%

MCF10CA Breast Cancer Cells Utilize Hyaluronan-Coated EV-Rich Trails for Coordinated Migration

et al. 2022

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Invasion of tumor cells through the stroma is coordinated in response to migratory cues provided by the extracellular environment. One of the most abundant molecules in the tumor microenvironment is hyaluronan, a glycosaminoglycan known to promote many hallmarks of tumor progression, including the migratory potential of tumor cells. Strikingly, hyaluronan is also often found to coat extracellular vesicles (EVs) that originate from plasma membrane tentacles of tumor cells crucial for migration, such as filopodia, and are abundant in tumor niches. Thus, it is possible that hyaluronan and hyaluronan-coated EVs have a cooperative role in promoting migration. In this work, we compared the hyaluronan synthesis, EV secretion and migratory behavior of normal and aggressive breast cell lines from MCF10 series. Single live cell confocal imaging, electron microscopy and correlative light and electron microscopy experiments revealed that migrating tumor cells form EV-rich and hyaluronan -coated trails. These trails promote the pathfinding behavior of follower cells, which is dependent on hyaluronan. Specifically, we demonstrated that plasma membrane protrusions and EVs left behind by tumor cells during migration are strongly positive for CD9. Single cell tracking demonstrated a leader-follower behavior, which was significantly decreased upon removal of pericellular hyaluronan, indicating that hyaluronan promotes the pathfinding behavior of follower cells. Chick chorioallantoic membrane assays in ovo suggest that tumor cells behave similarly in 3D conditions. This study strengthens the important role of extracellular matrix production and architecture in coordinated tumor cell movements and validates the role of EVs as important components and regulators of tumor matrix. The results suggest that tumor cells can modify the extracellular niche by forming trails, which they subsequently follow coordinatively. Future studies will clarify in more detail the orchestrated role of hyaluronan, EVs and other extracellular cues in coordinated migration and pathfinding behavior of follower cells.

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In sickness and in health: The functional role of extracellular vesicles in physiology and pathology in vivo

Cited by 91 publications

References 183 publications

Abnormal molecular signatures of inflammation, energy metabolism and vesicle biology in human Huntington disease peripheral tissues

Abnormal molecular signatures of inflammation, energy metabolism and vesicle biology in human Huntington disease peripheral tissues

L1CAM‐associated extracellular vesicles: A systematic review of nomenclature, sources, separation, and characterization

MCF10CA Breast Cancer Cells Utilize Hyaluronan-Coated EV-Rich Trails for Coordinated Migration

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