Extracellular vesicles and intercellular communication within the nervous system

Zappulli, Valentina; Friis, Kristina Pagh; Fitzpatrick, Zachary; Maguire, Casey A.; Breakefield, Xandra O.

doi:10.1172/jci81134

Cited by 200 publications

(170 citation statements)

References 151 publications

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“…Uptake of all these different types of vesicles into recipient cells occurs typically through endocytosis. EVs, a generic term which includes all types of shedded vesicles, have been implicated both in communication between cells and in the elimination of unwanted products in the nervous system and other tissues (Schneider and Simons 2013; Zappulli et al 2015). In other neurodegenerative diseases, including prion disease and Alzheimer’s disease, there is strong evidence that the scrapie form of prion and the Aβ peptide, respectively, can be transferred via EVs, potentially contributing to the spread of toxicity within the brain (Alais et al 2008; Joshi et al 2015; Saman et al 2014).…”

Section: Extracellular Vesicles As Potential Transport Vehicles In Hdmentioning

confidence: 99%

Potential Transfer of Polyglutamine and CAG-Repeat RNA in Extracellular Vesicles in Huntington’s Disease: Background and Evaluation in Cell Culture

et al. 2016

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In Huntington’s disease (HD) the imperfect expanded CAG repeat in the first exon of the HTT gene leads to the generation of a polyglutamine (polyQ) protein, which has some neuronal toxicity, potentially mollified by formation of aggregates. Accumulated research, reviewed here, implicates both the polyQ protein and the expanded repeat RNA in causing toxicity leading to neurodegeneration in HD. Different theories have emerged as to how the neurodegeneration spreads throughout the brain, with one possibility being the transport of toxic protein and RNA in extracellular vesicles (EVs). Most cell types in the brain release EVs and these have been shown to contain neurodegenerative proteins in the case of prion protein and amyloid-beta peptide. In this study, we used a model culture system with an overexpression of HTT-exon 1 polyQ-GFP constructs in human 293T cells and found that the EVs did incorporate both the polyQ-GFP protein and expanded repeat RNA. Striatal mouse neural cells were able to take up these EVs with a consequent increase in the green fluorescent protein (GFP) and polyQ-GFP RNAs, but with no evidence of uptake of polyQ-GFP protein or any apparent toxicity, at least over a relatively short period of exposure. A differentiated striatal cell line expressing endogenous levels of Hdh mRNA containing the expanded repeat incorporated more of this mRNA into EVs as compared to similar cells expressing this mRNA with a normal repeat length. These findings support the potential of EVs to deliver toxic expanded trinucleotide repeat RNAs from one cell to another, but further work will be needed to evaluate potential EV and cell-type specificity of transfer and effects of long-term exposure. It seems likely that expanded HD-associated repeat RNA may appear in biofluids and may have use as biomarkers of disease state and response to therapy.

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Section: Extracellular Vesicles As Potential Transport Vehicles In Hdmentioning

confidence: 99%

Potential Transfer of Polyglutamine and CAG-Repeat RNA in Extracellular Vesicles in Huntington’s Disease: Background and Evaluation in Cell Culture

et al. 2016

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“…We and other groups have shown that a reduction of Treg frequency is an immunological hallmark of RA [3,4,17]. Because exosomes were shown to contribute to intercellular communication by transporting signals into the target cells either close to or distant from the cells of exosome origin [12,16], we investigated the effect of RA-exosomes on Treg differentiation and found that RA-exosomes could inhibit Treg differentiation in vitro. Because miRNA has been shown to play an important role in the differentiation and function of immune cells [18][19][20][21][22][23], we next analyzed miRNA expression profiles in RA-exosomes as compared with those in HC-exosomes by microarray analysis.…”

Section: Discussionmentioning

confidence: 99%

“…Exosomes can affect the target cells via gene regulation, which is mediated by transfer of miRNAs [12][13][14]. Critical involvement of exosomes has been demonstrated in various human disorders, including cancer and neurodegenerative diseases [15,16]. However, exosomal miRNA function in Treg differentiation has not been studied in RA.…”

Section: Cd25mentioning

confidence: 99%

Circulating Exosomal miR-17 Inhibits the Induction of Regulatory T Cells via Suppressing TGFBR II Expression in Rheumatoid Arthritis

Wang

Jia

et al. 2018

Cell Physiol Biochem

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Background/Aims: A reduced prevalence of circulating regulatory T cells (Tregs)is a hallmark of inflammatory rheumatoid arthritis (RA). However, the underlying mechanisms of alterations of Tregs are unclear. Methods: The ratio of Tregs in peripheral blood of healthy controls (HCs) and patients with RA was determined by flow cytometry. MicroRNA (miRNA) expression profiles in exosomes derived from RA patients (RA-exosomes) and in those from HCs (HC-exosomes) were detected by microarray analysis, and miR-17 was measured by quantitative real-time PCR. Transforming growth factor beta receptor II (TGFBR II) expressed by T cells was measured by flow cytometry. The interaction between miR-17 and TGFBR II was evaluated by dual-luciferase reporter assay. Results: We found that RA-exosomes can selectively affect Treg differentiation in vitro. Several miRNAs are more abundant in the RA-exosomes than in HC-exosomes. Among those upregulated in patients with RA, miR-17 can suppress Treg induction by inhibiting the expression of TGFBR II. Conclusion: Our findings imply that altered miRNA expression in RA-exosomes may contribute to the pathogenesis of RA by disrupting the homeostasis of Tregs.

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“…In the last few years, different studies have shown as exosomes, microvesicles (40-100 nm) produced by almost all cells, are important in cellular communications, both in physiologic and pathologic conditions [28][29][30]. Exosomes from different cell types (MSCs, immune cells, etc.)…”

Section: Non-viral Vectormentioning

confidence: 99%

Gene therapy for chondral and osteochondral regeneration: is the future now?

Bellavia

Veronesi

Carina

et al. 2017

Cell. Mol. Life Sci.

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Gene therapy might represent a promising strategy for chondral and osteochondral defects repair by balancing the management of temporary joint mechanical incompetence with altered metabolic and inflammatory homeostasis. This review analysed preclinical and clinical studies on gene therapy for the repair of articular cartilage defects performed over the last 10 years, focussing on expression vectors (non-viral and viral), type of genes delivered and gene therapy procedures (direct or indirect). Plasmids (non-viral expression vectors) and adenovirus (viral vectors) were the most employed vectors in preclinical studies. Genes delivered encoded mainly for growth factors, followed by transcription factors, anti-inflammatory cytokines and, less frequently, by cell signalling proteins, matrix proteins and receptors. Direct injection of the expression vector was used less than indirect injection of cells, with or without scaffolds, transduced with genes of interest and then implanted into the lesion site. Clinical trials (phases I, II or III) on safety, biological activity, efficacy, toxicity or bio-distribution employed adenovirus viral vectors to deliver growth factors or anti-inflammatory cytokines, for the treatment of osteoarthritis or degenerative arthritis, and tumour necrosis factor receptor or interferon for the treatment of inflammatory arthritis

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Extracellular vesicles and intercellular communication within the nervous system

Cited by 200 publications

References 151 publications

Potential Transfer of Polyglutamine and CAG-Repeat RNA in Extracellular Vesicles in Huntington’s Disease: Background and Evaluation in Cell Culture

Potential Transfer of Polyglutamine and CAG-Repeat RNA in Extracellular Vesicles in Huntington’s Disease: Background and Evaluation in Cell Culture

Circulating Exosomal miR-17 Inhibits the Induction of Regulatory T Cells via Suppressing TGFBR II Expression in Rheumatoid Arthritis

Gene therapy for chondral and osteochondral regeneration: is the future now?

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