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Nucleic Acids within Extracellular Vesicles: Functional Role in Health and...
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Nucleic Acids within Extracellular Vesicles: Functional Role in Health and Disease

A special issue of Genes (ISSN 2073-4425). This special issue belongs to the section "Molecular Genetics and Genomics".

Deadline for manuscript submissions: closed (26 April 2021) | Viewed by 22396

Special Issue Editors

Prof. Dr. Carla Emiliani

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Guest Editor
Department of Chemistry, Universita degli Studi di Perugia, Perugia, Italy
Interests: gene expression; lysosomes and vesicular trafficking; autophagy and related diseases; extracellular vesicles
Dr. Sandra Buratta

E-Mail Website
Guest Editor
Department of Chemistry, Biology and Biotechnology, University of Perugia, Via del Giochetto, 06123 Perugia, Italy
Interests: extracellular vesicles; lipidomics; phospholipid metabolism; cell signaling
Special Issues, Collections and Topics in MDPI journals
Prof. Brunella Tancini

E-Mail Website
Guest Editor
Department of Chemistry, Universita degli Studi di Perugia, Perugia, Italy
Interests: cell biology; gene expression; autophagy and related diseases
Dr. Lorena Urbanelli

E-Mail Website
Guest Editor
Department of Chemistry, Biology and Biotechnology, University of Perugia, Via del Giochetto, 06123 Perugia, Italy
Interests: extracellular vesicles; autophagy; lysosomes; senescence; aging; lipidomics
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Extracellular vesicles (EVs) are membrane-enclosed vesicles of nanometric size that are released outside the cell and present in every fluid of the body. They were initially considered a garbage disposal tool, but current advances indicate that they play an important role in intercellular signaling. A major feature of EVs is their ability to carry functional macromolecules. These include not only proteins and lipids, but also nucleic acids. EVs carry both DNA and RNA, and for this reason, they are considered a means of horizontal gene transfer. Different nucleic acids are carried by EVs. As for DNA, the presence of genomic and mitochondrial DNA into EVs has been reported, as well as the presence of oncogenic DNA in vesicles circulating in cancer patients. As for RNA, the presence of miRNA has been widely observed, as well as the presence of lncRNA and mRNA, which are also key functional effectors of EVs. Further, advanced sequencing techniques have also provided evidence of the presence of other RNA species, such as snRNA, snoRNA, and piRNA. EVs are relatively stable and can be easily isolated from body fluids; therefore, the presence of nucleic acids has attracted considerable interest for diagnostic purposes. In this Special Issue of Genes, we invite authors to submit original research and review articles illustrating the presence and functional role of different nucleic acids in EVs, the molecular mechanism underlying their loading, and their possible applications in diagnosis and therapy.

Prof. Carla Emiliani
Prof. Sandra Buratta
Prof. Brunella Tancini
Prof. Lorena Urbanelli
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Genes is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2600 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • extracellular vesicles
  • exosomes
  • microvesicles
  • apoptotic bodies
  • oncosomes
  • vesicle Genomic DNA
  • vesicle Mytochondrial DNA
  • vesicle lncRNA
  • vesicle miRNA
  • vesicle mRNA

Published Papers (7 papers)

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Research

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16 pages, 10042 KiB  
Article
Kinetics and Topology of DNA Associated with Circulating Extracellular Vesicles Released during Exercise
by Elmo W. I. Neuberger, Barlo Hillen, Katharina Mayr, Perikles Simon, Eva-Maria Krämer-Albers and Alexandra Brahmer
Genes 2021, 12(4), 522; https://doi.org/10.3390/genes12040522 - 2 Apr 2021
Cited by 22 | Viewed by 3172
Abstract
Although it is widely accepted that cancer-derived extracellular vesicles (EVs) carry DNA cargo, the association of cell-free circulating DNA (cfDNA) and EVs in plasma of healthy humans remains elusive. Using a physiological exercise model, where EVs and cfDNA are synchronously released, we aimed [...] Read more.
Although it is widely accepted that cancer-derived extracellular vesicles (EVs) carry DNA cargo, the association of cell-free circulating DNA (cfDNA) and EVs in plasma of healthy humans remains elusive. Using a physiological exercise model, where EVs and cfDNA are synchronously released, we aimed to characterize the kinetics and localization of DNA associated with EVs. EVs were separated from human plasma using size exclusion chromatography or immuno-affinity capture for CD9+, CD63+, and CD81+ EVs. DNA was quantified with an ultra-sensitive qPCR assay targeting repetitive LINE elements, with or without DNase digestion. This model shows that a minute part of circulating cell-free DNA is associated with EVs. During rest and following exercise, only 0.12% of the total cfDNA occurs in association with CD9+/CD63+/CD81+EVs. DNase digestion experiments indicate that the largest part of EV associated DNA is sensitive to DNase digestion and only ~20% are protected within the lumen of the separated EVs. A single bout of running or cycling exercise increases the levels of EVs, cfDNA, and EV-associated DNA. While EV surface DNA is increasing, DNAse-resistant DNA remains at resting levels, indicating that EVs released during exercise (ExerVs) do not contain DNA. Consequently, DNA is largely associated with the outer surface of circulating EVs. ExerVs recruit cfDNA to their corona, but do not carry DNA in their lumen. Full article
(This article belongs to the Special Issue Nucleic Acids within Extracellular Vesicles: Functional Role in Health and Disease)
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10 pages, 3361 KiB  
Article
Extracellular Vesicles-Mediated Transfer of miRNA Let-7b from PC3 Cells to Macrophages
by Egidia Costanzi, Rita Romani, Paolo Scarpelli and Ilaria Bellezza
Genes 2020, 11(12), 1495; https://doi.org/10.3390/genes11121495 - 12 Dec 2020
Cited by 8 | Viewed by 2039
Abstract
Prostate-derived extracellular vesicles (pEVs) may represent a way to selectively transport cargo molecules from the producing cells to the target cells to allow biological events, both in physiological and pathological circumstances. pEVs cargo participates in the modulation of the inflammatory responses in physiological [...] Read more.
Prostate-derived extracellular vesicles (pEVs) may represent a way to selectively transport cargo molecules from the producing cells to the target cells to allow biological events, both in physiological and pathological circumstances. pEVs cargo participates in the modulation of the inflammatory responses in physiological conditions and during cancer progression. In the present study, we examined the expression levels of miRNA Let-7b, in both precursor and mature forms, in noncancerous and cancerous prostate cell lines, PNT2 and PC3 respectively, and in their extracellular vesicles (EVs) using reverse-transcription quantitative PCR strategies. We showed that miRNA Let-7b was highly expressed in noncancerous cells and strongly decreased in cancerous PC3 cells, while the opposite was observed in the respective EVs, thus supporting the tumor suppressor role of miRNA Let7-b. We also demonstrated that miRNA Let-7b can be transferred to THP-1 cells via EVs, which are known to induce TAM-like polarization. Our results support the view that miRNA Let-7 b, contained in PC3-derived EVs, is associated with the increase in the miRNA Let7-b observed in TAM-like macrophages. Overall, our results indicate that circulating EV-loaded miRNA might be useful biomarkers for prostate cancer progression and might also support a possible use of pEVs as targets for prostate cancer therapy. Full article
(This article belongs to the Special Issue Nucleic Acids within Extracellular Vesicles: Functional Role in Health and Disease)
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Review

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20 pages, 1085 KiB  
Review
The Role of Extracellular Vesicles as Shuttles of RNA and Their Clinical Significance as Biomarkers in Hepatocellular Carcinoma
by Eva Costanzi, Carolina Simioni, Gabriele Varano, Cinzia Brenna, Ilaria Conti and Luca Maria Neri
Genes 2021, 12(6), 902; https://doi.org/10.3390/genes12060902 - 11 Jun 2021
Cited by 4 | Viewed by 2923
Abstract
Extracellular vesicles (EVs) have attracted interest as mediators of intercellular communication following the discovery that EVs contain RNA molecules, including non-coding RNA (ncRNA). Growing evidence for the enrichment of peculiar RNA species in specific EV subtypes has been demonstrated. ncRNAs, transferred from donor [...] Read more.
Extracellular vesicles (EVs) have attracted interest as mediators of intercellular communication following the discovery that EVs contain RNA molecules, including non-coding RNA (ncRNA). Growing evidence for the enrichment of peculiar RNA species in specific EV subtypes has been demonstrated. ncRNAs, transferred from donor cells to recipient cells, confer to EVs the feature to regulate the expression of genes involved in differentiation, proliferation, apoptosis, and other biological processes. These multiple actions require accuracy in the isolation of RNA content from EVs and the methodologies used play a relevant role. In liver, EVs play a crucial role in regulating cell–cell communications and several pathophysiological events in the heterogeneous liver class of cells via horizontal transfer of their cargo. This review aims to discuss the rising role of EVs and their ncRNAs content in regulating specific aspects of hepatocellular carcinoma development, including tumorigenesis, angiogenesis, and tumor metastasis. We analyze the progress in EV-ncRNAs’ potential clinical applications as important diagnostic and prognostic biomarkers for liver conditions. Full article
(This article belongs to the Special Issue Nucleic Acids within Extracellular Vesicles: Functional Role in Health and Disease)
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29 pages, 3009 KiB  
Review
The “Vesicular Intelligence” Strategy of Blood Cancers
by Dorian Forte, Martina Barone, Francesca Palandri and Lucia Catani
Genes 2021, 12(3), 416; https://doi.org/10.3390/genes12030416 - 13 Mar 2021
Cited by 8 | Viewed by 2837
Abstract
Blood cancers are a heterogeneous group of disorders including leukemia, multiple myeloma, and lymphoma. They may derive from the clonal evolution of the hemopoietic stem cell compartment or from the transformation of progenitors with immune potential. Extracellular vesicles (EVs) are membrane-bound nanovesicles which [...] Read more.
Blood cancers are a heterogeneous group of disorders including leukemia, multiple myeloma, and lymphoma. They may derive from the clonal evolution of the hemopoietic stem cell compartment or from the transformation of progenitors with immune potential. Extracellular vesicles (EVs) are membrane-bound nanovesicles which are released by cells into body fluids with a role in intercellular communication in physiology and pathology, including cancer. EV cargos are enriched in nucleic acids, proteins, and lipids, and these molecules can be delivered to target cells to influence their biological properties and modify surrounding or distant targets. In this review, we will describe the “smart strategy” on how blood cancer-derived EVs modulate tumor cell development and maintenance. Moreover, we will also depict the function of microenvironment-derived EVs in blood cancers and discuss how the interplay between tumor and microenvironment affects blood cancer cell growth and spreading, immune response, angiogenesis, thrombogenicity, and drug resistance. The potential of EVs as non-invasive biomarkers will be also discussed. Lastly, we discuss the clinical application viewpoint of EVs in blood cancers. Overall, blood cancers apply a ‘vesicular intelligence’ strategy to spread signals over their microenvironment, promoting the development and/or maintenance of the malignant clone. Full article
(This article belongs to the Special Issue Nucleic Acids within Extracellular Vesicles: Functional Role in Health and Disease)
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16 pages, 2497 KiB  
Review
The Multifunctionality of Exosomes; from the Garbage Bin of the Cell to a Next Generation Gene and Cellular Therapy
by Surya Shrivastava and Kevin V. Morris
Genes 2021, 12(2), 173; https://doi.org/10.3390/genes12020173 - 27 Jan 2021
Cited by 12 | Viewed by 3431
Abstract
Exosomes are packaged with a variety of cellular cargo including RNA, DNA, lipids and proteins. For several decades now there has been ongoing debate as to what extent exosomes are the garbage bin of the cell or if these entities function as a [...] Read more.
Exosomes are packaged with a variety of cellular cargo including RNA, DNA, lipids and proteins. For several decades now there has been ongoing debate as to what extent exosomes are the garbage bin of the cell or if these entities function as a distributer of cellular cargo which acts in a meaningful mechanistic way on target cells. Are the contents of exosomes unwanted excess cellular produce or are they selective nucleic acid packaged nanoparticles used to communicate in a paracrine fashion? Overexpressed RNAs and fragments of DNA have been shown to collect into exosomes which are jettisoned from cells in response to particular stimuli to maintain homeostasis suggesting exosomes are functional trash bins of the cell. Other studies however have deciphered selective packaging of particular nucleic acids into exosomes. Nucleic acids packaged into exosomes are increasingly reported to exert transcriptional control on recipient cells, supporting the notion that exosomes may provide a role in signaling and intracellular communication. We survey the literature and conclude that exosomes are multifunctional entities, with a plethora of roles that can each be taken advantage to functionally modulate cells. We also note that the potential utility of developing exosomes as a next generation genetic therapy may in future transform cellular therapies. We also depict three models of methodologies which can be adopted by researchers intending to package nucleic acid in exosomes for developing gene and cell therapy. Full article
(This article belongs to the Special Issue Nucleic Acids within Extracellular Vesicles: Functional Role in Health and Disease)
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17 pages, 770 KiB  
Review
The Significance of Exosomal RNAs in the Development, Diagnosis, and Treatment of Gastric Cancer
by Guiping Zhao, Anni Zhou, Xiao Li, Shengtao Zhu, Yongjun Wang, Shutian Zhang and Peng Li
Genes 2021, 12(1), 73; https://doi.org/10.3390/genes12010073 - 8 Jan 2021
Cited by 12 | Viewed by 3145
Abstract
Gastric cancer (GC) is one of the most common malignancies in the world. Exosomes, a subset of extracellular vesicles with an average diameter of 100 nm, contain and transfer a variety of functional macromolecules such as proteins, lipids, and nucleic acids. A large [...] Read more.
Gastric cancer (GC) is one of the most common malignancies in the world. Exosomes, a subset of extracellular vesicles with an average diameter of 100 nm, contain and transfer a variety of functional macromolecules such as proteins, lipids, and nucleic acids. A large number of studies indicated that exosomes can play a significant role in the initiation and development of GC via facilitating intercellular communication between gastric cancer cells and microenvironment. Exosomal RNAs, one of the key functional cargos, are involved in the pathogenesis, development, and metastasis of GC. In addition, recent studies elucidated that exosomal RNAs may serve as diagnostic and prognostic biomarkers or therapeutic targets for GC. In this review, we summarized the function of exosomal RNA in the tumorigenesis, progression, diagnosis, and treatment of GC, which may further unveil the functions of exosome and promote the potentially diagnostic and therapeutic application of exosomes in GC. Full article
(This article belongs to the Special Issue Nucleic Acids within Extracellular Vesicles: Functional Role in Health and Disease)
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13 pages, 547 KiB  
Review
DNA Associated with Circulating Exosomes as a Biomarker for Glioma
by Manjusha Vaidya and Kiminobu Sugaya
Genes 2020, 11(11), 1276; https://doi.org/10.3390/genes11111276 - 29 Oct 2020
Cited by 19 | Viewed by 3761
Abstract
Cancerous and non-cancerous cells secrete exosomes, a type of nanovesicle known to carry the molecular signature of the parent for intercellular communications. Exosomes secreted by tumor cells carry abnormal DNA, RNA, and protein molecules that reflect the cancerous status. DNA is the master [...] Read more.
Cancerous and non-cancerous cells secrete exosomes, a type of nanovesicle known to carry the molecular signature of the parent for intercellular communications. Exosomes secreted by tumor cells carry abnormal DNA, RNA, and protein molecules that reflect the cancerous status. DNA is the master molecule that ultimately affects the function of RNA and proteins. Aberrations in DNA can potentially lead a cell to malignancy. Deviant quantities and the differential sequences of exosomal DNA are useful characteristics as cancer biomarkers. Since these alterations are either associated with specific stages of cancer or caused due to a clinical treatment, exosomal DNA is valuable as a diagnostic, prognostic, predictive, and therapeutic-intervention response biomarker. Notably, the exosomes can cross an intact blood–brain barrier and anatomical compartments by transcytosis. As such, the cancer-specific trademark molecules can be detected in systemic blood circulation and other body fluids, including cerebrospinal fluid, with non-invasive or minimally invasive procedures. This comprehensive review highlights the cancer-specific modulations of DNA associated with circulating exosomes that are beneficial as glioma biomarkers. Full article
(This article belongs to the Special Issue Nucleic Acids within Extracellular Vesicles: Functional Role in Health and Disease)
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