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Exosomes and Extracellular Vesicles in Health and Diseases

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: closed (30 July 2023) | Viewed by 16567

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Dr. Manuela Zavatti

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Department of Biomedical, Metabolic and Neural Sciences, University of Modena and Reggio Emilia, 41125 Modena, Italy
Interests: molecular mechanism in cancer; PI3K/Akt signaling; adaptive resistance to Akt inhibitors in prostate cancer; immunomodulatory properties of stem cells extracellular vesicle; neurodegenerative disorders
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Dr. Francesca Beretti

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Department of Biomedical, Metabolic and Neural Sciences, University of Modena and Reggio Emilia, 41125 Modena, Italy
Interests: exosomes; extracellular vesicles; microRNA; amnion fluid
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

The rising interest in exosomes and extracellular vesicles and their applications are well-documented by the increasing level of research in these fields.

These vesicles are naturally produced by any type of cells and play multiple roles in cell-to-cell communication, in both healthy and diseased states. Because they carry different donor-derived cargos, including DNA, RNA, proteins and lipids, they are pivotal for inducing network signals in recipient cells.

In particular, stem-cell-derived extracellular vesicles play roles in regenerative medicine and have the advantage of being a cell-free therapy; therefore, these vesicles are safer than those associated with the transplantation of live cells.

Furthermore, in recent years, exosomes and extracellular vesicles have emerged as promising biomarkers in the diagnosis and prognosis of different diseases, but also as macromolecule delivery carriers in the therapy of a wide spectrum of pathologies.

This Special Issue, entitled “Exosomes and Extracellular Vesicles in Health and Disease”, welcomes original research articles that contribute to broadening our knowledge of extracellular vesicles and exosomes in different fields of application, starting from the healthy state in order to comprehend mechanisms of individual production, and moving to pathological conditions, such as tumors, neurodegenerative diseases, cardiovascular diseases, chronic and acute inflammation state, etc.

Dr. Manuela Zavatti
Dr. Francesca Beretti
Guest Editors

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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. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. 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
exosome
biomarkers
cell-to-cell communication
signal transduction
diseases
therapy
regenerative medicine
cargo

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Published Papers (9 papers)

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14 pages, 9528 KiB

Open AccessArticle

Isolation of Extracellular Vesicles of Holothuria (Sea Cucumber Eupentacta fraudatrix)

by Anastasiya V. Tupitsyna, Alina E. Grigorieva, Svetlana E. Soboleva, Nadezhda A. Maltseva, Sergey E. Sedykh, Julia Poletaeva, Pavel S. Dmitrenok, Elena I. Ryabchikova and Georgy A. Nevinsky

Int. J. Mol. Sci. 2023, 24(16), 12907; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms241612907 - 17 Aug 2023

Viewed by 883

Abstract

Extracellular vesicles (EVs), carriers of molecular signals, are considered a critical link in maintaining homeostasis in mammals. Currently, there is growing interest in studying the role of EVs, including exosomes (subpopulation of EVs), in animals of other evolutionary levels, including marine invertebrates. We have studied the possibility of obtaining appropriate preparations of EVs from whole-body extract of holothuria Eupentacta fraudatrix using a standard combination of centrifugation and ultracentrifugation. However, the preparations were heavily polluted, which did not allow us to conclude that they contained vesicles. Subsequent purification by FLX gel filtration significantly reduced the pollution but did not increase vesicle concentration to a necessary level. To detect EVs presence in the body of holothurians, we used transmission electron microscopy of ultrathin sections. Late endosomes, producing the exosomes, were found in the cells of the coelom epithelium covering the gonad, digestive tube and respiratory tree, as well as in the parenchyma cells of these organs. The study of purified homogenates of these organs revealed vesicles (30–100 nm) morphologically corresponding to exosomes. Thus, we can say for sure that holothurian cells produce EVs including exosomes, which can be isolated from homogenates of visceral organs. Full article

(This article belongs to the Special Issue Exosomes and Extracellular Vesicles in Health and Diseases)

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15 pages, 8148 KiB

Open AccessArticle

Engineered Human Dendritic Cell Exosomes as Effective Delivery System for Immune Modulation

by Ranya Elsayed, Mahmoud Elashiry, Cathy Tran, Tigerwin Yang, Angelica Carroll, Yutao Liu, Mark Hamrick and Christopher W. Cutler

Int. J. Mol. Sci. 2023, 24(14), 11306; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms241411306 - 11 Jul 2023

Cited by 2 | Viewed by 1542

Abstract

Exosomes (exos) contain molecular cargo of therapeutic and diagnostic value for cancers and other inflammatory diseases, but their therapeutic potential for periodontitis (PD) remains unclear. Dendritic cells (DCs) are the directors of immune response and have been extensively used in immune therapy. We previously reported in a mouse model of PD that custom murine DC-derived exo subtypes could reprogram the immune response toward a bone-sparing or bone-loss phenotype, depending on immune profile. Further advancement of this technology requires the testing of human DC-based exos with human target cells. Our main objective in this study is to test the hypothesis that human monocyte-derived dendritic cell (MoDC)-derived exos constitute a well-tolerated and effective immune therapeutic approach to modulate human target DC and T cell immune responses in vitro. MoDC subtypes were generated with TGFb/IL-10 (regulatory (reg) MoDCs, CD86^lowHLA-DR^lowPDL1^high), E. coli LPS (stimulatory (stim) MoDCs, CD86^highHLA-DR^highPDL1^low) and buffer (immature (i) MoDCs, CD86^lowHLA-DR^medPDL1^low). Exosomes were isolated from different MoDC subtypes and characterized. Once released from the secreting cell into the surrounding environment, exosomes protect their prepackaged molecular cargo and deliver it to bystander cells. This modulates the functions of these cells, depending on the cargo content. RegMoDCexos were internalized by recipient MoDCs and induced upregulation of PDL1 and downregulation of costimulatory molecules CD86, HLADR, and CD80, while stimMoDCexos had the opposite influence. RegMoDCexos induced CD25+Foxp3+ Tregs, which expressed CTLA4 and PD1 but not IL-17A. In contrast, T cells treated with stimMoDCexos induced IL-17A+ Th17 T cells, which were negative for immunoregulatory CTLA4 and PD1. T cells and DCs treated with iMoDCexos were immune ‘neutral’, equivalent to controls. In conclusion, human DC exos present an effective delivery system to modulate human DC and T cell immune responses in vitro. Thus, MoDC exos may present a viable immunotherapeutic agent for modulating immune response in the gingival tissue to inhibit bone loss in periodontal disease. Full article

(This article belongs to the Special Issue Exosomes and Extracellular Vesicles in Health and Diseases)

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17 pages, 2610 KiB

Open AccessArticle

Human Umbilical Cord Blood Endothelial Progenitor Cell-Derived Extracellular Vesicles Control Important Endothelial Cell Functions

by Sawssen Ben Fraj, Sina Naserian, Bileyle Lorenzini, Sylvie Goulinet, Philippe Mauduit, Georges Uzan and Houda Haouas

Int. J. Mol. Sci. 2023, 24(12), 9866; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms24129866 - 7 Jun 2023

Cited by 1 | Viewed by 1260

Abstract

Circulating endothelial progenitor cells (EPCs) play a pivotal role in the repair of diseases in which angiogenesis is required. Although they are a potentially valuable cell therapy tool, their clinical use remains limited due to suboptimal storage conditions and, especially, long-term immune rejection. EPC-derived extracellular vesicles (EPC-EVs) may be an alternative to EPCs given their key role in cell–cell communication and expression of the same parental markers. Here, we investigated the regenerative effects of umbilical cord blood (CB) EPC-EVs on CB-EPCs in vitro. After amplification, EPCs were cultured in a medium containing an EVs-depleted serum (EV-free medium). Then, EVs were isolated from the conditioned medium with tangential flow filtration (TFF). The regenerative effects of EVs on cells were investigated by analyzing cell migration, wound healing, and tube formation. We also analyzed their effects on endothelial cell inflammation and Nitric Oxide (NO) production. We showed that adding different doses of EPC-EVs on EPCs does not alter the basal expression of the endothelial cell markers nor change their proliferative potential and NO production level. Furthermore, we demonstrated that EPC-EVs, when used at a higher dose than the physiological dose, create a mild inflammatory condition that activates EPCs and boosts their regenerative features. Our results reveal for the first time that EPC-EVs, when used at a high dose, enhance EPC regenerative functions without altering their endothelial identity. Full article

(This article belongs to the Special Issue Exosomes and Extracellular Vesicles in Health and Diseases)

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19 pages, 5287 KiB

Open AccessArticle

Human Neuromuscular Junction on a Chip: Impact of Amniotic Fluid Stem Cell Extracellular Vesicles on Muscle Atrophy and NMJ Integrity

by Martina Gatti, Katarina Stoklund Dittlau, Francesca Beretti, Laura Yedigaryan, Manuela Zavatti, Pietro Cortelli, Carla Palumbo, Emma Bertucci, Ludo Van Den Bosch, Maurilio Sampaolesi and Tullia Maraldi

Int. J. Mol. Sci. 2023, 24(5), 4944; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms24054944 - 3 Mar 2023

Cited by 3 | Viewed by 2129

Abstract

Neuromuscular junctions (NMJs) are specialized synapses, crucial for the communication between spinal motor neurons (MNs) and skeletal muscle. NMJs become vulnerable in degenerative diseases, such as muscle atrophy, where the crosstalk between the different cell populations fails, and the regenerative ability of the entire tissue is hampered. How skeletal muscle sends retrograde signals to MNs through NMJs represents an intriguing field of research, and the role of oxidative stress and its sources remain poorly understood. Recent works demonstrate the myofiber regeneration potential of stem cells, including amniotic fluid stem cells (AFSC), and secreted extracellular vesicles (EVs) as cell-free therapy. To study NMJ perturbations during muscle atrophy, we generated an MN/myotube co-culture system through Xona^TM microfluidic devices, and muscle atrophy was induced in vitro by Dexamethasone (Dexa). After atrophy induction, we treated muscle and MN compartments with AFSC-derived EVs (AFSC-EVs) to investigate their regenerative and anti-oxidative potential in counteracting NMJ alterations. We found that the presence of EVs reduced morphological and functional in vitro defects induced by Dexa. Interestingly, oxidative stress, occurring in atrophic myotubes and thus involving neurites as well, was prevented by EV treatment. Here, we provided and validated a fluidically isolated system represented by microfluidic devices for studying human MN and myotube interactions in healthy and Dexa-induced atrophic conditions—allowing the isolation of subcellular compartments for region-specific analyses—and demonstrated the efficacy of AFSC-EVs in counteracting NMJ perturbations. Full article

(This article belongs to the Special Issue Exosomes and Extracellular Vesicles in Health and Diseases)

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18 pages, 3059 KiB

Open AccessArticle

Expression of Epithelial and Mesenchymal Markers in Plasmatic Extracellular Vesicles as a Diagnostic Tool for Neoplastic Processes

by Begoña O. Alen, Lara Sofía Estévez-Pérez, María Otero Alén, Saioa Domínguez Hormaetxe, Laureano Simón and Ángel Concha

Int. J. Mol. Sci. 2023, 24(4), 3578; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms24043578 - 10 Feb 2023

Cited by 1 | Viewed by 1596

Abstract

Tumor-derived extracellular vesicles (TD-EVs) have active roles as cancer hallmark enablers. EVs RNA of epithelial and stromal cells carry information that facilitates the communication processes that contribute to oncological progression, so the objective of this work was to validate by RT-PCR the presence of epithelial (KRT19; CEA) and stromal (COL1A2; COL11A1) markers in RNA of plasmatic EVs in healthy and diverse-malignancy patients for the development of a non-invasive cancer diagnosis system using liquid biopsy. Ten asymptomatic controls and 20 cancer patients were included in the study, and results showed that the isolated plasmatic EVs by scanning transmission electron microscopy (STEM) andBiomedical Research Institute A Coruña nanoparticle tracking analysis (NTA) contained most exosome structures with also a considerable percentage of microvesicles. No differences were found in concentration and size distribution between the two cohorts of patients, but significant gene expression in epithelial and mesenchymal markers between healthy donors and patients with active oncological disease was shown. Results of quantitative RT-PCR are solid and reliable for KRT19, COL1A2, and COL11A1, so the analysis of RNA extracted from TD-EVs could be a correct approach to develop a diagnostic tool in oncological processes. Full article

(This article belongs to the Special Issue Exosomes and Extracellular Vesicles in Health and Diseases)

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19 pages, 2637 KiB

Open AccessArticle

Protein-Coding Region Derived Small RNA in Exosomes from Influenza A Virus–Infected Cells

by Malgorzata Kwasnik, Wojciech Socha, Bartosz Czech, Magdalena Wasiak, Jerzy Rola and Wojciech Rozek

Int. J. Mol. Sci. 2023, 24(1), 867; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms24010867 - 3 Jan 2023

Viewed by 2085

Abstract

Exosomes may function as multifactorial mediators of cell-to-cell communication, playing crucial roles in both physiological and pathological processes. Exosomes released from virus-infected cells may contain RNA and proteins facilitating infection spread. The purpose of our study was to analyze how the small RNA content of exosomes is affected by infection with the influenza A virus (IAV). Exosomes were isolated by ultracentrifugation after hemadsorption of virions and their small RNA content was identified using high-throughput sequencing. As compared to mock-infected controls, 856 RNA transcripts were significantly differentially expressed in exosomes from IAV-infected cells, including fragments of 458 protein-coding (pcRNA), 336 small, 28 long intergenic non-coding RNA transcripts, and 33 pseudogene transcripts. Upregulated pcRNA species corresponded mainly to proteins associated with translation and antiviral response, and the most upregulated among them were RSAD2, CCDC141 and IFIT2. Downregulated pcRNA species corresponded to proteins associated with the cell cycle and DNA packaging. Analysis of differentially expressed pseudogenes showed that in most cases, an increase in the transcription level of pseudogenes was correlated with an increase in their parental genes. Although the role of exosome RNA in IAV infection remains undefined, the biological processes identified based on the corresponding proteins may indicate the roles of some of its parts in IAV replication. Full article

(This article belongs to the Special Issue Exosomes and Extracellular Vesicles in Health and Diseases)

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12 pages, 1113 KiB

Open AccessArticle

Upregulation of miR145 and miR126 in EVs from Renal Cells Undergoing EMT and Urine of Diabetic Nephropathy Patients

by Veronica Dimuccio, Linda Bellucci, Marianna Genta, Cristina Grange, Maria Felice Brizzi, Maddalena Gili, Sara Gallo, Maria Laura Centomo, Federica Collino and Benedetta Bussolati

Int. J. Mol. Sci. 2022, 23(20), 12098; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms232012098 - 11 Oct 2022

Cited by 6 | Viewed by 2035

Abstract

Diabetic nephropathy (DN) is a severe kidney-related complication of type 1 and type 2 diabetes and the most frequent cause of end-stage kidney disease. Extracellular vesicles (EVs) present in the urine mainly derive from the cells of the nephron, thus representing an interesting tool mirroring the kidney’s physiological state. In search of the biomarkers of disease progression, we here assessed a panel of urinary EV miRNAs previously related to DN in type 2 diabetic patients stratified based on proteinuria levels. We found that during DN progression, miR145 and miR126 specifically increased in urinary EVs from diabetic patients together with albuminuria. In vitro, miRNA modulation was assessed in a model of TGF-β1-induced glomerular damage within a three-dimensional perfusion system, as well as in a model of tubular damage induced by albumin and glucose overload. Both renal tubular cells and podocytes undergoing epithelial to mesenchymal transition released EVs containing increased miR145 and miR126 levels. At the same time, miR126 levels were reduced in EVs released by glomerular endothelial cells. This work highlights a modulation of miR126 and miR145 during the progression of kidney damage in diabetes as biomarkers of epithelial to mesenchymal transition. Full article

(This article belongs to the Special Issue Exosomes and Extracellular Vesicles in Health and Diseases)

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15 pages, 2619 KiB

Open AccessArticle

Cancer Three-Dimensional Spheroids Mimic In Vivo Tumor Features, Displaying “Inner” Extracellular Vesicles and Vasculogenic Mimicry

by Ilaria Giusti, Giuseppina Poppa, Sandra D’Ascenzo, Letizia Esposito, Anna Rita Vitale, Giuseppe Calvisi and Vincenza Dolo

Int. J. Mol. Sci. 2022, 23(19), 11782; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms231911782 - 4 Oct 2022

Cited by 9 | Viewed by 1826

Abstract

The role of extracellular vesicles (EVs) as mediators of cell-to-cell communication in cancer progression is widely recognized. In vitro studies are routinely performed on 2D culture models, but recent studies suggest that 3D cultures could represent a more valid model. Human ovarian cancer cells CABA I were cultured by the hanging drop method to form tumor spheroids, that were moved to low adhesion supports to observe their morphology by Scanning Electron Microscopy (SEM) and to isolate the EVs. EVs release was verified by SEM and their identity confirmed by morphology (Transmission Electron Microscopy, TEM), size distribution (Nanoparticles Tracking Analysis), and markers (CD63, CD9, TSG-101, Calnexin). CABA I form spheroids with a clinically relevant size, above 400 μm; they release EVs on their external surface and also trap “inner” EVs. They also produce vasculogenic mimicry-like tubules, that bulge from the spheroid and are composed of a hollow lumen delimited by tumor cells. CABA I can be grown as multicellular spheroids to easily isolate EVs. The presence of features typical of in vivo tumors (inner entrapped EVs and vasculogenic mimicry) suggests their use as faithful experimental models to screen therapeutic drugs targeting these pro-tumorigenic processes. Full article

(This article belongs to the Special Issue Exosomes and Extracellular Vesicles in Health and Diseases)

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17 pages, 1169 KiB

Open AccessReview

Extracellular Vesicles in Haematological Disorders: A Friend or a Foe?

by Ioanna Lazana

Int. J. Mol. Sci. 2022, 23(17), 10118; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms231710118 - 4 Sep 2022

Cited by 2 | Viewed by 2030

Abstract

Extracellular vesicles (EVs) have emerged as important mediators of homeostasis, immune modulation and intercellular communication. They are released by every cell of the human body and accordingly detected in a variety of body fluids. Interestingly, their expression can be upregulated under various conditions, such as stress, hypoxia, irradiation, inflammation, etc. Their cargo, which is variable and may include lipids, proteins, RNAs and DNA, reflects that of the parental cell, which offers a significant diagnostic potential to EVs. In line with this, an increasing number of studies have reported the important contribution of cancer-derived EVs in altering the tumour microenvironment and allowing for cancer progression and metastasis. As such, cancer-derived EVs may be used to monitor the development and progression of disease and to evaluate the potential response to treatment, which has generated much excitement in the field of oncology and particularly in haemato-oncology. Finally, EVs are able to transfer their cargo to target cells, modifying the properties of the recipient cell, which offers great therapeutic potential for EVs (either by specific drug delivery or by delivery of siRNAs and other inhibitory proteins). In this manuscript, we review the potential diagnostic use and therapeutic options of EVs in the context of haematological malignancies. Full article

(This article belongs to the Special Issue Exosomes and Extracellular Vesicles in Health and Diseases)

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