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Roles and Function of Extracellular Vesicles in Diseases 2.0

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Endocrinology and Metabolism".

Deadline for manuscript submissions: closed (30 April 2024) | Viewed by 14835

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Special Issue Editor

Dr. Won Jong Rhee

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Guest Editor

Department of Bioengineering and Nano-Bioengineering, Incheon National University, Incheon 22012, Republic of Korea
Interests: exosome; cell engineering; liquid biopsy; disease diagnosis; biologics development
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Extracellular vesicles (EVs) are small nano-sized particles that are constantly produced and secreted by cells. Since EVs originate from cells, they contain cellular components such as proteins, lipids, carbohydrates, DNAs, and RNAs. They play key roles in cell-to-cell communication through the transfer of those encapsulated components. As central mediators of intercellular communication, EVs play important roles in the pathogenesis of various diseases, such as cancer progression and metastasis. In this context, understanding the roles and function of EVs in our bodies is essential for the practical application of EVs in therapy and diagnosis.

This Special Issue of the International Journal of Molecular Sciences, “Roles and Function of Extracellular Vesicles in Disease”, will focus on (1) biogenesis or biochemical properties of EVs, (2) functions of EVs, (3) engineering EVs for therapeutic development, (4) development of novel EV sources, and (5) EV-based applications in therapy and diagnosis. Experimental papers, up-to-date review articles, and commentaries are all welcome.

Dr. Won Jong Rhee
Guest Editor

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. 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 vesicle
exosome
disease
roles and function

Published Papers (10 papers)

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Research

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18 pages, 7218 KiB

Open AccessArticle

Combinatory Nanovesicle with siRNA-Loaded Extracellular Vesicle and IGF-1 for Osteoarthritis Treatments

by Jun Yong Kim, Seung Yeon Lee, Seung-Gyu Cha, Jung Min Park, Duck Hyun Song, Sang-Hyuk Lee, Dong-Youn Hwang, Byoung Ju Kim, Seungsoo Rho, Chun Gwon Park, Won-Kyu Rhim and Dong Keun Han

Int. J. Mol. Sci. 2024, 25(10), 5242; https://doi.org/10.3390/ijms25105242 - 11 May 2024

Viewed by 431

Abstract

Extracellular vesicles (EVs) have been found to have the characteristics of their parent cells. Based on the characteristics of these EVs, various studies on disease treatment using mesenchymal stem cell (MSC)-derived EVs with regenerative activity have been actively conducted. The therapeutic nature of MSC-derived EVs has been shown in several studies, but in recent years, there have been many efforts to functionalize EVs to give them more potent therapeutic effects. Strategies for functionalizing EVs include endogenous and exogenous methods. In this study, human umbilical cord MSC (UCMSC)-derived EVs were selected for optimum OA treatments with expectation via bioinformatics analysis based on antibody array. And we created a novel nanovesicle system called the IGF-si-EV, which has the properties of both cartilage regeneration and long-term retention in the lesion site, attaching positively charged insulin-like growth factor-1 (IGF-1) to the surface of the UCMSC-derived Evs carrying siRNA, which inhibits MMP13. The downregulation of inflammation-related cytokine (MMP13, NF-kB, and IL-6) and the upregulation of cartilage-regeneration-related factors (Col2, Acan) were achieved with IGF-si-EV. Moreover, the ability of IGF-si-EV to remain in the lesion site for a long time has been proven through an ex vivo system. Collectively, the final constructed IGF-si-EV can be proposed as an effective OA treatment through its successful MMP13 inhibition, chondroprotective effect, and cartilage adhesion ability. We also believe that this EV-based nanoparticle-manufacturing technology can be applied as a platform technology for various diseases. Full article

(This article belongs to the Special Issue Roles and Function of Extracellular Vesicles in Diseases 2.0)

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23 pages, 4070 KiB

Open AccessArticle

Levels of Small Extracellular Vesicles Containing hERG-1 and Hsp47 as Potential Biomarkers for Cardiovascular Diseases

by Luis A. Osorio, Mauricio Lozano, Paola Soto, Viviana Moreno-Hidalgo, Angely Arévalo-Gil, Angie Ramírez-Balaguera, Daniel Hevia, Jorge Cifuentes, Yessia Hidalgo, Francisca Alcayaga-Miranda, Consuelo Pasten, Danna Morales, Diego Varela, Cinthya Urquidi, Andrés Iturriaga, Alejandra Rivera-Palma, Ricardo Larrea-Gómez and Carlos E. Irarrázabal

Int. J. Mol. Sci. 2024, 25(9), 4913; https://doi.org/10.3390/ijms25094913 - 30 Apr 2024

Viewed by 473

Abstract

The diagnosis of cardiovascular disease (CVD) is still limited. Therefore, this study demonstrates the presence of human ether-a-go-go-related gene 1 (hERG1) and heat shock protein 47 (Hsp47) on the surface of small extracellular vesicles (sEVs) in human peripheral blood and their association with CVD. In this research, 20 individuals with heart failure and 26 participants subjected to cardiac stress tests were enrolled. The associations between hERG1 and/or Hsp47 in sEVs and CVD were established using Western blot, flow cytometry, electron microscopy, ELISA, and nanoparticle tracking analysis. The results show that hERG1 and Hsp47 were present in sEV membranes, extravesicularly exposing the sequences ⁴³⁰AFLLKETEEGPPATE⁴⁴⁵ for hERG1 and ¹⁶⁹ALQSINEWAAQTT- DGKLPEVTKDVERTD¹⁹⁶ for Hsp47. In addition, upon exposure to hypoxia, rat primary cardiomyocytes released sEVs into the media, and human cardiomyocytes in culture also released sEVs containing hERG1 (EV-hERG1) and/or Hsp47 (EV-Hsp47). Moreover, the levels of sEVs increased in the blood when cardiac ischemia was induced during the stress test, as well as the concentrations of EV-hERG1 and EV-Hsp47. Additionally, the plasma levels of EV-hERG1 and EV-Hsp47 decreased in patients with decompensated heart failure (DHF). Our data provide the first evidence that hERG1 and Hsp47 are present in the membranes of sEVs derived from the human cardiomyocyte cell line, and also in those isolated from human peripheral blood. Total sEVs, EV-hERG1, and EV-Hsp47 may be explored as biomarkers for heart diseases such as heart failure and cardiac ischemia. Full article

(This article belongs to the Special Issue Roles and Function of Extracellular Vesicles in Diseases 2.0)

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19 pages, 3418 KiB

Open AccessArticle

Transcriptomic Analysis of Extracellular Vesicles in the Search for Novel Plasma and Thrombus Biomarkers of Ischemic Stroke Etiologies

by Florencio J. D. M. Machado, Juan Marta-Enguita, Susan U. Gómez, Jose A. Rodriguez, José Antonio Páramo-Fernández, María Herrera, Beatriz Zandio, Nuria Aymerich, Roberto Muñoz, Rebeca Bermejo, Javier Marta-Moreno, Begoña López, Arantxa González, Carmen Roncal and Josune Orbe

Int. J. Mol. Sci. 2024, 25(8), 4379; https://doi.org/10.3390/ijms25084379 - 16 Apr 2024

Viewed by 733

Abstract

Accurate etiologic diagnosis provides an appropriate secondary prevention and better prognosis in ischemic stroke (IS) patients; still, 45% of IS are cryptogenic, urging us to enhance diagnostic precision. We have studied the transcriptomic content of plasma extracellular vesicles (EVs) (n = 21) to identify potential biomarkers of IS etiologies. The proteins encoded by the selected genes were measured in the sera of IS patients (n = 114) and in hypertensive patients with (n = 78) and without atrial fibrillation (AF) (n = 20). IGFBP-2, the most promising candidate, was studied using immunohistochemistry in the IS thrombi (n = 23) and atrium of AF patients (n = 13). In vitro, the IGFBP-2 blockade was analyzed using thromboelastometry and endothelial cell cultures. We identified 745 differentially expressed genes among EVs of cardioembolic, atherothrombotic, and ESUS groups. From these, IGFBP-2 (cutoff > 247.6 ng/mL) emerged as a potential circulating biomarker of embolic IS [OR = 8.70 (1.84–41.13) p = 0.003], which was increased in patients with AF vs. controls (p < 0.001) and was augmented in cardioembolic vs. atherothrombotic thrombi (p < 0.01). Ex vivo, the blockage of IGFBP-2 reduced clot firmness (p < 0.01) and lysis time (p < 0.001) and in vitro, diminished endothelial permeability (p < 0.05) and transmigration (p = 0.06). IGFBP-2 could be a biomarker of embolic IS and a new therapeutic target involved in clot formation and endothelial dysfunction. Full article

(This article belongs to the Special Issue Roles and Function of Extracellular Vesicles in Diseases 2.0)

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12 pages, 4142 KiB

Open AccessArticle

Role of Exosomal miR-205-5p Cargo in Angiogenesis and Cell Migration

by Miriam Martínez-Santos, María Ybarra, María Oltra, María Muriach, Francisco J. Romero, Maria E. Pires, Javier Sancho-Pelluz and Jorge M. Barcia

Int. J. Mol. Sci. 2024, 25(2), 934; https://doi.org/10.3390/ijms25020934 - 11 Jan 2024

Viewed by 974

Abstract

Exosomes or small extracellular vesicles (sEVs) represent a pivotal component in intercellular communication, carrying a diverse array of biomolecules. Several factors can affect sEVs release dynamics, as occurs in hyperglycemia or inflammation. In fact, sEVs release has been associated with the promotion of physio-pathological processes. Among the sEVs cargo, microRNAs play an essential role in cell-to-cell regulation. More concretely, miR-205-5p is related to angiogenesis and cell proliferation. The aim of this study is to understand the specific role of sEVs containing miR-205-5p under high glucose conditions. ARPE-19 cells were cultured with high glucose (HG) for 5 days. sEVs were isolated and characterized. sEVs from ARPE-19 were used for angiogenesis and cell proliferation. HG increased sEVs release but downregulated miR-205-5p cargo expression compared to the control. sEVs from HG-treated ARPE-19 cells promoted tube formation and migration processes. In contrast, miR-205-5p overexpression (by mimic transfection) decreased angiogenesis and cell migration. Our results demonstrate how ARPE-19 cells respond to HG challenge by increasing sEVs with weak miR-205-5p cargo. The absence of this miRNA in sEVs is enough to promote angiogenesis. In contrast, restoring sEVs-miR-205-5p levels decreased it. These findings open new possibilities in sEVs-based therapies containing miR-205-5p against angiogenesis. Full article

(This article belongs to the Special Issue Roles and Function of Extracellular Vesicles in Diseases 2.0)

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13 pages, 3268 KiB

Open AccessArticle

Perilla-Leaf-Derived Extracellular Vesicles Selectively Inhibit Breast Cancer Cell Proliferation and Invasion

by Do Kyung Kim, Su Jin Kang and Won Jong Rhee

Int. J. Mol. Sci. 2023, 24(21), 15633; https://doi.org/10.3390/ijms242115633 - 26 Oct 2023

Viewed by 1258

Abstract

Breast cancer is a common type of cancer characterized by high mortality rates. However, chemotherapy is not selective and often leads to side-effects. Therefore, there is a need for the development of highly efficient drugs. Recent studies have shown that some extracellular vesicles (EVs) derived from cell cultures possess anti-cancer activity and hold great potential as cancer therapeutics. However, the use of mammalian cell cultures for EV production results in low productivity and high costs. To address this issue, extracellular vesicles derived from perilla leaves (Perex) were isolated and investigated for their anti-cancer activity in various cancer cells. Initially, a high concentration of Perex with a low level of impurities was successfully purified through a combination of ultrafiltration and size-exclusion chromatography. Perex exhibited potent anti-cancer activities, inhibiting the proliferation, migration, and invasion of MDA-MB-231 cancer cells, which have high levels of caveolin-1 compared to other cancer and normal cells. This selective attack on cancer cells with high levels of caveolin-1 reduces unwanted side-effects on normal cells. Considering its high productivity, low production cost, selective anti-cancer activity, and minimal side-effects, Perex represents a promising candidate for the therapeutic treatment of breast cancer. Full article

(This article belongs to the Special Issue Roles and Function of Extracellular Vesicles in Diseases 2.0)

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17 pages, 3738 KiB

Open AccessArticle

MiR-148a-3p within HucMSC-Derived Extracellular Vesicles Suppresses Hsp90b1 to Prevent Fibroblast Collagen Synthesis and Secretion in Silica-Induced Pulmonary Fibrosis

by Qiyue Jiang, Jing Zhao, Qiyue Jia, Hongwei Wang, Wenming Xue, Fuao Ning, Jiaxin Wang, Yan Wang, Zhonghui Zhu and Lin Tian

Int. J. Mol. Sci. 2023, 24(19), 14477; https://doi.org/10.3390/ijms241914477 - 23 Sep 2023

Cited by 2 | Viewed by 1313

Abstract

Silicosis is a fatal occupational respiratory disease caused by the prolonged inhalation of respirable silica. The core event of silicosis is the heightened activity of fibroblasts, which excessively synthesize extracellular matrix (ECM) proteins. Our previous studies have highlighted that human umbilical cord mesenchymal stem cell-derived extracellular vesicles (hucMSC-EVs) hold promise in mitigating silicosis and the significant role played by microRNAs (miRNAs) in this process. Delving deeper into this mechanism, we found that miR-148a-3p was the most abundant miRNA of the differential miRNAs in hucMSC-EVs, with the gene heat shock protein 90 beta family member 1 (Hsp90b1) as a potential target. Notably, miR-148a-3p’s expression was downregulated during the progression of silica-induced pulmonary fibrosis both in vitro and in vivo, but was restored after hucMSC-EVs treatment (p < 0.05). Introducing miR-148a-3p mimics effectively hindered the collagen synthesis and secretion of fibroblasts induced by transforming growth factor-β1 (TGF-β1) (p < 0.05). Confirming our hypothesis, Hsp90b1 was indeed targeted by miR-148a-3p, with significantly reduced collagen activity in TGF-β1-treated fibroblasts upon Hsp90b1 inhibition (p < 0.05). Collectively, our findings provide compelling evidence that links miR-148a-3p present in hucMSC-EVs with the amelioration of silicosis, suggesting its therapeutic potential by specifically targeting Hsp90b1, thereby inhibiting fibroblast collagen activities. This study sheds light on the role of miR-148a-3p in hucMSC-EVs, opening avenues for innovative therapeutic interventions targeting molecular pathways in pulmonary fibrosis. Full article

(This article belongs to the Special Issue Roles and Function of Extracellular Vesicles in Diseases 2.0)

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15 pages, 5103 KiB

Open AccessArticle

Analysis of MicroRNA Signature Differentially Expressed in Pancreatic Islet Cells Treated with Pancreatic Cancer-Derived Exosomes

by Young-gon Kim, Jisook Park, Eun Young Park, Sang-Mi Kim and Soo-Youn Lee

Int. J. Mol. Sci. 2023, 24(18), 14301; https://doi.org/10.3390/ijms241814301 - 19 Sep 2023

Cited by 1 | Viewed by 1251

Abstract

Since the majority of patients with pancreatic cancer (PC) develop insulin resistance and/or diabetes mellitus (DM) prior to PC diagnosis, PC-induced diabetes mellitus (PC-DM) has been a focus for a potential platform for PC detection. In previous studies, the PC-derived exosomes were shown to contain the mediators of PC-DM. In the present study, the response of normal pancreatic islet cells to the PC-derived exosomes was investigated to determine the potential biomarkers for PC-DM, and consequently, for PC. Specifically, changes in microRNA (miRNA) expression were evaluated. The miRNA specimens were prepared from the untreated islet cells as well as the islet cells treated with the PC-derived exosomes (from 50 patients) and the healthy-derived exosomes (from 50 individuals). The specimens were subjected to next-generation sequencing and bioinformatic analysis to determine the differentially expressed miRNAs (DEmiRNAs) only in the specimens treated with the PC-derived exosomes. Consequently, 24 candidate miRNA markers, including IRS1-modulating miRNAs such as hsa-miR-144-5p, hsa-miR-3148, and hsa-miR-3133, were proposed. The proposed miRNAs showed relevance to DM and/or insulin resistance in a literature review and pathway analysis, indicating a potential association with PC-DM. Due to the novel approach used in this study, additional evidence from future studies could corroborate the value of the miRNA markers discovered. Full article

(This article belongs to the Special Issue Roles and Function of Extracellular Vesicles in Diseases 2.0)

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21 pages, 774 KiB

Open AccessArticle

Extracellular Vesicles and Their Zeta Potential as Future Markers Associated with Nutrition and Molecular Biomarkers in Breast Cancer

by Herminia Mendivil-Alvarado, Ana Teresa Limon-Miro, Elizabeth Carvajal-Millan, Jaime Lizardi-Mendoza, Araceli Mercado-Lara, Carlos D. Coronado-Alvarado, María L. Rascón-Durán, Iván Anduro-Corona, Daniel Talamás-Lara, Antonio Rascón-Careaga and Humberto Astiazarán-García

Int. J. Mol. Sci. 2023, 24(7), 6810; https://doi.org/10.3390/ijms24076810 - 6 Apr 2023

Cited by 2 | Viewed by 2818

Abstract

A nutritional intervention promotes the loss of body and visceral fat while maintaining muscle mass in breast cancer patients. Extracellular vesicles (EVs) and their characteristics can be potential biomarkers of disease. Here, we explore the changes in the Zeta potential of EVs; the content of miRNA-30, miRNA-145, and miRNA-155; and their association with body composition and biomarkers of metabolic risk in breast cancer patients, before and 6 months after a nutritional intervention. Clinicopathological data (HER2neu, estrogen receptor, and Ki67), anthropometric and body composition data, and plasma samples were available from a previous study. Plasma EVs were isolated and characterized in 16 patients. The expression of miRNA-30, miRNA-145, and miRNA-155 was analyzed. The Zeta potential was associated with HER2neu (β = 2.1; p = 0.00), Ki67 (β = −1.39; p = 0.007), estrogen positive (β = 1.57; p = 0.01), weight (β = −0.09; p = 0.00), and visceral fat (β = 0.004; p = 0.00). miRNA-30 was associated with LDL (β = −0.012; p = 0.01) and HDL (β = −0.02; p = 0.05). miRNA-155 was associated with visceral fat (β = −0.0007; p = 0.05) and Ki67 (β = −0.47; p = 0.04). Our results reveal significant associations between the expression of miRNA-30 and miRNA-155 and the Zeta potential of the EVs with biomarkers of metabolic risk and disease prognosis in women with breast cancer; particularly, the Zeta potential of EVs can be a new biomarker sensitive to changes in the nutritional status and breast cancer progression. Full article

(This article belongs to the Special Issue Roles and Function of Extracellular Vesicles in Diseases 2.0)

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Review

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13 pages, 763 KiB

Open AccessReview

Treatment of Cardiac Fibrosis with Extracellular Vesicles: What Is Missing for Clinical Translation?

by Sebastian Neuber, Miriam R. Ermer, Maximilian Y. Emmert and Timo Z. Nazari-Shafti

Int. J. Mol. Sci. 2023, 24(13), 10480; https://doi.org/10.3390/ijms241310480 - 22 Jun 2023

Cited by 2 | Viewed by 1449

Abstract

Heart failure is the leading cause of morbidity and mortality and currently affects more than 60 million people worldwide. A key feature in the pathogenesis of almost all forms of heart failure is cardiac fibrosis, which is characterized by excessive accumulation of extracellular matrix components in the heart. Although cardiac fibrosis is beneficial in the short term after acute myocardial injury to preserve the structural and functional integrity of the heart, persistent cardiac fibrosis contributes to pathological cardiac remodeling, leading to mechanical and electrical dysfunction of the heart. Despite its high prevalence, standard therapies specifically targeting cardiac fibrosis are not yet available. Cell-based approaches have been extensively studied as potential treatments for cardiac fibrosis, but several challenges have been identified during clinical translation. The observation that extracellular vesicles (EVs) derived from stem and progenitor cells exhibit some of the therapeutic effects of the parent cells has paved the way to overcome limitations associated with cell therapy. However, to make EV-based products a reality, standardized methods for EV production, isolation, characterization, and storage must be established, along with concrete evidence of their safety and efficacy in clinical trials. This article discusses EVs as novel therapeutics for cardiac fibrosis from a translational perspective. Full article

(This article belongs to the Special Issue Roles and Function of Extracellular Vesicles in Diseases 2.0)

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28 pages, 2428 KiB

Open AccessReview

Outer Membrane Vesicles (OMVs) as Biomedical Tools and Their Relevance as Immune-Modulating Agents against H. pylori Infections: Current Status and Future Prospects

by Abeer Ahmed Qaed Ahmed, Roberta Besio, Lin Xiao and Antonella Forlino

Int. J. Mol. Sci. 2023, 24(10), 8542; https://doi.org/10.3390/ijms24108542 - 10 May 2023

Cited by 4 | Viewed by 3274

Abstract

Outer membrane vesicles (OMVs) are lipid-membrane-bounded nanoparticles that are released from Gram-negative bacteria via vesiculation of the outer membrane. They have vital roles in different biological processes and recently, they have received increasing attention as possible candidates for a broad variety of biomedical applications. In particular, OMVs have several characteristics that enable them to be promising candidates for immune modulation against pathogens, such as their ability to induce the host immune responses given their resemblance to the parental bacterial cell. Helicobacter pylori (H. pylori) is a common Gram-negative bacterium that infects half of the world’s population and causes several gastrointestinal diseases such as peptic ulcer, gastritis, gastric lymphoma, and gastric carcinoma. The current H. pylori treatment/prevention regimens are poorly effective and have limited success. This review explores the current status and future prospects of OMVs in biomedicine with a special focus on their use as a potential candidate in immune modulation against H. pylori and its associated diseases. The emerging strategies that can be used to design OMVs as viable immunogenic candidates are discussed. Full article

(This article belongs to the Special Issue Roles and Function of Extracellular Vesicles in Diseases 2.0)

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