The Role of Extracellular Vesicles in Pathogenesis and Therapeutic Strategies 2.0

A special issue of Biomedicines (ISSN 2227-9059). This special issue belongs to the section "Molecular and Translational Medicine".

Deadline for manuscript submissions: 30 April 2024 | Viewed by 5959

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Laboratory for Medical Mass Spectrometry, Biomedicine group, Alborg University, Aalborg, Denmark
Interests: proteomics; post-translational modifications; personalized medicine; liquid biomarkers
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Extracellular vesicles (EVs) are emerging as a valuable source of novel liquid biomarkers, insight into systemic signaling, and theranostic tools. EVs, including exosomes and other membrane-bound packets, are released by all cells under a range of conditions, ranging from homeostatic equilibrium to states of cellular stress.

Prior to their efficient application in strategies for prognostics, diagnostics, and use as theranostic tools or in functional studies, EVs and synthetic mimetic-EVs require preparation, during which a range of key points must be addressed, including regarding purification steps, characterization, cargo loading, surface targeting strategies, generation of membrane fragments for the construction of biomimetic materials, preparation of synthetic membranes inspired in EV composition, and subsequent surface decoration.

The outer surface and cargo contained within EV packets varies according to the cell origin and includes byproducts of cellular housekeeping activities as well as molecular signals to neighboring cells. These packets of information, whether transferred between different microorganisms and yeasts or between cells within the multicellular organisms, relay cell–cell information and thereby help to coordinate system-wide responses to stressors or changing conditions.

The in-depth characterization of EVs is still complicated by the small size of EVs and the lack of tools to study different populations of these nano-sized packages in detail. With the emergence of new tools and methods for EV research, these challenges are being overcome, and the heterogeneity of EVs, their cargo, and their function in health and disease are beginning to be understood. Several strategies have been reported for producing artificial EVs, but there has not yet been a clear criterion by which to differentiate these novel biomaterials.

In states of disease, these EVs, depending on their origin, may adaptively ameliorate the disease state or contribute to pathogenesis. Furthermore, because they are released from intercellular spaces into the circulation, they are being investigated through ‘liquid biopsies’ for various diseases and biological conditions.

The purpose of this Special Issue is to address specific attributes of EVs as liquid biomarkers for personalized medicine. In providing this overview, this Special Issue will delineate the current foundations and tools for the next steps toward the application of EV in therapeutic strategies for the treatment of a wide range of diseases. Manuscripts may cover either original data in a specialized field or be a comprehensive review. Contributions covering any aspect discussed here are encouraged, as are those on related topics that have not been explicitly mentioned.

Dr. Allan Stensballe
Guest Editor

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Keywords

  • exosomes
  • inflammation
  • extracellular vesicles
  • miRNA
  • proteomics
  • signaling
  • mimetic vesicles
 

Published Papers (3 papers)

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Research

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21 pages, 3202 KiB  
Article
New Enhancing MRI Lesions Associate with IL-17, Neutrophil Degranulation and Integrin Microparticles: Multi-Omics Combined with Frequent MRI in Multiple Sclerosis
by Zsolt Illes, Malene Møller Jørgensen, Rikke Bæk, Lisa-Marie Bente, Jørgen T. Lauridsen, Kirsten H. Hyrlov, Christopher Aboo, Jan Baumbach, Tim Kacprowski, Francois Cotton, Charles R. G. Guttmann and Allan Stensballe
Biomedicines 2023, 11(12), 3170; https://doi.org/10.3390/biomedicines11123170 - 28 Nov 2023
Viewed by 1645
Abstract
Background: Blood–barrier (BBB) breakdown and active inflammation are hallmarks of relapsing multiple sclerosis (RMS), but the molecular events contributing to the development of new lesions are not well explored. Leaky endothelial junctions are associated with increased production of endothelial-derived extracellular microvesicles (EVs) and [...] Read more.
Background: Blood–barrier (BBB) breakdown and active inflammation are hallmarks of relapsing multiple sclerosis (RMS), but the molecular events contributing to the development of new lesions are not well explored. Leaky endothelial junctions are associated with increased production of endothelial-derived extracellular microvesicles (EVs) and result in the entry of circulating immune cells into the brain. MRI with intravenous gadolinium (Gd) can visualize acute blood–barrier disruption as the initial event of the evolution of new lesions. Methods: Here, weekly MRI with Gd was combined with proteomics, multiplex immunoassay, and endothelial stress-optimized EV array to identify early markers related to BBB disruption. Five patients with RMS with no disease-modifying treatment were monitored weekly using high-resolution 3T MRI scanning with intravenous gadolinium (Gd) for 8 weeks. Patients were then divided into three groups (low, medium, or high MRI activity) defined by the number of new, total, and maximally enhancing Gd-enhancing lesions and the number of new FLAIR lesions. Plasma samples taken at each MRI were analyzed for protein biomarkers of inflammation by quantitative proteomics, and cytokines using multiplex immunoassays. EVs were characterized with an optimized endothelial stress EV array based on exosome surface protein markers for the detection of soluble secreted EVs. Results: Proteomics analysis of plasma yielded quantitative information on 208 proteins at each patient time point (n = 40). We observed the highest number of unique dysregulated proteins (DEPs) and the highest functional enrichment in the low vs. high MRI activity comparison. Complement activation and complement/coagulation cascade were also strongly overrepresented in the low vs. high MRI activity comparison. Activation of the alternative complement pathway, pathways of blood coagulation, extracellular matrix organization, and the regulation of TLR and IGF transport were unique for the low vs. high MRI activity comparison as well, with these pathways being overrepresented in the patient with high MRI activity. Principal component analysis indicated the individuality of plasma profiles in patients. IL-17 was upregulated at all time points during 8 weeks in patients with high vs. low MRI activity. Hierarchical clustering of soluble markers in the plasma indicated that all four MRI outcomes clustered together with IL-17, IL-12p70, and IL-1β. MRI outcomes also showed clustering with EV markers CD62E/P, MIC A/B, ICAM-1, and CD42A. The combined cluster of these cytokines, EV markers, and MRI outcomes clustered also with IL-12p40 and IL-7. All four MRI outcomes correlated positively with levels of IL-17 (p < 0.001, respectively), and EV-ICAM-1 (p < 0.0003, respectively). IL-1β levels positively correlated with the number of new Gd-enhancing lesions (p < 0.01), new FLAIR lesions (p < 0.001), and total number of Gd-enhancing lesions (p < 0.05). IL-6 levels positively correlated with the number of new FLAIR lesions (p < 0.05). Random Forests and linear mixed models identified IL-17, CCL17/TARC, CCL3/MIP-1α, and TNF-α as composite biomarkers predicting new lesion evolution. Conclusions: Combination of serial frequent MRI with proteome, neuroinflammation markers, and protein array data of EVs enabled assessment of temporal changes in inflammation and endothelial dysfunction in RMS related to the evolution of new and enhancing lesions. Particularly, the Th17 pathway and IL-1β clustered and correlated with new lesions and Gd enhancement, indicating their importance in BBB disruption and initiating acute brain inflammation in MS. In addition to the Th17 pathway, abundant protein changes between MRI activity groups suggested the role of EVs and the coagulation system along with innate immune responses including acute phase proteins, complement components, and neutrophil degranulation. Full article
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15 pages, 596 KiB  
Review
Engineered Extracellular Vesicles in Treatment of Type 1 Diabetes Mellitus: A Prospective Review
by Alok Raghav, Hamid Ashraf and Goo-Bo Jeong
Biomedicines 2022, 10(12), 3042; https://doi.org/10.3390/biomedicines10123042 - 25 Nov 2022
Cited by 3 | Viewed by 2037
Abstract
Insulin replacement is an available treatment for autoimmune type 1 diabetes mellitus (T1DM). There are multiple limitations in the treatment of autoimmune diseases such as T1DM by immunosuppression using drugs and chemicals. The advent of extracellular vesicle (EV)-based therapies for the treatment of [...] Read more.
Insulin replacement is an available treatment for autoimmune type 1 diabetes mellitus (T1DM). There are multiple limitations in the treatment of autoimmune diseases such as T1DM by immunosuppression using drugs and chemicals. The advent of extracellular vesicle (EV)-based therapies for the treatment of various diseases has attracted much attention to the field of bio-nanomedicine. Tolerogenic nanoparticles can induce immune tolerance, especially in autoimmune diseases. EVs can deliver cargo to specific cells without restrictions. Accordingly, EVs can be used to deliver tolerogenic nanoparticles, including iron oxide-peptide-major histocompatibility complex, polyethylene glycol-silver-2-(1′H-indole-3′-carbonyl)-thiazole-4-carboxylic acid methyl ester, and carboxylated poly (lactic-co-glycolic acid) nanoparticles coupled with or encapsulating an antigen, to effectively treat autoimmune T1DM. The present work highlights the advances in exosome-based delivery of tolerogenic nanoparticles for the treatment of autoimmune T1DM. Full article
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20 pages, 7747 KiB  
Protocol
Isolation of Bovine and Human Milk Extracellular Vesicles
by Ralf Weiskirchen, Sarah K. Schröder, Sabine Weiskirchen, Eva Miriam Buhl and Bodo Melnik
Biomedicines 2023, 11(10), 2715; https://doi.org/10.3390/biomedicines11102715 - 06 Oct 2023
Viewed by 1700
Abstract
Extracellular vesicles such as exosomes are small-sized, bilayered extracellular biovesicles generated by almost every cell and released into the surrounding body fluids upon the fusion of multivesicular bodies and the plasma membrane. Based on their origin, they are enriched with a variety of [...] Read more.
Extracellular vesicles such as exosomes are small-sized, bilayered extracellular biovesicles generated by almost every cell and released into the surrounding body fluids upon the fusion of multivesicular bodies and the plasma membrane. Based on their origin, they are enriched with a variety of biologically active components including proteins, lipids, nucleic acids, cellular metabolites, and many other constituents. They can either attach or fuse with the membrane of a target cell, or alternatively be taking up via endocytosis by a recipient cell. In particular, milk exosomes have been recently shown to be a fundamental factor supporting infant growth, health, and development. In addition, exosomes derived from different cell types have been shown to possess regenerative, immunomodulatory, and anti-inflammatory properties, suggesting that they are a potential therapeutic tool in modulating the pathogenesis of diverse diseases. Therefore, efficient protocols for the isolation of milk exosomes in a high quantity and purity are the basis for establishing clinical applications. Here, we present an easy-to-follow protocol for exosome isolation from bovine and human milk. Electron microscopic analysis and nanoparticle tracking analysis reveal that the protocols allow the isolation of highly enriched fractions of exosomes. The purified exosomes express the typical exosomal protein markers, CD81 and ALIX. Full article
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