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Extracellular Vesicles: Multifaceted Biological Nanoparticles in Health and Disease

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A special issue of Biology (ISSN 2079-7737). This special issue belongs to the section "Medical Biology".

Deadline for manuscript submissions: closed (30 September 2022) | Viewed by 41278

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Dr. Meena Kumari

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College of Veterinary Medicine, Kansas State University, Manhattan, KS 66506, USA
Interests: mRNA stability and alcohol addiction; exosomes and their role in differentiation and addiction to drugs of abuse
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Dear Colleagues,

Cells release vesicles of different sizes throughout life until their death. The mode of vesicle genesis dictates their size, content, function, and perhaps clues to their identification. Multivesicular endosomes-originated vesicles named exosomes are the smallest (35-150 nm) extracellular vesicles known to date, making their purification somewhat challenging. Once purified, exosomes can be easily characterized due to their association with specific marker proteins, their appearance under transmission electron microscope, and density. Originally described as “vesicles filled with unwanted cellular proteins” for disposal out of the maturing reticulocytes, exosomes have now become an important entity in the intercellular communication field. Exosomes exert their influence on gene expression of cells internalizing them. Release of exosomes by parent cells and the ability of recipient cells to internalize exosomes is key to cell-cell communication. Internalized exosomes modulate physiology of recipient cells during all stages of life ranging from normal to senescence including a diseased state. Exosome unique cargo of proteins, lipids, metabolites, and nucleic acids offers opportunities to employ them for identification of biomarkers associated with normal physiology and importantly as promising diagnostic tools in clinical practice. Exosomes can be employed for targeted therapeutic treatments by loading them with appropriate proteins and nuclei acids to alter gene expression in defined recipient cells. Exosomes present endless prospects in life sciences.

Dr. Meena Kumari
Guest Editor

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Keywords

extracellular vesicles and exosomes
isolation and characterization
biological activity in development, differentiation, health and disease
therapeutic applications

Published Papers (10 papers)

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Research

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11 pages, 914 KiB

Open AccessArticle

Biochemical Characterization of Human Salivary Extracellular Vesicles as a Valuable Source of Biomarkers

by Valentina Mangolini, Alice Gualerzi, Silvia Picciolini, Francesca Rodà, Angela Del Prete, Luana Forleo, Rudy Alexander Rossetto and Marzia Bedoni

Biology 2023, 12(2), 227; https://0-doi-org.brum.beds.ac.uk/10.3390/biology12020227 - 31 Jan 2023

Cited by 3 | Viewed by 1760

Abstract

Extracellular vesicles (EVs) are natural nanoparticles secreted under physiological and pathological conditions. Thanks to their diagnostic potential, EVs are increasingly being studied as biomarkers of a variety of diseases, including neurological disorders. To date, most studies on EV biomarkers use blood as the source, despite different disadvantages that may cause an impure isolation of the EVs. In the present article, we propose the use of saliva as a valuable source of EVs that could be studied as biomarkers in an easily accessible biofluid. Using a comparable protocol for the isolation of EVs from both liquid biopsies, salivary EVs showed greater purity in terms of co-isolates (evaluated by nanoparticle tracking analysis and Conan test). In addition, Raman spectroscopy was used for the identification of the overall biochemical composition of EVs coming from the two different biofluids. Even considering the limited amount of EVs that can be isolated from saliva, the use of Raman spectroscopy was not hampered, and it was able to provide a comprehensive characterization of EVs in a high throughput and repeatable manner. Raman spectroscopy can thus represent a turning point in the application of salivary EVs in clinics, taking advantage of the simple method of collection of the liquid biopsy and of the quick, sensitive and label-free biophotonics-based approach. Full article

(This article belongs to the Special Issue Extracellular Vesicles: Multifaceted Biological Nanoparticles in Health and Disease)

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20 pages, 10706 KiB

Open AccessArticle

A Different Exosome Secretion Pattern Characterizes Patient-Derived Colorectal Cancer Multicellular Spheroids and Their Mouse Xenografts

by Michela Relucenti, Federica Francescangeli, Maria Laura De Angelis, Vito D’Andrea, Selenia Miglietta, Orlando Donfrancesco, Xiaobo Li, Rui Chen, Ann Zeuner and Giuseppe Familiari

Biology 2022, 11(10), 1427; https://0-doi-org.brum.beds.ac.uk/10.3390/biology11101427 - 29 Sep 2022

Cited by 2 | Viewed by 1841

Abstract

Up-to-date in vitro and in vivo preclinical models expressing the patient-specific cancer lineage responsible for CRC and its metastatic behavior and responsiveness to therapy are needed. Exosomes’ role in tumorigenesis and the metastatic process was demonstrated, and the material content and size of the exosomes are associated with a poor prognosis of CRC. Exosomes are generally imagined after their recovery from blood serum as isolated entities, and our work aims to investigate them “in situ” in their native environment by scanning and transmission electron microscopy to understand their secretion modalities. We studied CRC stem cells in patient-derived multicellular tumor spheroids (MTSs) and in their mouse xenograft to find possible differences in terms of exosome amount, size, and secretion site between in vitro and in vivo models. We observed that MTSs’ exosome secretion patterns depend on their structural complexity: few-layer MTSs show a lesser exosome secretion, limited to the apical domain of cancer cells, secretion increases in multilayered MTSs, and it develops from apical and basolateral cancer cells domains. In xenograft models, exosome secretion occurs from all cancer cell domains, and it is quantitatively greater than that observed in MTSs. This difference in exosome secretion pattern between MTSs and xenografts may be due to the influence of surrounding non-tumor cells. Full article

(This article belongs to the Special Issue Extracellular Vesicles: Multifaceted Biological Nanoparticles in Health and Disease)

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20 pages, 3157 KiB

Open AccessFeature PaperArticle

Characterization of Extracellular Vesicles Secreted by a Clinical Isolate of Naegleria fowleri and Identification of Immunogenic Components within Their Protein Cargo

by Lissette Retana Moreira, María Fernanda Steller Espinoza, Natalia Chacón Camacho, Alberto Cornet-Gomez, Giovanni Sáenz-Arce, Antonio Osuna, Bruno Lomonte and Elizabeth Abrahams Sandí

Biology 2022, 11(7), 983; https://0-doi-org.brum.beds.ac.uk/10.3390/biology11070983 - 29 Jun 2022

Cited by 9 | Viewed by 2986

Abstract

Extracellular vesicles (EVs) are small lipid vesicles released by both prokaryotic and eukaryotic cells, involved in intercellular communication, immunomodulation and pathogenesis. In this study, we performed a characterization of the EVs produced by trophozoites of a clinical isolate of the free-living amoeba Naegleria fowleri (N. fowleri). Size distribution, zeta potential, protein profile and protease activity were analyzed. Under our incubation conditions, EVs of different sizes were observed, with a predominant population ranging from 206 to 227 nm. SDS-PAGE revealed protein bands of 25 to 260 KDa. The presence of antigenic proteins was confirmed by Western blot, which evidenced strongest recognition by rat polyclonal antibodies raised against N. fowleri in the region close to 80 KDa and included peptidases, as revealed by zymography. Proteins in selected immunorecognized bands were further identified using nano-ESI-MS/MS. A preliminary proteomic profile of the EVs identified at least 184 proteins as part of the vesicles’ cargo. Protease activity assays, in combination with the use of inhibitors, revealed the predominance of serine proteases. The present characterization uncovers the complexity of EVs produced by N. fowleri, suggesting their potential relevance in the release of virulence factors involved in pathogenicity. Owing to their cargo’s diversity, further research on EVs could reveal new therapeutic targets or biomarkers for developing rapid and accurate diagnostic tools for lethal infections such as the one caused by this amoeba. Full article

(This article belongs to the Special Issue Extracellular Vesicles: Multifaceted Biological Nanoparticles in Health and Disease)

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18 pages, 26742 KiB

Open AccessArticle

Single Gene Mutations in Pkd1 or Tsc2 Alter Extracellular Vesicle Production and Trafficking

by Prashant Kumar, Fahad Zadjali, Ying Yao, Michael Köttgen, Alexis Hofherr, Kenneth W. Gross, Darshan Mehta and John J. Bissler

Biology 2022, 11(5), 709; https://0-doi-org.brum.beds.ac.uk/10.3390/biology11050709 - 06 May 2022

Cited by 3 | Viewed by 2587

Abstract

Patients with autosomal dominant polycystic kidney disease (ADPKD) and tuberous sclerosis complex (TSC) are born with normal or near-normal kidneys that later develop cysts and prematurely lose function. Both renal cystic diseases appear to be mediated, at least in part, by disease-promoting extracellular vesicles (EVs) that induce genetically intact cells to participate in the renal disease process. We used centrifugation and size exclusion chromatography to isolate the EVs for study. We characterized the EVs using tunable resistive pulse sensing, dynamic light scattering, transmission electron microscopy, and Western blot analysis. We performed EV trafficking studies using a dye approach in both tissue culture and in vivo studies. We have previously reported that loss of the Tsc2 gene significantly increased EV production and here demonstrate that the loss of the Pkd1 gene also significantly increases EV production. Using a cell culture system, we also show that loss of either the Tsc2 or Pkd1 gene results in EVs that exhibit an enhanced uptake by renal epithelial cells and a prolonged half-life. Loss of the primary cilia significantly reduces EV production in renal collecting duct cells. Cells that have a disrupted Pkd1 gene produce EVs that have altered kinetics and a prolonged half-life, possibly impacting the duration of the EV cargo effect on the recipient cell. These results demonstrate the interplay between primary cilia and EVs and support a role for EVs in polycystic kidney disease pathogenesis. Full article

(This article belongs to the Special Issue Extracellular Vesicles: Multifaceted Biological Nanoparticles in Health and Disease)

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13 pages, 1539 KiB

Open AccessArticle

Neuron-Derived Extracellular Vesicles Modulate Microglia Activation and Function

by Hui Peng, Brock T. Harvey, Christopher I. Richards and Kimberly Nixon

Biology 2021, 10(10), 948; https://0-doi-org.brum.beds.ac.uk/10.3390/biology10100948 - 22 Sep 2021

Cited by 14 | Viewed by 3045

Abstract

Microglia act as the immune cells of the central nervous system (CNS). They play an important role in maintaining brain homeostasis but also in mediating neuroimmune responses to insult. The interactions between neurons and microglia represent a key process for neuroimmune regulation and subsequent effects on CNS integrity. However, the molecular mechanisms of neuron-glia communication in regulating microglia function are not fully understood. One recently described means of this intercellular communication is via nano-sized extracellular vesicles (EVs) that transfer a large diversity of molecules between neurons and microglia, such as proteins, lipids, and nucleic acids. To determine the effects of neuron-derived EVs (NDEVs) on microglia, NDEVs were isolated from the culture supernatant of rat cortical neurons. When NDEVs were added to primary cultured rat microglia, we found significantly improved microglia viability via inhibition of apoptosis. Additionally, application of NDEVs to cultured microglia also inhibited the expression of activation surface markers on microglia. Furthermore, NDEVs reduced the LPS-induced proinflammatory response in microglia according to reduced gene expression of proinflammatory cytokines (TNF-α, IL-6, MCP-1) and iNOS, but increased expression of the anti-inflammatory cytokine, IL-10. These findings support that neurons critically regulate microglia activity and control inflammation via EV-mediated neuron–glia communication. (Supported by R21AA025563 and R01AA025591). Full article

(This article belongs to the Special Issue Extracellular Vesicles: Multifaceted Biological Nanoparticles in Health and Disease)

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22 pages, 32281 KiB

Open AccessArticle

LC-MS/MS Proteomic Study of MCF-7 Cell Treated with Dox and Dox-Loaded Calcium Carbonate Nanoparticles Revealed Changes in Proteins Related to Glycolysis, Actin Signalling, and Energy Metabolism

by Hamidu Ahmed, Mokrish Ajat, Rana I. Mahmood, Rozaihan Mansor, Intan Shameha Abdul Razak, Jameel R. Al-Obaidi, Nurhanani Razali, Alhaji Zubair Jaji, Abubakar Danmaigoro and Md Zuki Abu Bakar

Biology 2021, 10(9), 909; https://0-doi-org.brum.beds.ac.uk/10.3390/biology10090909 - 13 Sep 2021

Cited by 7 | Viewed by 3020

Abstract

One of the most prevalent death causes among women worldwide is breast cancer. This study aimed to characterise and differentiate the proteomics profiles of breast cancer cell lines treated with Doxorubicin (DOX) and Doxorubicin-CaCO₃-nanoparticles (DOX-Ar-CC-NPs). This study determines the therapeutic potential of doxorubicin-loaded aragonite CaCO₃ nanoparticles using a Liquid Chromatography/Mass Spectrometry analysis. In total, 334 proteins were expressed in DOX-Ar-CC-NPs treated cells, while DOX treatment expressed only 54 proteins. Out of the 334 proteins expressed in DOX-CC-NPs treated cells, only 36 proteins showed changes in abundance, while in DOX treated cells, only 7 out of 54 proteins were differentially expressed. Most of the 30 identified proteins that are differentially expressed in DOX-CC-NPs treated cells are key enzymes that have an important role in the metabolism of carbohydrates as well as energy, including: pyruvate kinase, ATP synthase, enolase, glyceraldehyde-3-phosphate dehydrogenase, mitochondrial ADP/ATP carrier, and trypsin. Other identified proteins are structural proteins which included; Keratin, α- and β-tubulin, actin, and actinin. Additionally, one of the heat shock proteins was identified, which is Hsp90; other proteins include Annexins and Human epididymis protein 4. While the proteins identified in DOX-treated cells were tubulin alpha-1B chain and a beta chain, actin cytoplasmic 1, annexin A2, IF rod domain-containing protein, and 78 kDa glucose-regulated protein. Bioinformatics analysis revealed the predicted canonical pathways linking the signalling of the actin cytoskeleton, ILK, VEGF, BAG2, integrin and paxillin, as well as glycolysis. This research indicates that proteomic analysis is an effective technique for proteins expression associated with chemotherapy drugs on cancer tumours; this method provides the opportunity to identify treatment targets for MCF-7 cancer cells, and a liquid chromatography-mass spectrometry (LC-MS/MS) system allowed the detection of a larger number of proteins than 2-DE gel analysis, as well as proteins with maximum pIs and high molecular weight. Full article

(This article belongs to the Special Issue Extracellular Vesicles: Multifaceted Biological Nanoparticles in Health and Disease)

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Review

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27 pages, 3942 KiB

Open AccessReview

Overview and Update on Extracellular Vesicles: Considerations on Exosomes and Their Application in Modern Medicine

by Maria Antonietta Di Bella

Biology 2022, 11(6), 804; https://0-doi-org.brum.beds.ac.uk/10.3390/biology11060804 - 24 May 2022

Cited by 43 | Viewed by 6577

Abstract

In recent years, there has been a rapid growth in the knowledge of cell-secreted extracellular vesicle functions. They are membrane enclosed and loaded with proteins, nucleic acids, lipids, and other biomolecules. After being released into the extracellular environment, some of these vesicles are delivered to recipient cells; consequently, the target cell may undergo physiological or pathological changes. Thus, extracellular vesicles as biological nano-carriers, have a pivotal role in facilitating long-distance intercellular communication. Understanding the mechanisms that mediate this communication process is important not only for basic science but also in medicine. Indeed, extracellular vesicles are currently seen with immense interest in nanomedicine and precision medicine for their potential use in diagnostic, prognostic, and therapeutic applications. This paper aims to summarize the latest advances in the study of the smallest subtype among extracellular vesicles, the exosomes. The article is divided into several sections, focusing on exosomes’ nature, characteristics, and commonly used strategies and methodologies for their separation, characterization, and visualization. By searching an extended portion of the relevant literature, this work aims to give a quick outline of advances in exosomes’ extensive nanomedical applications. Moreover, considerations that require further investigations before translating them to clinical applications are summarized. Full article

(This article belongs to the Special Issue Extracellular Vesicles: Multifaceted Biological Nanoparticles in Health and Disease)

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38 pages, 4195 KiB

Open AccessReview

Small but Mighty—Exosomes, Novel Intercellular Messengers in Neurodegeneration

by Meena Kumari and Antje Anji

Biology 2022, 11(3), 413; https://0-doi-org.brum.beds.ac.uk/10.3390/biology11030413 - 08 Mar 2022

Cited by 17 | Viewed by 6410

Abstract

Exosomes of endosomal origin are one class of extracellular vesicles that are important in intercellular communication. Exosomes are released by all cells in our body and their cargo consisting of lipids, proteins and nucleic acids has a footprint reflective of their parental origin. The exosomal cargo has the power to modulate the physiology of recipient cells in the vicinity of the releasing cells or cells at a distance. Harnessing the potential of exosomes relies upon the purity of exosome preparation. Hence, many methods for isolation have been developed and we provide a succinct summary of several methods. In spite of the seclusion imposed by the blood–brain barrier, cells in the CNS are not immune from exosomal intrusive influences. Both neurons and glia release exosomes, often in an activity-dependent manner. A brief description of exosomes released by different cells in the brain and their role in maintaining CNS homeostasis is provided. The hallmark of several neurodegenerative diseases is the accumulation of protein aggregates. Recent studies implicate exosomes’ intercellular communicator role in the spread of misfolded proteins aiding the propagation of pathology. In this review, we discuss the potential contributions made by exosomes in progression of Alzheimer’s disease, Parkinson’s disease, and amyotrophic lateral sclerosis. Understanding contributions made by exosomes in pathogenesis of neurodegeneration opens the field for employing exosomes as therapeutic agents for drug delivery to brain since exosomes do cross the blood–brain barrier. Full article

(This article belongs to the Special Issue Extracellular Vesicles: Multifaceted Biological Nanoparticles in Health and Disease)

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24 pages, 700 KiB

Open AccessReview

Nutraceuticals in HIV and COVID-19-Related Neurological Complications: Opportunity to Use Extracellular Vesicles as Drug Delivery Modality

by Sunitha Kodidela, Sandip Godse, Asit Kumar, Xuyen H. Nguyen, Alina Cernasev, Lina Zhou, Ajay Kumar Singh, Hari K. Bhat and Santosh Kumar

Biology 2022, 11(2), 177; https://0-doi-org.brum.beds.ac.uk/10.3390/biology11020177 - 23 Jan 2022

Cited by 4 | Viewed by 3880

Abstract

People living with HIV/AIDS (PLWHA) are at an increased risk of severe and critical COVID-19 infection. There is a steady increase in neurological complications associated with COVID-19 infection, exacerbating HIV-associated neurocognitive disorders (HAND) in PLWHA. Nutraceuticals, such as phytochemicals from medicinal plants and dietary supplements, have been used as adjunct therapies for many disease conditions, including viral infections. Appropriate use of these adjunct therapies with antiviral proprieties may be beneficial in treating and/or prophylaxis of neurological complications associated with these co-infections. However, most of these nutraceuticals have poor bioavailability and cannot cross the blood–brain barrier (BBB). To overcome this challenge, extracellular vesicles (EVs), biological nanovesicles, can be used. Due to their intrinsic features of biocompatibility, stability, and their ability to cross BBB, as well as inherent homing capabilities, EVs hold immense promise for therapeutic drug delivery to the brain. Therefore, in this review, we summarize the potential role of different nutraceuticals in reducing HIV- and COVID-19-associated neurological complications and the use of EVs as nutraceutical/drug delivery vehicles to treat HIV, COVID-19, and other brain disorders. Full article

(This article belongs to the Special Issue Extracellular Vesicles: Multifaceted Biological Nanoparticles in Health and Disease)

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Other

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29 pages, 1877 KiB

Open AccessSystematic Review

Preconditioning Methods to Improve Mesenchymal Stromal Cell-Derived Extracellular Vesicles in Bone Regeneration—A Systematic Review

by Fernanda Campos Hertel, Aline Silvestrini da Silva, Adriano de Paula Sabino, Fabrício Luciani Valente and Emily Correna Carlo Reis

Biology 2022, 11(5), 733; https://0-doi-org.brum.beds.ac.uk/10.3390/biology11050733 - 11 May 2022

Cited by 7 | Viewed by 5831

Abstract

Mesenchymal stromal cells (MSCs) have long been used in research for bone regeneration, with evidence of their beneficial properties. In the segmental area of MSC-based therapies, MSC-derived extracellular vesicles (EVs) have also shown great therapeutic effects in several diseases, including bone healing. This study aimed to assess whether the conditioning of MSCs improves the therapeutic effects of their derived extracellular vesicles for bone regeneration. Electronic research was performed until February 2021 to recover the studies in the following databases: PubMed, Scopus, and Web of Science. The studies were screened based on the inclusion criteria. Relevant information was extracted, including in vitro and in vivo experiments, and the animal studies were evaluated for risk of bias by the SYRCLE tool. A total of 463 studies were retrieved, and 18 studies met the inclusion criteria (10 studies for their in vitro analysis, and 8 studies for their in vitro and in vivo analysis). The conditioning methods reported included: osteogenic medium; dimethyloxalylglycine; dexamethasone; strontium-substituted calcium silicate; hypoxia; 3D mechanical microenvironment; and the overexpression of miR-375, bone morphogenetic protein-2, and mutant hypoxia-inducible factor-1α. The conditioning methods of MSCs in the reported studies generate exosomes able to significantly promote bone regeneration. However, heterogeneity regarding cell source, conditioning method, EV isolation and concentration, and defect model was observed among the studies. The different conditioning methods reported in this review do improve the therapeutic effects of MSC-derived EVs for bone regeneration, but they still need to be addressed in larger animal models for further clinical application. Full article

(This article belongs to the Special Issue Extracellular Vesicles: Multifaceted Biological Nanoparticles in Health and Disease)

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