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Shedding New Light on the Cell Biology and Medicine of Extracellular Vesicles

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A special issue of Membranes (ISSN 2077-0375). This special issue belongs to the section "Biological Membrane Functions".

Deadline for manuscript submissions: closed (30 April 2022) | Viewed by 36202

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Dr. Tak-Wah Wong

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Guest Editor

Department of Dermatology, National Cheng Kung University Hospital, Biochemistry & Molecular Biology, College of Medicine, Center of Applied Nanomedicine, National Cheng Kung University, 138 Sheng-Li Road, Tainan 704, Taiwan
Interests: dermatology; photomedicine; photodynamic therapy; wound healing; oncology; biochemistry; nanomedicine

Dr. Wei-Peng Li

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Department of Medicinal and Applied Chemistry, Kaohsiung Medical University, Kaohsiung 807, Taiwan
Interests: materials chemistry; nanotechnology; nanomedicine; microbial electrochemistry; liposome; exosome; outer membrane vesicle

Special Issue Information

Dear colleagues,

Extracellular vesicles (EV), including exosomes, microvesicles (MV) and apoptotic bodies, are biogenetic nanoparticles shedding and originate from cell-derived membranous structures. Lipid bilayers’ structured EVs have been demonstrated to be loaded with natural biocomponents such as proteins, lipids and genes, showing immense potential as advanced vesicular-like liposomes. In recent years, EVs have played major roles in multiple biologic and pathological processes in immunity, cancer metastasis, membrane fusion process, intercellular communication, quorum sensing, extracellular electron transport, drug-resistance, and bacterial defense to phage.

This Special Issue on "Shedding New Light on the Cell Biology and Medicine of Extracellular Vesicles” of the journal Membranes seeks contributions to advance the current and frontier developments in the field of biological nanoparticles with natural membrane features. Topics include but are not limited to: the biogenetic or artificial methods for EV production; the mechanism of membrane vesicle production; membrane fusion and liberation processes; characteristics of EVs and membrane proteins; the functions of EVs in increasing extracellular electron transport; the catalytic activity of functional membrane proteins; cancer metastasis; immunotherapy; liquid biopsy by detecting EVs; and novel applications. Authors are invited to submit their new findings; both original papers and reviews are welcome.

Dr. Tak-Wah Wong
Dr. Wei-Peng Li
Guest Editors

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Keywords

methodology for studying EVs
biology and endogenous function
membrane fusion
functional membrane proteins
EVs in medicine

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Published Papers (10 papers)

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Research

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21 pages, 2387 KiB

Open AccessArticle

Characterizing Extracellular Vesicles and Particles Derived from Skeletal Muscle Myoblasts and Myotubes and the Effect of Acute Contractile Activity

by Benjamin Bydak, Taiana M. Pierdoná, Samira Seif, Karim Sidhom, Patience O. Obi, Hagar I. Labouta, Joseph W. Gordon and Ayesha Saleem

Membranes 2022, 12(5), 464; https://doi.org/10.3390/membranes12050464 - 26 Apr 2022

Cited by 9 | Viewed by 3388

Abstract

Extracellular vesicles (EVs), released from all cells, are essential to cellular communication and contain biomolecular cargo that can affect recipient cell function. Studies on the effects of contractile activity (exercise) on EVs usually rely on plasma/serum-based assessments, which contain EVs from many different cells. To specifically characterize skeletal muscle–derived vesicles and the effect of acute contractile activity, we used an in vitro model where C2C12 mouse myoblasts were differentiated to form myotubes. EVs were isolated from conditioned media from muscle cells at pre-differentiation (myoblasts) and post-differentiation (myotubes) and also from acutely stimulated myotubes (1 h @ 14 V, C-Pace EM, IonOptix, Westwood, MA, USA) using total exosome isolation reagent (TEI, ThermoFisher (Waltham, MA, USA), referred to as extracellular particles [EPs]) and differential ultracentrifugation (dUC; EVs). Myotube-EPs (~98 nm) were 41% smaller than myoblast-EPs (~167 nm, p < 0.001, n = 8–10). Two-way ANOVA showed a significant main effect for the size distribution of myotube vs. myoblast-EPs (p < 0.01, n = 10–13). In comparison, myoblast-EPs displayed a bimodal size distribution profile with peaks at <200 nm and 400–600, whereas myotube-Eps were largely 50–300 nm in size. Total protein yield from myotube-EPs was nearly 15-fold higher than from the myoblast-EPs, (p < 0.001 n = 6–9). Similar biophysical characteristics were observed when EVs were isolated using dUC: myotube-EVs (~195 nm) remained 41% smaller in average size than myoblast-EVs (~330 nm, p = 0.07, n = 4–6) and had comparable size distribution profiles to EPs isolated via TEI. Myotube-EVs also had 4.7-fold higher protein yield vs. myoblast EVs (p < 0.05, n = 4–6). Myotube-EPs exhibited significantly decreased expression of exosomal marker proteins TSG101, CD63, ALIX and CD81 compared with myoblast-EPs (p < 0.05, n = 7–12). Conversely, microvesicle marker ARF6 and lipoprotein marker APO-A1 were only found in the myotube-EPs (p < 0.05, n = 4–12). There was no effect of acute stimulation on myotube-EP biophysical characteristics (n = 7) or on the expression of TSG101, ARF6 or CD81 (n = 5–6). Myoblasts treated with control or acute stimulation–derived EPs (13 µg/well) for 48 h and 72 h showed no changes in mitochondrial mass (MitoTracker Red, ThermoFisher, Waltham, MA, USA), cell viability or cell count (n = 3–4). Myoblasts treated with EP-depleted media (72 h) exhibited ~90% lower cell counts (p < 0.01, n = 3). Our data show that EVs differed in size, distribution, protein yield and expression of subtype markers pre vs. post skeletal muscle–differentiation into myotubes. There was no effect of acute stimulation on biophysical profile or protein markers in EPs. Acute stimulation–derived EPs did not alter mitochondrial mass or cell count/viability. Further investigation into the effects of chronic contractile activity on the biophysical characteristics and cargo of skeletal muscle–specific EVs are warranted. Full article

(This article belongs to the Special Issue Shedding New Light on the Cell Biology and Medicine of Extracellular Vesicles)

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16 pages, 2623 KiB

Open AccessCommunication

Protein Profiling of Malaria-Derived Extracellular Vesicles Reveals Distinct Subtypes

by Tosin Opadokun, Jeffrey Agyapong and Petra Rohrbach

Membranes 2022, 12(4), 397; https://doi.org/10.3390/membranes12040397 - 1 Apr 2022

Cited by 9 | Viewed by 3357

Abstract

Malaria is caused by obligate intracellular parasites belonging to the genus Plasmodium. Red blood cells (RBCs) infected with different stages of Plasmodium spp. release extracellular vesicles (EVs). Extensive studies have recently shown that these EVs are involved in key aspects of the parasite’s biology and disease pathogenesis. However, they are yet to be fully characterized. The blood stages of Plasmodium spp., namely the rings, trophozoites and schizonts, are phenotypically distinct, hence, may induce the release of characteristically different EVs from infected RBCs. To gain insights into the biology and biogenesis of malaria EVs, it is important to characterize their biophysical and biochemical properties. By differential centrifugation, we isolated EVs from in vitro cultures of RBCs infected with different stages of Plasmodium falciparum. We performed a preliminary characterization of these EVs and observed that important EV markers were differentially expressed in EVs with different sedimentation properties as well as across EVs released from ring-, trophozoite- or schizont-infected RBCs. Our findings show that RBCs infected with different stages of malaria parasites release EVs with distinct protein expression profiles. Full article

(This article belongs to the Special Issue Shedding New Light on the Cell Biology and Medicine of Extracellular Vesicles)

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31 pages, 6178 KiB

Open AccessArticle

Characterization of the Role of Extracellular Vesicles Released from Chicken Tracheal Cells in the Antiviral Responses against Avian Influenza Virus

by Kelsey O’Dowd, Laura Sánchez, Jennifer Ben Salem, Francis Beaudry and Neda Barjesteh

Membranes 2022, 12(1), 53; https://doi.org/10.3390/membranes12010053 - 31 Dec 2021

Cited by 2 | Viewed by 2645

Abstract

During viral respiratory infections, the innate antiviral response engages a complex network of cells and coordinates the secretion of key antiviral factors, such as cytokines, which requires high levels of regulation and communication. Extracellular vesicles (EVs) are particles released from cells that contain an array of biomolecules, including lipids, proteins, and RNAs. The contents of EVs can be influenced by viral infections and may play a role in the regulation of antiviral responses. We hypothesized that the contents of EVs released from chicken tracheal cells are influenced by viral infection and that these EVs regulate the function of other immune cells, such as macrophages. To this end, we characterized the protein profile of EVs during avian influenza virus (AIV) infection and evaluated the impact of EV stimulation on chicken macrophage functions. A total of 140 differentially expressed proteins were identified upon stimulation with various stimuli. These proteins were shown to be involved in immune responses and cell signaling pathways. In addition, we demonstrated that EVs can activate macrophages. These results suggest that EVs play a role in the induction and modulation of antiviral responses during viral respiratory infections in chickens. Full article

(This article belongs to the Special Issue Shedding New Light on the Cell Biology and Medicine of Extracellular Vesicles)

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18 pages, 3383 KiB

Open AccessEditor’s ChoiceArticle

Extracellular Vesicles Tropism: A Comparative Study between Passive Innate Tropism and the Active Engineered Targeting Capability of Lymphocyte-Derived EVs

by Tania Limongi, Francesca Susa, Bianca Dumontel, Luisa Racca, Michela Perrone Donnorso, Doriana Debellis and Valentina Cauda

Membranes 2021, 11(11), 886; https://doi.org/10.3390/membranes11110886 - 18 Nov 2021

Cited by 16 | Viewed by 4181

Abstract

Cellular communications take place thanks to a well-connected network of chemical–physical signals, biomolecules, growth factors, and vesicular messengers that travel inside or between cells. A deep knowledge of the extracellular vesicle (EV) system allows for a better understanding of the whole series of phenomena responsible for cell proliferation and death. To this purpose, here, a thorough immuno-phenotypic characterization of B-cell EV membranes is presented. Furthermore, the cellular membrane of B lymphocytes, Burkitt lymphoma, and human myeloid leukemic cells were characterized through cytofluorimetry assays and fluorescent microscopy analysis. Through cytotoxicity and internalization tests, the tropism of B lymphocyte-derived EVs was investigated toward the parental cell line and two different cancer cell lines. In this study, an innate capability of passive targeting of the native EVs was distinguished from the active targeting capability of monoclonal antibody-engineered EVs, able to selectively drive the vesicles, enhancing their internalization into the target cancer cells. In particular, the specific targeting ability of anti-CD20 engineered EVs towards Daudi cells, highly expressing CD20 marker on their cell membrane, was proved, while almost no internalization events were observed in HL60 cells, since they did not express an appreciable amount of the CD20 marker on their plasma membranes. Full article

(This article belongs to the Special Issue Shedding New Light on the Cell Biology and Medicine of Extracellular Vesicles)

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18 pages, 3956 KiB

Open AccessArticle

Dynamic Landscape of Extracellular Vesicle-Associated Proteins Is Related to Treatment Response of Patients with Metastatic Breast Cancer

by Olivia Ruhen, Xinyu Qu, M. Fairuz B. Jamaluddin, Carlos Salomon, Aesha Gandhi, Michael Millward, Brett Nixon, Matthew D. Dun and Katie Meehan

Membranes 2021, 11(11), 880; https://doi.org/10.3390/membranes11110880 - 16 Nov 2021

Cited by 4 | Viewed by 2962

Abstract

Breast cancer is the leading cause of cancer death in women. The majority of these deaths are due to disease metastasis, in which cancer cells disseminate to multiple organs and disrupt vital physiological functions. It is widely accepted that breast cancer cells secrete extracellular vesicles (EVs), which contain dynamic molecular cargo that act as versatile mediators of intercellular communication. Therefore, Evs. secreted by breast cancer cells could be involved in the development of metastatic disease and resistance to treatment. Moreover, changes in EV cargo could reflect the effects of therapy on their parent tumor cells. The aim of this feasibility study was to quantitatively profile the proteomes of Evs. isolated from blood samples taken from treatment sensitive and resistant metastatic breast cancer patients to identify proteins associated with responses. Three serial blood samples were collected from three patients with metastatic breast cancer receiving systemic therapy including a responder, a non-responder, and a mixed-responder. Evs. were isolated from plasma using size exclusion chromatography and their protein cargo was prepared for tandem mass tag (TMT)-labelling and quantitative analyses using two-dimensional high-performance liquid chromatography followed by tandem mass spectrometry. After filtering, we quantitatively identified 286 proteins with high confidence using a q value of 0.05. Of these, 149 were classified as EV associated candidate proteins and 137 as classical, high abundant plasma proteins. After comparing EV protein abundance between the responder and non-responder, we identified 35 proteins with unique de-regulated abundance patterns that was conserved at multiple time points. We propose that this proof-of-concept approach can be used to identify proteins which have potential as predictors of metastatic breast cancer response to treatment. Full article

(This article belongs to the Special Issue Shedding New Light on the Cell Biology and Medicine of Extracellular Vesicles)

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10 pages, 3092 KiB

Open AccessCommunication

Synthetic Poly(lactic-co-glycolic Acid) Microvesicles as a Feasible Carbon Monoxide-Releasing Platform for Cancer Treatment

by Wen-Jyun Wang, Chung-Dann Kan, Chih-Yen Chen, Yi-Yao Meng, Jieh-Neng Wang, Wei-Ling Chen, Chia-Hsiang Chen and Wei-Peng Li

Membranes 2021, 11(11), 818; https://doi.org/10.3390/membranes11110818 - 26 Oct 2021

Cited by 1 | Viewed by 2165

Abstract

Biogenic microvesicles (MVs) play a pivotal role in intercellular signal communication, thus initiating critical biological responses such as the proliferation of cancer cells, gene and protein transport, and chemo-drug resistance. In addition, they have been recognized as having great potential in drug delivery applications. However, the productivity of biologically produced MVs is not sufficient for clinical applications. In this study, synthetic poly(lactic-co-glycolic acid) (PLGA) MVs were prepared via a double emulsion method. The PLGA MVs had a biogenic MV-mimic vesicular structure with a hydrophilic core/surface and hydrophobic interior of the shell, showing great potential for drug delivery. We successfully embedded hydrophobic iron carbonyl (IC), a carbon monoxide (CO) donor, in the PLGA shell region, enabling the delivery of IC in an aqueous solution. Because of the intrinsic properties of PLGA, it was susceptible to temperature, and the MVs could easily collapse in a warm environment, leading to the decomposition of IC into CO. The in vitro result indicated that the cell viability of A549 lung carcinoma cells significantly decreased to 14% after treatment with IC-loaded PLGA MVs for 24 h, suggesting that these synthetic PLGA MVs constitute an excellent drug delivery platform. Full article

(This article belongs to the Special Issue Shedding New Light on the Cell Biology and Medicine of Extracellular Vesicles)

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13 pages, 1489 KiB

Open AccessArticle

Toxicological Profile of Umbilical Cord Blood-Derived Small Extracellular Vesicles

by Silvia C. Rodrigues, Renato M. S. Cardoso, Claudia F. Gomes, Filipe V. Duarte, Patricia C. Freire, Ricardo Neves and Joana Simoes-Correia

Membranes 2021, 11(9), 647; https://doi.org/10.3390/membranes11090647 - 24 Aug 2021

Cited by 13 | Viewed by 3595

Abstract

The development and adoption of cell therapies has been largely limited by difficulties associated with their safety, handling, and storage. Extracellular vesicles (EV) have recently emerged as a likely mediator for the therapeutic effect of cells, offering several advantages over cell therapies. Due to their small size and inability to expand and metastasize, EV are generally considered safer than cell transplantation. Nevertheless, few studies have scrutinized the toxicity profile of EV, particularly after repeated high-dose administration. The present study aimed to evaluate a preparation of small EV obtained from umbilical cord blood mononuclear cells (UCB-MNC-sEV) for its cytotoxicity in different cell lines, as well as its differential accumulation, distribution, and toxicity following repeated intravenous (IV) administrations in a rodent model. In vitro, repeated sEV exposure in concentrations up to 1 × 10¹¹ particles/mL had no deleterious impact on the viability or metabolic activity of peripheral blood mononuclear cells, THP-1 monocytes, THP-1-derived macrophages, normal dermal human fibroblasts, or human umbilical vein endothelial cells. DiR-labelled sEV, injected intravenously for four weeks in healthy rats, were detected in clearance organs, particularly the kidneys, spleen, and liver, similarly to control dye. Moreover, repeated administrations for six and twelve weeks of up to 1 × 10¹⁰ total particles of sEV dye were well-tolerated, with no changes in general haematological cell counts, or kidney and liver toxicity markers. More importantly, unlabelled sEV likewise did not induce significant alterations in cellular and biochemical blood parameters, nor any morphological changes in the heart, kidney, lung, spleen, or liver tissue. In sum, our data show that UCB-MNC-sEV have no significant toxicity in vitro or in vivo, even when administered repeatedly at high concentrations, therefore confirming their safety profile and potential suitability for future clinical use. Full article

(This article belongs to the Special Issue Shedding New Light on the Cell Biology and Medicine of Extracellular Vesicles)

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Review

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14 pages, 788 KiB

Open AccessReview

The Role of Extracellular Vesicles in Osteoporosis: A Scoping Review

by Weifei Zhang, Pengzhou Huang, Jianjing Lin and Hui Zeng

Membranes 2022, 12(3), 324; https://doi.org/10.3390/membranes12030324 - 14 Mar 2022

Cited by 15 | Viewed by 4120

Abstract

As an insidious metabolic bone disease, osteoporosis plagues the world, with high incidence rates. Patients with osteoporosis are prone to falls and becoming disabled, and their cone fractures and hip fractures are very serious, so the diagnosis and treatment of osteoporosis is very urgent. Extracellular vesicles (EVs) are particles secreted from cells to the outside of the cell and they are wrapped in a bilayer of phospholipids. According to the size of the particles, they can be divided into three categories, namely exosomes, microvesicles, and apoptotic bodies. The diameter of exosomes is 30–150 nm, the diameter of microvesicles is 100–1000 nm, and the diameter of apoptotic bodies is about 50–5000 nm. EVs play an important role in various biological process and diseases including osteoporosis. In this review, the role of EVs in osteoporosis is systematically reviewed and some insights for the prevention and treatment of osteoporosis are provided. Full article

(This article belongs to the Special Issue Shedding New Light on the Cell Biology and Medicine of Extracellular Vesicles)

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15 pages, 1614 KiB

Open AccessReview

Improving Isolation of Extracellular Vesicles by Utilizing Nanomaterials

by Haiyang Zhang, Qi Zhang, Yuanyuan Deng, Mengxi Chen and Chenxi Yang

Membranes 2022, 12(1), 55; https://doi.org/10.3390/membranes12010055 - 31 Dec 2021

Cited by 12 | Viewed by 3292

Abstract

Extracellular vesicles (EVs) as the new form of cellular communication have been demonstrated their potential use for disease diagnosis, prognosis and treatment. EVs are vesicles with a lipid bilayer and are present in various biofluids, such as blood, saliva and urine. Therefore, EVs have emerged as one of the most appealing sources for the discovery of clinical biomarkers. However, isolation of the target EVs from different biofluids is required for the use of EVs as diagnostic and therapeutic entities in clinical settings. Owing to their unique properties and versatile functionalities, nanomaterials have been widely investigated for EV isolation with the aim to provide rapid, simple, and efficient EV enrichment. Herein, this review presents the progress of nanomaterial-based isolations for EVs over the past five years (from 2017 to 2021) and discusses the use of nanomaterials for EV isolations based on the underlying mechanism in order to offer insights into the design of nanomaterials for EV isolations. Full article

(This article belongs to the Special Issue Shedding New Light on the Cell Biology and Medicine of Extracellular Vesicles)

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19 pages, 831 KiB

Open AccessReview

Mesenchymal Stem Cell-Derived Extracellular Vesicle-Based Therapy for Alzheimer’s Disease: Progress and Opportunity

by Yi-An Chen, Cheng-Hsiu Lu, Chien-Chih Ke and Ren-Shyan Liu

Membranes 2021, 11(10), 796; https://doi.org/10.3390/membranes11100796 - 19 Oct 2021

Cited by 13 | Viewed by 4307

Abstract

Alzheimer’s disease (AD), as a neurodegenerative disorder, is characterized by mass neuronal and synaptic loss and, currently, there are no successful curative therapies. Extracellular vesicles (EVs) are an emerging approach to intercellular communication via transferring cellular materials such as proteins, lipids, mRNAs, and miRNAs from parental cells to recipient cells, leading to the reprogramming of the molecular machinery. Numerous studies have suggested the therapeutic potential of EVs derived from mesenchymal stem cells (MSCs) in the treatment of AD, based on the neuroprotective, regenerative and immunomodulatory effects as effective as MSCs. In this review, we focus on the biology and function of EVs, the potential of MSC-derived EVs for AD therapy in preclinical and clinical studies, as well as the potent mechanisms of MSC-derived EVs actions. Finally, we highlight the modification strategies and diagnosis utilities in order to make advance in this field. Full article

(This article belongs to the Special Issue Shedding New Light on the Cell Biology and Medicine of Extracellular Vesicles)

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