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Extracellular Vesicles in Inflammation
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Extracellular Vesicles in Inflammation

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

Deadline for manuscript submissions: closed (28 February 2021) | Viewed by 78317

Special Issue Editors

Dr. Andreas Spittler

E-Mail Website
Guest Editor
Department of Surgery and Core Facility Flow Cytometry, Medical University of Vienna, Vienna, Austria
Interests: sepsis immunology; inflammation; monocytes; immunoglobulins; extracellular vesicles; flow cytometry
Special Issues, Collections and Topics in MDPI journals
Dr. Wolfgang Holnthoner

E-Mail Website
Guest Editor
Ludwig-Boltzmann-Institute for Experimental and Clinical Traumatology, 1200 Vienna, Austria
Interests: angiogenesis; lymphangiogenesis; tissue engineering; extracellular vesicles in the vasculature
Special Issues, Collections and Topics in MDPI journals
Prof. Dr. Viktoria Weber

E-Mail Website
Guest Editor
Department for Biomedical Research, Danube University Krems, 3500 Krems, Austria
Interests: extracellular vesicles; sepsis; inflammation; extracorporeal therapies; blood–biomaterial interface; blood compatibility
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Cells need to communicate with each other to exchange information and to fulfill their physiological roles. In addition to direct contact from cell to cell and exchange of soluble factors, there is a third method of information transfer that has received a lot of attention recently—extracellular vesicles (EVs). These vesicles in the nanometer range are responsible for the exchange of small and large molecules between cells and tissues and affect our bodies in a variety of ways.

For the Special Issue “Extracellular Vesicles in Inflammation”, we accept both reviews and original articles. Reviews should provide a state-of-the-art overview of extracellular vesicles in the context of inflammation and may also highlight new approaches to enrich and characterize extracellular vesicles from biological fluids. Original Articles should address the pathophysiology of extracellular vesicles in experimental cell culture environments as well as in clinical practice, including new findings on the use of extracellular vesicles as biomarkers, and on new therapeutic strategies.

You may choose our Joint Special Issue in Biomedicines.

Dr. Andreas Spittler
Dr. Wolfgang Holnthoner
Prof. Dr. Viktoria Weber
Guest Editors

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 vesicles
  • inflammation
  • immunomodulation
  • coagulation
  • intercellular communication
  • flow cytometry

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Published Papers (20 papers)

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Research

Jump to: Review

13 pages, 28055 KiB  
Article
Extracellular Vesicles as Biological Indicators and Potential Sources of Autologous Therapeutics in Osteoarthritis
by Xin Zhang, Janet L. Huebner and Virginia Byers Kraus
Int. J. Mol. Sci. 2021, 22(15), 8351; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22158351 - 03 Aug 2021
Cited by 10 | Viewed by 2465
Abstract
Along with cytokines, extracellular vesicles (EVs) released by immune cells in the joint contribute to osteoarthritis (OA) pathogenesis. By high-resolution flow cytometry, we characterized 18 surface markers and 4 proinflammatory cytokines carried by EVs of various sizes in plasma and synovial fluid (SF) [...] Read more.
Along with cytokines, extracellular vesicles (EVs) released by immune cells in the joint contribute to osteoarthritis (OA) pathogenesis. By high-resolution flow cytometry, we characterized 18 surface markers and 4 proinflammatory cytokines carried by EVs of various sizes in plasma and synovial fluid (SF) from individuals with knee OA, with a primary focus on immune cells that play a major role in OA pathogenesis. By multiplex immunoassay, we also measured concentrations of cytokines within (endo) and outside (exo) EVs. EVs carrying HLA-DR, -DP and -DQ were the most enriched subpopulations in SF relative to plasma (25–50-fold higher depending on size), suggesting a major contribution to the SF EV pool from infiltrating immune cells in OA joints. In contrast, the CD34+ medium and small EVs, reflecting hematopoietic stem cells, progenitor cells, and endothelial cells, were the most significantly enriched subpopulations in plasma relative to SF (7.3- and 7.7-fold higher). Ratios of EVs derived from neutrophils and lymphocytes were highly correlated between SF and plasma, indicating that plasma EVs could reflect OA severity and serve as systemic biomarkers of OA joint pathogenesis. Select subsets of plasma EVs might also provide next generation autologous biological products for intra-articular therapy of OA joints. Full article
(This article belongs to the Special Issue Extracellular Vesicles in Inflammation)
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15 pages, 2570 KiB  
Article
Effects of Extracellular Vesicles from Blood-Derived Products on Osteoarthritic Chondrocytes within an Inflammation Model
by Alexander Otahal, Karina Kramer, Olga Kuten-Pella, Lukas B. Moser, Markus Neubauer, Zsombor Lacza, Stefan Nehrer and Andrea De Luna
Int. J. Mol. Sci. 2021, 22(13), 7224; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22137224 - 05 Jul 2021
Cited by 8 | Viewed by 3352
Abstract
Osteoarthritis (OA) is hallmarked by a progressive degradation of articular cartilage. One major driver of OA is inflammation, in which cytokines such as IL-6, TNF-α and IL-1β are secreted by activated chondrocytes, as well as synovial cells—including macrophages. Intra-articular injection of blood products—such [...] Read more.
Osteoarthritis (OA) is hallmarked by a progressive degradation of articular cartilage. One major driver of OA is inflammation, in which cytokines such as IL-6, TNF-α and IL-1β are secreted by activated chondrocytes, as well as synovial cells—including macrophages. Intra-articular injection of blood products—such as citrate-anticoagulated plasma (CPRP), hyperacute serum (hypACT), and extracellular vesicles (EVs) isolated from blood products—is gaining increasing importance in regenerative medicine for the treatment of OA. A co-culture system of primary OA chondrocytes and activated M1 macrophages was developed to model an OA joint in order to observe the effects of EVs in modulating the inflammatory environment. Primary OA chondrocytes were obtained from patients undergoing total knee replacement. Primary monocytes obtained from voluntary healthy donors and the monocytic cell line THP-1 were differentiated and activated into proinflammatory M1 macrophages. EVs were isolated by ultracentrifugation and characterized by nanoparticle tracking analysis and Western blot. Gene expression analysis of chondrocytes by RT-qPCR revealed increased type II collagen expression, while cytokine profiling via ELISA showed lower TNF-α and IL-1β levels associated with EV treatment. In conclusion, the inflammation model provides an accessible tool to investigate the effects of blood products and EVs in the inflammatory context of OA. Full article
(This article belongs to the Special Issue Extracellular Vesicles in Inflammation)
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21 pages, 39957 KiB  
Article
Human Mesenchymal Stromal Cell-Derived Exosomes Promote In Vitro Wound Healing by Modulating the Biological Properties of Skin Keratinocytes and Fibroblasts and Stimulating Angiogenesis
by Raluca Tutuianu, Ana-Maria Rosca, Daniela Madalina Iacomi, Maya Simionescu and Irina Titorencu
Int. J. Mol. Sci. 2021, 22(12), 6239; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22126239 - 09 Jun 2021
Cited by 47 | Viewed by 4750
Abstract
Bone marrow-derived mesenchymal stromal cells (MSCs) are major players in regenerative therapies for wound healing via their paracrine activity, mediated partially by exosomes. Our purpose was to test if MSC-derived exosomes could accelerate wound healing by enhancing the biological properties of the main [...] Read more.
Bone marrow-derived mesenchymal stromal cells (MSCs) are major players in regenerative therapies for wound healing via their paracrine activity, mediated partially by exosomes. Our purpose was to test if MSC-derived exosomes could accelerate wound healing by enhancing the biological properties of the main cell types involved in the key phases of this process. Thus, the effects of exosomes on (i) macrophage activation, (ii) angiogenesis, (iii) keratinocytes and dermal fibroblasts proliferation and migration, and (iv) the capacity of myofibroblasts to regulate the turnover of the extracellular matrix were evaluated. The results showed that, although exosomes did not exhibit anti-inflammatory properties, they stimulated angiogenesis. Exposure of keratinocytes and dermal (myo)fibroblasts to exosomes enhanced their proliferation and migratory capacity. Additionally, exosomes prevented the upregulation of gene expression for type I and III collagen, α-smooth muscle actin, and MMP2 and 14, and they increased MMP13 expression during the fibroblast–myofibroblast transition. The regenerative properties of exosomes were validated using a wound healing skin organotypic model, which exhibited full re-epithelialization upon exosomes exposure. In summary, these data indicate that exosomes enhance the biological properties of keratinocytes, fibroblasts, and endothelial cells, thus providing a reliable therapeutic tool for skin regeneration. Full article
(This article belongs to the Special Issue Extracellular Vesicles in Inflammation)
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14 pages, 1322 KiB  
Article
Extracellular Vesicles in Synovial Fluid from Rheumatoid Arthritis Patients Contain miRNAs with Capacity to Modulate Inflammation
by Andrew D. Foers, Alexandra L. Garnham, Simon Chatfield, Gordon K. Smyth, Lesley Cheng, Andrew F. Hill, Ian P. Wicks and Ken C. Pang
Int. J. Mol. Sci. 2021, 22(9), 4910; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22094910 - 06 May 2021
Cited by 15 | Viewed by 3972
Abstract
In rheumatoid arthritis (RA), extracellular vesicles (EVs) are associated with both the propagation and attenuation of joint inflammation and destruction. However, the specific EV content responsible for these processes is largely unknown. Investigations into identifying EV content are confounded by the challenges in [...] Read more.
In rheumatoid arthritis (RA), extracellular vesicles (EVs) are associated with both the propagation and attenuation of joint inflammation and destruction. However, the specific EV content responsible for these processes is largely unknown. Investigations into identifying EV content are confounded by the challenges in obtaining high-quality EV preparations from synovial fluid. Implementing a size exclusion chromatography-based method of EV isolation, coupled with small RNA sequencing, we accurately characterised EV miRNAs in synovial fluid obtained from RA patients and investigated the differences between joints with high- and low-grade inflammation. Synovial fluid was obtained from the joints of 12 RA patients and, based on leukocyte counts, classified as either high (n = 7)- or low (n = 5)-grade inflammation. Using size exclusion chromatography, EVs were purified and small RNA was extracted and sequenced on a NextSeq 500. Sequencing reads were aligned to miRBase v21, and differences in miRNA profiles between RA patients with high- and low-grade joint inflammation were analysed. In total, 1972 distinct miRNAs were identified from RA synovial fluid EVs. miRNAs with less than five reads in fewer than five patients were filtered out, leaving 318 miRNAs for analysis. Analysis of the most abundant miRNAs suggested that they negatively regulate multiple genes relevant to inflammation, including signal transducer and activator of transcription 3 (STAT3), which lies downstream of IL-6 and has a pro-inflammatory role in RA. Synovial fluid from joints with high-grade inflammation contained 3.5-fold more EV miRNA per mL of synovial fluid (p = 0.0017). Seventy-eight EV miRNAs were differentially expressed between RA joints with high- and low-grade inflammation, and pathway analysis revealed that their target genes were commonly involved a variety of processes, including cellular apoptosis, proliferation and migration. Of the 49 miRNAs that were elevated in joints with high-grade inflammation, pathway analysis revealed that genes involved in cytokine-mediated signalling pathways were significantly enriched targets. In contrast, genes associated with reactive oxygen species signalling were significantly enriched as targets of the 29 miRNAs elevated in joints with low-grade inflammation. Our study identified an abundance of EV miRNAs from the synovial fluid of RA patients with the potential to modulate inflammation. In doing so, we defined potential mechanisms by which synovial fluid EVs may contribute to RA pathophysiology. Full article
(This article belongs to the Special Issue Extracellular Vesicles in Inflammation)
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15 pages, 13917 KiB  
Article
Immune-Associated Proteins Are Enriched in Lung Tissue-Derived Extracellular Vesicles during Allergen-Induced Eosinophilic Airway Inflammation
by Cecilia Lässer, Yasunari Kishino, Kyong-su Park, Ganesh Vilas Shelke, Nasibeh Karimi, Shintaro Suzuki, Lilit Hovhannisyan, Madeleine Rådinger and Jan Lötvall
Int. J. Mol. Sci. 2021, 22(9), 4718; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22094718 - 29 Apr 2021
Cited by 5 | Viewed by 2978
Abstract
Studying the proteomes of tissue-derived extracellular vesicles (EVs) can lead to the identification of biomarkers of disease and can provide a better understanding of cell-to-cell communication in both healthy and diseased tissue. The aim of this study was to apply our previously established [...] Read more.
Studying the proteomes of tissue-derived extracellular vesicles (EVs) can lead to the identification of biomarkers of disease and can provide a better understanding of cell-to-cell communication in both healthy and diseased tissue. The aim of this study was to apply our previously established tissue-derived EV isolation protocol to mouse lungs in order to determine the changes in the proteomes of lung tissue-derived EVs during allergen-induced eosinophilic airway inflammation. A mouse model for allergic airway inflammation was used by sensitizing the mice intraperitoneal with ovalbumin (OVA), and one week after the final sensitization, the mice were challenged intranasal with OVA or PBS. The animals were sacrificed 24 h after the final challenge, and their lungs were removed and sliced into smaller pieces that were incubated in culture media with DNase I and Collagenase D for 30 min at 37 °C. Vesicles were isolated from the medium by ultracentrifugation and bottom-loaded iodixanol density cushions, and the proteomes were determined using quantitative mass spectrometry. More EVs were present in the lungs of the OVA-challenged mice compared to the PBS-challenged control mice. In total, 4510 proteins were quantified in all samples. Among them, over 1000 proteins were significantly altered (fold change >2), with 614 proteins being increased and 425 proteins being decreased in the EVs from OVA-challenged mice compared to EVs from PBS-challenged animals. The associated cellular components and biological processes were analyzed for the altered EV proteins, and the proteins enriched during allergen-induced airway inflammation were mainly associated with gene ontology (GO) terms related to immune responses. In conclusion, EVs can be isolated from mouse lung tissue, and the EVs’ proteomes undergo changes in response to allergen-induced airway inflammation. This suggests that the composition of lung-derived EVs is altered in diseases associated with inflammation of the lung, which may have implications in type-2 driven eosinophilic asthma pathogenesis. Full article
(This article belongs to the Special Issue Extracellular Vesicles in Inflammation)
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19 pages, 7573 KiB  
Article
Isolation of Small Extracellular Vesicles from Human Sera
by Małgorzata S. Małys, Christof Aigner, Stefan M. Schulz, Helga Schachner, Andrew J. Rees and Renate Kain
Int. J. Mol. Sci. 2021, 22(9), 4653; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22094653 - 28 Apr 2021
Cited by 14 | Viewed by 3029
Abstract
Robust, well-characterized methods for purifying small extracellular vesicles (sEV) from blood are needed before their potential as disease biomarkers can be realized. Here, we compared isolation of sEV from serum by differential ultracentrifugation (DUC) and by exclusion chromatography using commercially available Exo-spin™ columns. [...] Read more.
Robust, well-characterized methods for purifying small extracellular vesicles (sEV) from blood are needed before their potential as disease biomarkers can be realized. Here, we compared isolation of sEV from serum by differential ultracentrifugation (DUC) and by exclusion chromatography using commercially available Exo-spin™ columns. We show that sEV can be purified by both methods but Exo-spin™ columns contain copious additional particles recorded by nanoparticle tracking analysis, invalidating its use for quantifying yields. DUC samples contained higher concentrations of exosome specific proteins CD9, CD63 and CD81 and electron microscopy confirmed that most particles in DUC preparations were sEV, whereas Exo-spin™ samples also contained copious co-purified plasma lipids. MACSPlex bead analysis identified multiple exosome surface proteins, with stronger signals in DUC samples, enabling detection of 21 of 37, compared to only 10 in Exo-spin™ samples. Nevertheless, the pattern of expression was consistent in both preparations, indicating that lipids do not interfere with bead-based technologies. Thus, both DUC and Exo-spin™ can be used to isolate sEV from human serum and what is most appropriate depends on the subsequent use of sEV. In summary, Exo-spin™ enables isolation of sEV from blood with vesicle populations similar to the ones recovered by DUC, but with lower concentrations. Full article
(This article belongs to the Special Issue Extracellular Vesicles in Inflammation)
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19 pages, 5422 KiB  
Article
Cre mRNA Is Not Transferred by EVs from Endothelial and Adipose-Derived Stromal/Stem Cells during Vascular Network Formation
by Jaana Schneider, Marianne Pultar, Johannes Oesterreicher, Madhusudhan Reddy Bobbili, Severin Mühleder, Eleni Priglinger, Heinz Redl, Andreas Spittler, Johannes Grillari and Wolfgang Holnthoner
Int. J. Mol. Sci. 2021, 22(8), 4050; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22084050 - 14 Apr 2021
Cited by 1 | Viewed by 3616
Abstract
Coculture systems employing adipose tissue-derived mesenchymal stromal/stem cells (ASC) and endothelial cells (EC) represent a widely used technique to model vascularization. Within this system, cell–cell communication is crucial for the achievement of functional vascular network formation. Extracellular vesicles (EVs) have recently emerged as [...] Read more.
Coculture systems employing adipose tissue-derived mesenchymal stromal/stem cells (ASC) and endothelial cells (EC) represent a widely used technique to model vascularization. Within this system, cell–cell communication is crucial for the achievement of functional vascular network formation. Extracellular vesicles (EVs) have recently emerged as key players in cell communication by transferring bioactive molecules between cells. In this study we aimed to address the role of EVs in ASC/EC cocultures by discriminating between cells, which have received functional EV cargo from cells that have not. Therefore, we employed the Cre-loxP system, which is based on donor cells expressing the Cre recombinase, whose mRNA was previously shown to be packaged into EVs and reporter cells containing a construct of floxed dsRed upstream of the eGFP coding sequence. The evaluation of Cre induced color switch in the reporter system via EVs indicated that there is no EV-mediated RNA transmission either between EC themselves or EC and ASC. However, since Cre mRNA was not found present in EVs, it remains unclear if Cre mRNA is generally not packaged into EVs or if EVs are not taken up by the utilized cell types. Our data indicate that this technique may not be applicable to evaluate EV-mediated cell-to-cell communication in an in vitro setting using EC and ASC. Further investigations will require a functional system showing efficient and specific loading of Cre mRNA or protein into EVs. Full article
(This article belongs to the Special Issue Extracellular Vesicles in Inflammation)
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21 pages, 3820 KiB  
Article
Hypoxic Conditions Promote the Angiogenic Potential of Human Induced Pluripotent Stem Cell-Derived Extracellular Vesicles
by André Cronemberger Andrade, Martin Wolf, Heide-Marie Binder, Fausto Gueths Gomes, Felix Manstein, Patricia Ebner-Peking, Rodolphe Poupardin, Robert Zweigerdt, Katharina Schallmoser and Dirk Strunk
Int. J. Mol. Sci. 2021, 22(8), 3890; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22083890 - 09 Apr 2021
Cited by 15 | Viewed by 4023
Abstract
Stem cells secrete paracrine factors including extracellular vesicles (EVs) which can mediate cellular communication and support the regeneration of injured tissues. Reduced oxygen (hypoxia) as a key regulator in development and regeneration may influence cellular communication via EVs. We asked whether hypoxic conditioning [...] Read more.
Stem cells secrete paracrine factors including extracellular vesicles (EVs) which can mediate cellular communication and support the regeneration of injured tissues. Reduced oxygen (hypoxia) as a key regulator in development and regeneration may influence cellular communication via EVs. We asked whether hypoxic conditioning during human induced pluripotent stem cell (iPSC) culture effects their EV quantity, quality or EV-based angiogenic potential. We produced iPSC-EVs from large-scale culture-conditioned media at 1%, 5% and 18% air oxygen using tangential flow filtration (TFF), with or without subsequent concentration by ultracentrifugation (TUCF). EVs were quantified by tunable resistive pulse sensing (TRPS), characterized according to MISEV2018 guidelines, and analyzed for angiogenic potential. We observed superior EV recovery by TFF compared to TUCF. We confirmed hypoxia efficacy by HIF-1α stabilization and pimonidazole hypoxyprobe. EV quantity did not differ significantly at different oxygen conditions. Significantly elevated angiogenic potential was observed for iPSC-EVs derived from 1% oxygen culture by TFF or TUCF as compared to EVs obtained at higher oxygen or the corresponding EV-depleted soluble factor fractions. Data thus demonstrate that cell-culture oxygen conditions and mode of EV preparation affect iPSC-EV function. We conclude that selecting appropriate protocols will further improve production of particularly potent iPSC-EV-based therapeutics. Full article
(This article belongs to the Special Issue Extracellular Vesicles in Inflammation)
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16 pages, 3989 KiB  
Article
Fluorescence-Based Nanoparticle Tracking Analysis and Flow Cytometry for Characterization of Endothelial Extracellular Vesicle Release
by Johannes Oesterreicher, Marianne Pultar, Jaana Schneider, Severin Mühleder, Johannes Zipperle, Johannes Grillari and Wolfgang Holnthoner
Int. J. Mol. Sci. 2020, 21(23), 9278; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21239278 - 04 Dec 2020
Cited by 10 | Viewed by 4126
Abstract
As extracellular vesicles (EVs) have become a prominent topic in life sciences, a growing number of studies are published on a regular basis addressing their biological relevance and possible applications. Nevertheless, the fundamental question of the true vesicular nature as well as possible [...] Read more.
As extracellular vesicles (EVs) have become a prominent topic in life sciences, a growing number of studies are published on a regular basis addressing their biological relevance and possible applications. Nevertheless, the fundamental question of the true vesicular nature as well as possible influences on the EV secretion behavior have often been not adequately addressed. Furthermore, research regarding endothelial cell-derived EVs (EndoEVs) often focused on the large vesicular fractions comprising of microvesicles (MV) and apoptotic bodies. In this study we aimed to further extend the current knowledge of the influence of pre-isolation conditions, such as cell density and conditioning time, on EndoEV release from human umbilical vein endothelial cells (HUVECs). We combined fluorescence nanoparticle tracking analysis (NTA) and the established fluorescence-triggered flow cytometry (FT-FC) protocol to allow vesicle-specific detection and characterization of size and surface markers. We found significant effects of cell density and conditioning time on both abundance and size distribution of EndoEVs. Additionally, we present detailed information regarding the surface marker display on EVs from different fractions and size ranges. Our data provide crucial relevance for future projects aiming to elucidate EV secretion behavior of endothelial cells. Moreover, we show that the influence of different conditioning parameters on the nature of EndoEVs has to be considered. Full article
(This article belongs to the Special Issue Extracellular Vesicles in Inflammation)
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11 pages, 1012 KiB  
Article
Stimulation of THP-1 Macrophages with LPS Increased the Production of Osteopontin-Encapsulating Exosome
by Gaowa Bai, Takashi Matsuba, Toshiro Niki and Toshio Hattori
Int. J. Mol. Sci. 2020, 21(22), 8490; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21228490 - 11 Nov 2020
Cited by 9 | Viewed by 4525
Abstract
Osteopontin (OPN) mediates bone remodeling and tissue debridement. The OPN protein is cleaved, but it is unclear how full-length (FL)-OPN or its cleaved form perform their biological activities in target cells. We, therefore, performed the molecular characterization of OPN in exosomes (Exo). The [...] Read more.
Osteopontin (OPN) mediates bone remodeling and tissue debridement. The OPN protein is cleaved, but it is unclear how full-length (FL)-OPN or its cleaved form perform their biological activities in target cells. We, therefore, performed the molecular characterization of OPN in exosomes (Exo). The Exo were isolated from lipopolysaccharide (LPS)-stimulated phorbol 12-myristate 13-acetate (PMA)-differentiated THP-1 macrophages. The Exo were also isolated from PMA-differentiated THP-1 macrophages. The Exo were identified using the qNano multiple analyzer (diameter 59–315 nm) and western blotting with a CD9 antibody. LPS-stimulated cells produced more particles than non-stimulated cells. The presence of the FL or the cleaved form of OPN was confirmed using western blot analysis. A mixture of FL and cleaved OPN was also measured using an ELISA system (Ud-OPN) and their presence in the Exo was confirmed. Ud/FL ratios became low after LPS stimulation, indicating the enhanced encapsulation of FL-OPN in the Exo by LPS. These findings suggest that LPS stimulation of human macrophages facilitates the synthesis of FL-OPN, which is cleaved in cells or the Exo after release. These findings indicate that Exo is a suitable vehicle to transfer OPN to the target cells. Full article
(This article belongs to the Special Issue Extracellular Vesicles in Inflammation)
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Review

Jump to: Research

17 pages, 13672 KiB  
Review
Targeting Inflammation after Myocardial Infarction: A Therapeutic Opportunity for Extracellular Vesicles?
by Margarida Viola, Saskia C. A. de Jager and Joost P. G. Sluijter
Int. J. Mol. Sci. 2021, 22(15), 7831; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22157831 - 22 Jul 2021
Cited by 23 | Viewed by 5222
Abstract
After myocardial infarction (MI), a strong inflammatory response takes place in the heart to remove the dead tissue resulting from ischemic injury. A growing body of evidence suggests that timely resolution of this inflammatory process may aid in the prevention of adverse cardiac [...] Read more.
After myocardial infarction (MI), a strong inflammatory response takes place in the heart to remove the dead tissue resulting from ischemic injury. A growing body of evidence suggests that timely resolution of this inflammatory process may aid in the prevention of adverse cardiac remodeling and heart failure post-MI. The present challenge is to find a way to stimulate this process without interfering with the reparative role of the immune system. Extracellular vesicles (EVs) are natural membrane particles that are released by cells and carry different macromolecules, including proteins and non-coding RNAs. In recent years, EVs derived from various stem and progenitor cells have been demonstrated to possess regenerative properties. They can provide cardioprotection via several mechanisms of action, including immunomodulation. In this review, we summarize the role of the innate immune system in post-MI healing. We then discuss the mechanisms by which EVs modulate cardiac inflammation in preclinical models of myocardial injury through regulation of monocyte influx and macrophage function. Finally, we provide suggestions for further optimization of EV-based therapy to improve its potential for the treatment of MI. Full article
(This article belongs to the Special Issue Extracellular Vesicles in Inflammation)
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18 pages, 807 KiB  
Review
Extracellular Vesicles as Potential Therapeutics for Inflammatory Diseases
by Hee Sook Hwang, Hyosuk Kim, Geonhee Han, Jong Won Lee, Kwangmeyung Kim, Ick Chan Kwon, Yoosoo Yang and Sun Hwa Kim
Int. J. Mol. Sci. 2021, 22(11), 5487; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22115487 - 22 May 2021
Cited by 17 | Viewed by 3239
Abstract
Extracellular vesicles (EV) deliver cargoes such as nucleic acids, proteins, and lipids between cells and serve as an intercellular communicator. As it is revealed that most of the functions associated to EVs are closely related to the immune response, the important role of [...] Read more.
Extracellular vesicles (EV) deliver cargoes such as nucleic acids, proteins, and lipids between cells and serve as an intercellular communicator. As it is revealed that most of the functions associated to EVs are closely related to the immune response, the important role of EVs in inflammatory diseases is emerging. EVs can be functionalized through EV surface engineering and endow targeting moiety that allows for the target specificity for therapeutic applications in inflammatory diseases. Moreover, engineered EVs are considered as promising nanoparticles to develop personalized therapeutic carriers. In this review, we highlight the role of EVs in various inflammatory diseases, the application of EV as anti-inflammatory therapeutics, and the current state of the art in EV engineering techniques. Full article
(This article belongs to the Special Issue Extracellular Vesicles in Inflammation)
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19 pages, 5413 KiB  
Review
Bacterial Membrane Vesicles in Pneumonia: From Mediators of Virulence to Innovative Vaccine Candidates
by Felix Behrens, Teresa C. Funk-Hilsdorf, Wolfgang M. Kuebler and Szandor Simmons
Int. J. Mol. Sci. 2021, 22(8), 3858; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22083858 - 08 Apr 2021
Cited by 16 | Viewed by 3146
Abstract
Pneumonia due to respiratory infection with most prominently bacteria, but also viruses, fungi, or parasites is the leading cause of death worldwide among all infectious disease in both adults and infants. The introduction of modern antibiotic treatment regimens and vaccine strategies has helped [...] Read more.
Pneumonia due to respiratory infection with most prominently bacteria, but also viruses, fungi, or parasites is the leading cause of death worldwide among all infectious disease in both adults and infants. The introduction of modern antibiotic treatment regimens and vaccine strategies has helped to lower the burden of bacterial pneumonia, yet due to the unavailability or refusal of vaccines and antimicrobials in parts of the global population, the rise of multidrug resistant pathogens, and high fatality rates even in patients treated with appropriate antibiotics pneumonia remains a global threat. As such, a better understanding of pathogen virulence on the one, and the development of innovative vaccine strategies on the other hand are once again in dire need in the perennial fight of men against microbes. Recent data show that the secretome of bacteria consists not only of soluble mediators of virulence but also to a significant proportion of extracellular vesicles—lipid bilayer-delimited particles that form integral mediators of intercellular communication. Extracellular vesicles are released from cells of all kinds of organisms, including both Gram-negative and Gram-positive bacteria in which case they are commonly termed outer membrane vesicles (OMVs) and membrane vesicles (MVs), respectively. (O)MVs can trigger inflammatory responses to specific pathogens including S. pneumonia, P. aeruginosa, and L. pneumophila and as such, mediate bacterial virulence in pneumonia by challenging the host respiratory epithelium and cellular and humoral immunity. In parallel, however, (O)MVs have recently emerged as auspicious vaccine candidates due to their natural antigenicity and favorable biochemical properties. First studies highlight the efficacy of such vaccines in animal models exposed to (O)MVs from B. pertussis, S. pneumoniae, A. baumannii, and K. pneumoniae. An advanced and balanced recognition of both the detrimental effects of (O)MVs and their immunogenic potential could pave the way to novel treatment strategies in pneumonia and effective preventive approaches. Full article
(This article belongs to the Special Issue Extracellular Vesicles in Inflammation)
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26 pages, 2186 KiB  
Review
EVs from BALF—Mediators of Inflammation and Potential Biomarkers in Lung Diseases
by Lukasz Zareba, Jacek Szymanski, Zuzanna Homoncik and Malgorzata Czystowska-Kuzmicz
Int. J. Mol. Sci. 2021, 22(7), 3651; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22073651 - 01 Apr 2021
Cited by 21 | Viewed by 3897
Abstract
Extracellular vesicles (EVs) have been identified as key messengers of intracellular communication in health and disease, including the lung. EVs that can be found in bronchoalveolar lavage fluid (BALF) are released by multiple cells of the airways including bronchial epithelial cells, endothelial cells, [...] Read more.
Extracellular vesicles (EVs) have been identified as key messengers of intracellular communication in health and disease, including the lung. EVs that can be found in bronchoalveolar lavage fluid (BALF) are released by multiple cells of the airways including bronchial epithelial cells, endothelial cells, alveolar macrophages, and other immune cells, and they have been shown to mediate proinflammatory signals in many inflammatory lung diseases. They transfer complex molecular cargo, including proteins, cytokines, lipids, and nucleic acids such as microRNA, between structural cells such as pulmonary epithelial cells and innate immune cells such as alveolar macrophages, shaping mutually their functions and affecting the alveolar microenvironment homeostasis. Here, we discuss this distinct molecular cargo of BALF-EVs in the context of inducing and propagating inflammatory responses in particular acute and chronic lung disorders. We present different identified cellular interactions in the inflammatory lung via EVs and their role in lung pathogenesis. We also summarize the latest studies on the potential use of BALF-EVs as diagnostic and prognostic biomarkers of lung diseases, especially of lung cancer. Full article
(This article belongs to the Special Issue Extracellular Vesicles in Inflammation)
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20 pages, 1483 KiB  
Review
Extracellular Vesicles and Their Role in the Spatial and Temporal Expansion of Tumor–Immune Interactions
by Simone Lipinski and Katharina Tiemann
Int. J. Mol. Sci. 2021, 22(7), 3374; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22073374 - 25 Mar 2021
Cited by 8 | Viewed by 2652
Abstract
Extracellular vesicles (EVs) serve as trafficking vehicles and intercellular communication tools. Their cargo molecules directly reflect characteristics of their parental cell. This includes information on cell identity and specific cellular conditions, ranging from normal to pathological states. In cancer, the content of EVs [...] Read more.
Extracellular vesicles (EVs) serve as trafficking vehicles and intercellular communication tools. Their cargo molecules directly reflect characteristics of their parental cell. This includes information on cell identity and specific cellular conditions, ranging from normal to pathological states. In cancer, the content of EVs derived from tumor cells is altered and can induce oncogenic reprogramming of target cells. As a result, tumor-derived EVs compromise antitumor immunity and promote cancer progression and spreading. However, this pro-oncogenic phenotype is constantly being challenged by EVs derived from the local tumor microenvironment and from remote sources. Here, we summarize the role of EVs in the tumor–immune cross-talk that includes, but is not limited to, immune cells in the tumor microenvironment. We discuss the potential of remotely released EVs from the microbiome and during physical activity to shape the tumor–immune cross-talk, directly or indirectly, and confer antitumor activity. We further discuss the role of proinflammatory EVs in the temporal development of the tumor–immune interactions and their potential use for cancer diagnostics. Full article
(This article belongs to the Special Issue Extracellular Vesicles in Inflammation)
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15 pages, 1312 KiB  
Review
Stem Cells-Derived Extracellular Vesicles: Potential Therapeutics for Wound Healing in Chronic Inflammatory Skin Diseases
by Enzo Manchon, Nell Hirt, Jean-David Bouaziz, Nabila Jabrane-Ferrat and Reem Al-Daccak
Int. J. Mol. Sci. 2021, 22(6), 3130; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22063130 - 19 Mar 2021
Cited by 20 | Viewed by 3872
Abstract
Endosome-derived small extracellular vesicles (EVs), often referred to as exosomes, are produced by almost all, if not all, cell types, and are critical for intercellular communication. They are composed of a lipid bilayer associated with membrane proteins and contain a payload of lipids, [...] Read more.
Endosome-derived small extracellular vesicles (EVs), often referred to as exosomes, are produced by almost all, if not all, cell types, and are critical for intercellular communication. They are composed of a lipid bilayer associated with membrane proteins and contain a payload of lipids, proteins and regulatory RNAs that depends on the parental cell physiological condition. By transferring their “cargo”, exosomes can modulate the phenotype of neighboring and distant cells. Stem cells (SC) were widely studied for therapeutic applications regarding their regenerative/reparative potential as well as their immunomodulatory properties. Whether from autologous or allogeneic source, SC beneficial effects in terms of repair and regeneration are largely attributed to their paracrine signaling notably through secreted EVs. Subsequently, SC-derived EVs have been investigated for the treatment of various diseases, including inflammatory skin disorders, and are today fast-track cell-free tools for regenerative/reparative strategies. Yet, their clinical application is still facing considerable challenges, including production and isolation procedures, and optimal cell source. Within the emerging concept of “allogeneic-driven benefit” for SC-based therapies, the use of EVs from allogeneic sources becomes the pragmatic choice although a universal allogeneic cell source is still needed. As a unique temporary organ that ensures the mutual coexistence of two allogeneic organisms, mother and fetus, the human placenta offers a persuasive allogeneic stem cell source for development of therapeutic EVs. Advancing cell-free therapeutics nurtures great hope and provides new perspectives for the development of safe and effective treatment in regenerative/reparative medicine and beyond. We will outline the current state of the art in regard of EVs, summarize their therapeutic potential in the context of skin inflammatory disorders, and discuss their translational advantages and hurdles. Full article
(This article belongs to the Special Issue Extracellular Vesicles in Inflammation)
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34 pages, 1625 KiB  
Review
Extracellular Vesicles from Mesenchymal Stromal Cells for the Treatment of Inflammation-Related Conditions
by Sean T. Ryan, Elham Hosseini-Beheshti, Dinara Afrose, Xianting Ding, Binbin Xia, Georges E. Grau, Christopher B. Little, Lana McClements and Jiao Jiao Li
Int. J. Mol. Sci. 2021, 22(6), 3023; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22063023 - 16 Mar 2021
Cited by 28 | Viewed by 5314
Abstract
Over the past two decades, mesenchymal stromal cells (MSCs) have demonstrated great potential in the treatment of inflammation-related conditions. Numerous early stage clinical trials have suggested that this treatment strategy has potential to lead to significant improvements in clinical outcomes. While promising, there [...] Read more.
Over the past two decades, mesenchymal stromal cells (MSCs) have demonstrated great potential in the treatment of inflammation-related conditions. Numerous early stage clinical trials have suggested that this treatment strategy has potential to lead to significant improvements in clinical outcomes. While promising, there remain substantial regulatory hurdles, safety concerns, and logistical issues that need to be addressed before cell-based treatments can have widespread clinical impact. These drawbacks, along with research aimed at elucidating the mechanisms by which MSCs exert their therapeutic effects, have inspired the development of extracellular vesicles (EVs) as anti-inflammatory therapeutic agents. The use of MSC-derived EVs for treating inflammation-related conditions has shown therapeutic potential in both in vitro and small animal studies. This review will explore the current research landscape pertaining to the use of MSC-derived EVs as anti-inflammatory and pro-regenerative agents in a range of inflammation-related conditions: osteoarthritis, rheumatoid arthritis, Alzheimer’s disease, cardiovascular disease, and preeclampsia. Along with this, the mechanisms by which MSC-derived EVs exert their beneficial effects on the damaged or degenerative tissues will be reviewed, giving insight into their therapeutic potential. Challenges and future perspectives on the use of MSC-derived EVs for the treatment of inflammation-related conditions will be discussed. Full article
(This article belongs to the Special Issue Extracellular Vesicles in Inflammation)
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27 pages, 3083 KiB  
Review
Exosomes: A Key Piece in Asthmatic Inflammation
by José A. Cañas, José M. Rodrigo-Muñoz, Marta Gil-Martínez, Beatriz Sastre and Victoria del Pozo
Int. J. Mol. Sci. 2021, 22(2), 963; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22020963 - 19 Jan 2021
Cited by 13 | Viewed by 3686
Abstract
Asthma is a chronic disease of the airways that has an important inflammatory component. Multiple cells are implicated in asthma pathogenesis (lymphocytes, eosinophils, mast cells, basophils, neutrophils), releasing a wide variety of cytokines. These cells can exert their inflammatory functions throughout extracellular vesicles [...] Read more.
Asthma is a chronic disease of the airways that has an important inflammatory component. Multiple cells are implicated in asthma pathogenesis (lymphocytes, eosinophils, mast cells, basophils, neutrophils), releasing a wide variety of cytokines. These cells can exert their inflammatory functions throughout extracellular vesicles (EVs), which are small vesicles released by donor cells into the extracellular microenvironment that can be taken up by recipient cells. Depending on their size, EVs can be classified as microvesicles, exosomes, or apoptotic bodies. EVs are heterogeneous spherical structures secreted by almost all cell types. One of their main functions is to act as transporters of a wide range of molecules, such as proteins, lipids, and microRNAs (miRNAs), which are single-stranded RNAs of approximately 22 nucleotides in length. Therefore, exosomes could influence several physiological and pathological processes, including those involved in asthma. They can be detected in multiple cell types and biofluids, providing a wealth of information about the processes that take account in a pathological scenario. This review thus summarizes the most recent insights concerning the role of exosomes from different sources (several cell populations and biofluids) in one of the most prevalent respiratory diseases, asthma. Full article
(This article belongs to the Special Issue Extracellular Vesicles in Inflammation)
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16 pages, 1426 KiB  
Review
Stoking the Fire: How Dying Cells Propagate Inflammatory Signalling through Extracellular Vesicle Trafficking
by Amy A. Baxter
Int. J. Mol. Sci. 2020, 21(19), 7256; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21197256 - 01 Oct 2020
Cited by 12 | Viewed by 3763
Abstract
Communication between dying cells and their environment is a critical process that promotes tissue homeostasis during normal cellular turnover, whilst during disease settings, it can contribute to inflammation through the release of intracellular factors. Extracellular vesicles (EVs) are a heterogeneous class of membrane-bound [...] Read more.
Communication between dying cells and their environment is a critical process that promotes tissue homeostasis during normal cellular turnover, whilst during disease settings, it can contribute to inflammation through the release of intracellular factors. Extracellular vesicles (EVs) are a heterogeneous class of membrane-bound cell-derived structures that can engage in intercellular communication via the trafficking of bioactive molecules between cells and tissues. In addition to the well-described functions of EVs derived from living cells, the ability of dying cells to release EVs capable of mediating functions on target cells or tissues is also of significant interest. In particular, during inflammatory settings such as acute tissue injury, infection and autoimmunity, the EV-mediated transfer of proinflammatory cargo from dying cells is an important process that can elicit profound proinflammatory effects in recipient cells and tissues. Furthermore, the biogenesis of EVs via unique cell-death-associated pathways has also been recently described, highlighting an emerging niche in EV biology. This review outlines the mechanisms and functions of dying-cell-derived EVs and their ability to drive inflammation during various modes of cell death, whilst reflecting on the challenges and knowledge gaps in investigating this subgenre of extracellular vesicles research. Full article
(This article belongs to the Special Issue Extracellular Vesicles in Inflammation)
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24 pages, 4907 KiB  
Review
Therapeutic Potentials of Extracellular Vesicles for the Treatment of Diabetes and Diabetic Complications
by Wei Hu, Xiang Song, Haibo Yu, Jingyu Sun and Yong Zhao
Int. J. Mol. Sci. 2020, 21(14), 5163; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21145163 - 21 Jul 2020
Cited by 25 | Viewed by 4694
Abstract
Extracellular vesicles (EVs), including exosomes and microvesicles, are nano-to-micrometer vesicles released from nearly all cellular types. EVs comprise a mixture of bioactive molecules (e.g., mRNAs, miRNAs, lipids, and proteins) that can be transported to the targeted cells/tissues via the blood or lymph circulation. [...] Read more.
Extracellular vesicles (EVs), including exosomes and microvesicles, are nano-to-micrometer vesicles released from nearly all cellular types. EVs comprise a mixture of bioactive molecules (e.g., mRNAs, miRNAs, lipids, and proteins) that can be transported to the targeted cells/tissues via the blood or lymph circulation. Recently, EVs have received increased attention, owing to their emerging roles in cell-to-cell communication, or as biomarkers with the therapeutic potential to replace cell-based therapy. Diabetes comprises a group of metabolic disorders characterized by hyperglycemia that cause the development of life-threatening complications. The impacts of conventional clinical treatment are generally limited and are followed by many side effects, including hypoglycemia, obesity, and damage to the liver and kidney. Recently, several studies have shown that EVs released by stem cells and immune cells can regulate gene expression in the recipient cells, thus providing a strategy to treat diabetes and its complications. In this review, we summarize the results from currently available studies, demonstrating the therapeutic potentials of EVs in diabetes and diabetic complications. Additionally, we highlight recommendations for future research. Full article
(This article belongs to the Special Issue Extracellular Vesicles in Inflammation)
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