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14 pages, 1926 KiB

Open AccessArticle

A First Phenotypic and Functional Characterization of Placental Extracellular Vesicles from Women with Multiple Sclerosis

by Serena Martire, Francesca Montarolo, Michela Spadaro, Simona Perga, Maria Ludovica Sforza, Luca Marozio, Federica Frezet, Stefania Bruno, Giulia Chiabotto, Maria Chiara Deregibus, Giovanni Camussi, Giovanni Botta, Chiara Benedetto and Antonio Bertolotto

Int. J. Mol. Sci. 2021, 22(6), 2875; https://doi.org/10.3390/ijms22062875 - 12 Mar 2021

Cited by 4 | Viewed by 2760

Abstract

Pregnancy is a unique situation of physiological immunomodulation, as well as a strong Multiple Sclerosis (MS) disease modulator whose mechanisms are still unclear. Both maternal (decidua) and fetal (trophoblast) placental cells secrete extracellular vesicles (EVs), which are known to mediate cellular communication and [...] Read more.

Pregnancy is a unique situation of physiological immunomodulation, as well as a strong Multiple Sclerosis (MS) disease modulator whose mechanisms are still unclear. Both maternal (decidua) and fetal (trophoblast) placental cells secrete extracellular vesicles (EVs), which are known to mediate cellular communication and modulate the maternal immune response. Their contribution to the MS disease course during pregnancy, however, is unexplored. Here, we provide a first phenotypic and functional characterization of EVs isolated from cultures of term placenta samples of women with MS, differentiating between decidua and trophoblast. In particular, we analyzed the expression profile of 37 surface proteins and tested the functional role of placental EVs on mono-cultures of CD14⁺ monocytes and co-cultures of CD4⁺ T and regulatory T (Treg) cells. Results indicated that placental EVs are enriched for surface markers typical of stem/progenitor cells, and that conditioning with EVs from samples of women with MS is associated to a moderate decrease in the expression of proinflammatory cytokines by activated monocytes and in the proliferation rate of activated T cells co-cultured with Tregs. Overall, our findings suggest an immunomodulatory potential of placental EVs from women with MS and set the stage for a promising research field aiming at elucidating their role in MS remission. Full article

(This article belongs to the Special Issue Extracellular Vesicles in Allergy, Autoimmunity and Immune Regulation)

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13 pages, 2632 KiB

Open AccessCommunication

Topical Application of Mesenchymal Stem Cell Exosomes Alleviates the Imiquimod Induced Psoriasis-Like Inflammation

by Bin Zhang, Ruenn Chai Lai, Wei Kian Sim, Andre Boon Hwa Choo, Ellen Birgit Lane and Sai Kiang Lim

Int. J. Mol. Sci. 2021, 22(2), 720; https://doi.org/10.3390/ijms22020720 - 13 Jan 2021

Cited by 55 | Viewed by 7206

Abstract

Severe psoriasis, a chronic inflammatory skin disease is increasingly being effectively managed by targeted immunotherapy but long-term immunotherapy poses health risk and loss of response. Therefore, there is a need for alternative therapy strategies. Mesenchymal stem/stromal cell (MSC) exosomes are widely known for [...] Read more.

Severe psoriasis, a chronic inflammatory skin disease is increasingly being effectively managed by targeted immunotherapy but long-term immunotherapy poses health risk and loss of response. Therefore, there is a need for alternative therapy strategies. Mesenchymal stem/stromal cell (MSC) exosomes are widely known for their potent immunomodulatory properties. Here we investigated if topically applied MSC exosomes could alleviate psoriasis-associated inflammation. Topically applied fluorescent exosomes on human skin explants were confined primarily to the stratum corneum with <1% input fluorescence exiting the explant over a 24-h period. Nevertheless, topically applied MSC exosomes in a mouse model of imiquimod (IMQ) psoriasis significantly reduced IL-17 and terminal complement activation complex C5b-9 in the mouse skin. MSC exosomes were previously shown to inhibit complement activation, specifically C5b-9 complex formation through CD59. Infiltration of neutrophils into the stratum corneum is characteristic of psoriasis and neutrophils are a major cellular source of IL-17 in psoriasis through the release of neutrophil extracellular traps (NETs). We propose that topically applied MSC exosomes inhibit complement activation in the stratum corneum and this alleviates IL-17 release by NETS from neutrophils that accumulate in and beneath the stratum corneum. Full article

(This article belongs to the Special Issue Extracellular Vesicles in Allergy, Autoimmunity and Immune Regulation)

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34 pages, 3929 KiB

Open AccessArticle

Orally Administered Exosomes Suppress Mouse Delayed-Type Hypersensitivity by Delivering miRNA-150 to Antigen-Primed Macrophage APC Targeted by Exosome-Surface Anti-Peptide Antibody Light Chains

by Katarzyna Nazimek, Krzysztof Bryniarski, Wlodzimierz Ptak, Tom Groot Kormelink and Philip W. Askenase

Int. J. Mol. Sci. 2020, 21(15), 5540; https://doi.org/10.3390/ijms21155540 - 2 Aug 2020

Cited by 20 | Viewed by 3688

Abstract

We previously discovered suppressor T cell-derived, antigen (Ag)-specific exosomes inhibiting mouse hapten-induced contact sensitivity effector T cells by targeting antigen-presenting cells (APCs). These suppressive exosomes acted Ag-specifically due to a coating of antibody free light chains (FLC) from Ag-activated B1a cells. Current studies [...] Read more.

We previously discovered suppressor T cell-derived, antigen (Ag)-specific exosomes inhibiting mouse hapten-induced contact sensitivity effector T cells by targeting antigen-presenting cells (APCs). These suppressive exosomes acted Ag-specifically due to a coating of antibody free light chains (FLC) from Ag-activated B1a cells. Current studies are aimed at determining if similar immune tolerance could be induced in cutaneous delayed-type hypersensitivity (DTH) to the protein Ag (ovalbumin, OVA). Intravenous administration of a high dose of OVA-coupled, syngeneic erythrocytes similarly induced CD3⁺CD8⁺ suppressor T cells producing suppressive, miRNA-150-carrying exosomes, also coated with B1a cell-derived, OVA-specific FLC. Simultaneously, OVA-immunized B1a cells produced an exosome subpopulation, originally coated with Ag-specific FLC, that could be rendered suppressive by in vitro association with miRNA-150. Importantly, miRNA-150-carrying exosomes from both suppressor T cells and B1a cells efficiently induced prolonged DTH suppression after single systemic administration into actively immunized mice, with the strongest effect observed after oral treatment. Current studies also showed that OVA-specific FLC on suppressive exosomes bind OVA peptides suggesting that exosome-coating FLC target APCs by binding to peptide-Ag-major histocompatibility complexes. This renders APCs capable of inhibiting DTH effector T cells. Thus, our studies describe a novel immune tolerance mechanism mediated by FLC-coated, Ag-specific, miRNA-150-carrying exosomes that act on the APC and are particularly effective after oral administration. Full article

(This article belongs to the Special Issue Extracellular Vesicles in Allergy, Autoimmunity and Immune Regulation)

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Review

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13 pages, 1273 KiB

Open AccessReview

Extracellular Vesicles in Allergic Rhinitis and Asthma and Laboratory Possibilities for Their Assessment

by Urszula Demkow and Anna Stelmaszczyk-Emmel

Int. J. Mol. Sci. 2021, 22(5), 2273; https://doi.org/10.3390/ijms22052273 - 25 Feb 2021

Cited by 7 | Viewed by 2165

Abstract

Currently, extracellular vesicles (EVs) have been implicated in the etiopathogenesis of many diseases, including lung disorders, with the possibility of diagnostic and therapeutic applications. The analysis of EV in respiratory tract diseases faces many obstacles, including material collection from airways, standardization of isolation [...] Read more.

Currently, extracellular vesicles (EVs) have been implicated in the etiopathogenesis of many diseases, including lung disorders, with the possibility of diagnostic and therapeutic applications. The analysis of EV in respiratory tract diseases faces many obstacles, including material collection from airways, standardization of isolation techniques, detection methods, the analysis of their content, etc. This review focuses on the role of extracellular vesicles in the pathogenesis of atopic respiratory diseases, especially asthma, with a special focus on their clinical applicability as a diagnostic tool. We also summarize available laboratory techniques that enable the detection of EVs in various biological materials, with particular emphasis on flow cytometry. The opportunities and limitations of detecting EV in bronchoalveolar lavage fluid (BALF) were also described. Full article

(This article belongs to the Special Issue Extracellular Vesicles in Allergy, Autoimmunity and Immune Regulation)

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13 pages, 433 KiB

Open AccessReview

Mesenchymal Stem Cell-Derived Exosomes as New Remedy for the Treatment of Neurocognitive Disorders

by Carl Randall Harrell, Ana Volarevic, Valentin Djonov and Vladislav Volarevic

Int. J. Mol. Sci. 2021, 22(3), 1433; https://doi.org/10.3390/ijms22031433 - 1 Feb 2021

Cited by 37 | Viewed by 6378

Abstract

Mesenchymal stem cell (MSC)-derived exosomes (MSC-Exo) are nano-sized extracellular vesicles enriched with MSC-sourced neuroprotective and immunomodulatory microRNAs, neural growth factors, and anti-inflammatory cytokines, which attenuate neuro-inflammation, promote neo-vascularization, induce neurogenesis, and reduce apoptotic loss of neural cells. Accordingly, a large number of experimental [...] Read more.

Mesenchymal stem cell (MSC)-derived exosomes (MSC-Exo) are nano-sized extracellular vesicles enriched with MSC-sourced neuroprotective and immunomodulatory microRNAs, neural growth factors, and anti-inflammatory cytokines, which attenuate neuro-inflammation, promote neo-vascularization, induce neurogenesis, and reduce apoptotic loss of neural cells. Accordingly, a large number of experimental studies demonstrated MSC-Exo-dependent improvement of cognitive impairment in experimental animals. In this review article, we summarized current knowledge about molecular and cellular mechanisms that were responsible for MSC-Exo-based restoration of cognitive function, emphasizing therapeutic potential of MSC-Exos in the treatment of neurocognitive disorders. Full article

(This article belongs to the Special Issue Extracellular Vesicles in Allergy, Autoimmunity and Immune Regulation)

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28 pages, 510 KiB

Open AccessReview

Ancient Evolutionary Origin and Properties of Universally Produced Natural Exosomes Contribute to Their Therapeutic Superiority Compared to Artificial Nanoparticles

by Phillip W. Askenase

Int. J. Mol. Sci. 2021, 22(3), 1429; https://doi.org/10.3390/ijms22031429 - 31 Jan 2021

Cited by 20 | Viewed by 3851

Abstract

Extracellular vesicles (EVs), such as exosomes, are newly recognized fundamental, universally produced natural nanoparticles of life that are seemingly involved in all biologic processes and clinical diseases. Due to their universal involvements, understanding the nature and also the potential therapeutic uses of these [...] Read more.

Extracellular vesicles (EVs), such as exosomes, are newly recognized fundamental, universally produced natural nanoparticles of life that are seemingly involved in all biologic processes and clinical diseases. Due to their universal involvements, understanding the nature and also the potential therapeutic uses of these nanovesicles requires innovative experimental approaches in virtually every field. Of the EV group, exosome nanovesicles and larger companion micro vesicles can mediate completely new biologic and clinical processes dependent on the intercellular transfer of proteins and most importantly selected RNAs, particularly miRNAs between donor and targeted cells to elicit epigenetic alterations inducing functional cellular changes. These recipient acceptor cells are nearby (paracrine transfers) or far away after distribution via the circulation (endocrine transfers). The major properties of such vesicles seem to have been conserved over eons, suggesting that they may have ancient evolutionary origins arising perhaps even before cells in the primordial soup from which life evolved. Their potential ancient evolutionary attributes may be responsible for the ability of some modern-day exosomes to withstand unusually harsh conditions, perhaps due to unique membrane lipid compositions. This is exemplified by ability of the maternal milk exosomes to survive passing the neonatal acid/enzyme rich stomach. It is postulated that this resistance also applies to their durable presence in phagolysosomes, thus suggesting a unique intracellular release of their contained miRNAs. A major discussed issue is the generally poorly realized superiority of these naturally evolved nanovesicles for therapies when compared to human-engineered artificial nanoparticles, e.g., for the treatment of diseases like cancers. Full article

(This article belongs to the Special Issue Extracellular Vesicles in Allergy, Autoimmunity and Immune Regulation)

22 pages, 1475 KiB

Open AccessReview

Therapeutic Application of Exosomes in Inflammatory Diseases

by Ju Hun Suh, Hyeon Su Joo, Eun Be Hong, Hyeon Ji Lee and Jung Min Lee

Int. J. Mol. Sci. 2021, 22(3), 1144; https://doi.org/10.3390/ijms22031144 - 24 Jan 2021

Cited by 33 | Viewed by 5223

Abstract

Immunomodulation is on the cusp of being an important therapy for treating many diseases, due to the significant role of the immune system in defending the human body. Although the immune system is an essential defense system, overactivity can result in diverse sicknesses [...] Read more.

Immunomodulation is on the cusp of being an important therapy for treating many diseases, due to the significant role of the immune system in defending the human body. Although the immune system is an essential defense system, overactivity can result in diverse sicknesses such as inflammation and autoimmune disease. Exosomes are emerging as a state-of-the-art therapeutic strategy for treating an overactive immune system. Thus, in this review, we will thoroughly review therapeutic applications of exosomes in various inflammatory and autoimmune diseases. Finally, issues for an outlook to the future of exosomal therapy will be introduced. Full article

(This article belongs to the Special Issue Extracellular Vesicles in Allergy, Autoimmunity and Immune Regulation)

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20 pages, 1818 KiB

Open AccessReview

Membrane Microvesicles as Potential Vaccine Candidates

by Layaly Shkair, Ekaterina E. Garanina, Robert J. Stott, Toshana L. Foster, Albert A. Rizvanov and Svetlana F. Khaiboullina

Int. J. Mol. Sci. 2021, 22(3), 1142; https://doi.org/10.3390/ijms22031142 - 24 Jan 2021

Cited by 10 | Viewed by 3743

Abstract

The prevention and control of infectious diseases is crucial to the maintenance and protection of social and public healthcare. The global impact of SARS-CoV-2 has demonstrated how outbreaks of emerging and re-emerging infections can lead to pandemics of significant public health and socio-economic [...] Read more.

The prevention and control of infectious diseases is crucial to the maintenance and protection of social and public healthcare. The global impact of SARS-CoV-2 has demonstrated how outbreaks of emerging and re-emerging infections can lead to pandemics of significant public health and socio-economic burden. Vaccination is one of the most effective approaches to protect against infectious diseases, and to date, multiple vaccines have been successfully used to protect against and eradicate both viral and bacterial pathogens. The main criterion of vaccine efficacy is the induction of specific humoral and cellular immune responses, and it is well established that immunogenicity depends on the type of vaccine as well as the route of delivery. In addition, antigen delivery to immune organs and the site of injection can potentiate efficacy of the vaccine. In light of this, microvesicles have been suggested as potential vehicles for antigen delivery as they can carry various immunogenic molecules including proteins, nucleic acids and polysaccharides directly to target cells. In this review, we focus on the mechanisms of microvesicle biogenesis and the role of microvesicles in infectious diseases. Further, we discuss the application of microvesicles as a novel and effective vaccine delivery system. Full article

(This article belongs to the Special Issue Extracellular Vesicles in Allergy, Autoimmunity and Immune Regulation)

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