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Extracellular Vesicles for Therapeutic Applications: What’s the Story?
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Extracellular Vesicles for Therapeutic Applications: What’s the Story?

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

Deadline for manuscript submissions: closed (30 April 2017) | Viewed by 152105

Special Issue Editors

Prof. Dr. Thomas Ritter

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Guest Editor
College of Medicine, Nursing and Health Sciences, School of Medicine, Regenerative Medicine Institute, National University of Ireland, Galway, Ireland
Prof. Dr. Matthew Griffin

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Guest Editor
College of Medicine, Nursing and Health Sciences, School of Medicine, Regenerative Medicine Institute, National University of Ireland, Galway, Ireland
Dr. Aideen Ryan

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Guest Editor
College of Medicine, Nursing and Health Sciences, School of Medicine, Regenerative Medicine Institute, National University of Ireland, Galway, Ireland

Special Issue Information

Dear Colleagues,

Exosomes are extracellular vesicles (EVs) released from the endosomal compartment and contain a cargo that includes miRNA, mRNA, and proteins from their cells of origin. Recent animal model-based studies suggest that EVs have significant potential as a novel alternative treatment option compared to cell therapies including reduced immunogenicity and superior safety profile. In this Special Issue we review the therapeutic potential and mechanism of action of EVs in various diseases models and discuss the promising future for EVs as an alternative, cell-free therapy.

Prof. Dr. Thomas Ritter
Guest Editor

Manuscript Submission Information

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Published Papers (16 papers)

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Research

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919 KiB  
Communication
An In Vitro Potency Assay for Monitoring the Immunomodulatory Potential of Stromal Cell-Derived Extracellular Vesicles
by Karin Pachler, Nina Ketterl, Alexandre Desgeorges, Zsuzsanna A. Dunai, Sandra Laner-Plamberger, Doris Streif, Dirk Strunk, Eva Rohde and Mario Gimona
Int. J. Mol. Sci. 2017, 18(7), 1413; https://doi.org/10.3390/ijms18071413 - 01 Jul 2017
Cited by 64 | Viewed by 7876
Abstract
The regenerative and immunomodulatory activity of mesenchymal stromal cells (MSCs) is partially mediated by secreted vesicular factors. Extracellular vesicles (EVs) exocytosed by MSCs are gaining increased attention as prospective non-cellular therapeutics for a variety of diseases. However, the lack of suitable in vitro [...] Read more.
The regenerative and immunomodulatory activity of mesenchymal stromal cells (MSCs) is partially mediated by secreted vesicular factors. Extracellular vesicles (EVs) exocytosed by MSCs are gaining increased attention as prospective non-cellular therapeutics for a variety of diseases. However, the lack of suitable in vitro assays to monitor the therapeutic potential of EVs currently restricts their application in clinical studies. We have evaluated a dual in vitro immunomodulation potency assay that reproducibly reports the inhibitory effect of MSCs on induced T-cell proliferation and the alloantigen-driven mixed leukocyte reaction of pooled peripheral blood mononuclear cells in a dose-dependent manner. Phytohemagglutinin-stimulated T-cell proliferation was inhibited by MSC-derived EVs in a dose-dependent manner comparable to MSCs. In contrast, inhibition of alloantigen-driven mixed leukocyte reaction was only observed for MSCs, but not for EVs. Our results support the application of a cell-based in vitro potency assay for reproducibly determining the immunomodulatory potential of EVs. Validation of this assay can help establish reliable release criteria for EVs for future clinical studies. Full article
(This article belongs to the Special Issue Extracellular Vesicles for Therapeutic Applications: What’s the Story?)
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1382 KiB  
Article
Chloramidine/Bisindolylmaleimide-I-Mediated Inhibition of Exosome and Microvesicle Release and Enhanced Efficacy of Cancer Chemotherapy
by Uchini S. Kosgodage, Rita P. Trindade, Paul R. Thompson, Jameel M. Inal and Sigrun Lange
Int. J. Mol. Sci. 2017, 18(5), 1007; https://doi.org/10.3390/ijms18051007 - 09 May 2017
Cited by 113 | Viewed by 8556
Abstract
Microvesicle (MV) release from tumour cells influences drug retention, contributing to cancer drug resistance. Strategically regulating MV release may increase drug retention within cancer cells and allow for lower doses of chemotherapeutic drugs. The contribution of exosomes to drug retention still remains unknown. [...] Read more.
Microvesicle (MV) release from tumour cells influences drug retention, contributing to cancer drug resistance. Strategically regulating MV release may increase drug retention within cancer cells and allow for lower doses of chemotherapeutic drugs. The contribution of exosomes to drug retention still remains unknown. Potential exosome and MV (EMV) biogenesis inhibitors, tested on human prostate cancer (PC3) cells for their capacity to inhibit EMV release, were also tested on PC3 and MCF-7 (breast cancer) cells for improving chemotherapy. Agents inhibiting EMV release most significantly, whilst maintaining cell viability, were chloramidine (Cl-amidine; 50 µM) and bisindolylmaleimide-I (10 µM). Apoptosis mediated by the chemotherapy drug 5-fluorouracil (5-FU) was significantly enhanced in PC3 cells in the presence of both these EMV inhibitors, resulting in a 62% (Cl-amidine + 5-FU) and 59% (bisindolylmaleimide-I + 5-FU) decrease in numbers of viable PC3 cells compared to 5-FU alone after 24 h. For MCF-7 cells, there were similar increased reductions of viable cells compared to 5-FU treatment alone ranging from 67% (Cl-amidine + 5-FU) to 58% (bisindolylmaleimide-I + 5-FU). Using combinatory treatment, the two EMV inhibitors further reduced the number of viable cancer cells tested. Neither inhibitor affected cell viability. Combining selected EMV inhibitors may pose as a novel strategy to enhance the efficacy of chemotherapeutic drug-mediated apoptosis. Full article
(This article belongs to the Special Issue Extracellular Vesicles for Therapeutic Applications: What’s the Story?)
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7335 KiB  
Article
Imipramine Protects against Bone Loss by Inhibition of Osteoblast-Derived Microvesicles
by Lili Deng, Ying Peng, Yuhai Jiang, Yu Wu, Yuedi Ding, Yaping Wang, Dong Xu and Qiang Fu
Int. J. Mol. Sci. 2017, 18(5), 1013; https://doi.org/10.3390/ijms18051013 - 08 May 2017
Cited by 34 | Viewed by 4783
Abstract
The maintenance of bone homeostasis is largely dependent upon cellular communication between osteoclasts and osteoblasts. Microvesicles (MVs) represent a novel mechanism for osteoblasts and osteoclasts communication, as has been demonstrated in our previous study. Sphingomyelinases catalyze the hydrolysis of sphingomyelin, which leads to [...] Read more.
The maintenance of bone homeostasis is largely dependent upon cellular communication between osteoclasts and osteoblasts. Microvesicles (MVs) represent a novel mechanism for osteoblasts and osteoclasts communication, as has been demonstrated in our previous study. Sphingomyelinases catalyze the hydrolysis of sphingomyelin, which leads to increased membrane fluidity and facilitates MV generation. This effect can be inhibited by imipramine, an inhibitor of acid sphingomyelinase (ASM), which is also known as a member of tricyclic antidepressants (TCAs). A recent study has reported that in vitro treatment of imipramine blocked MVs release from glial cells. However, whether imipramine has this effect on osteoblast-derived MVs and whether it is involved in MV generation in vivo is unclear. Here, our investigations found that imipramine slightly reduced the expression of osteoblast differentiation of related genes, but did not impact parathyroid hormone (PTH) regulation for these genes and also did not affect receptor activator of nuclear factor-κB ligand (RANKL)-mediated osteoclast formation; however, imipramine treatment blocked MVs released from osteoblasts and inhibited MV-induced osteoclast formation. In vivo, mice administrated with imipramine were protected from ovariectomy-induced bone loss as evaluated by various bone structural parameters and serum levels of biochemical markers. Our results suggest that inhibiting the production of MVs containing RANKL in vivo is very important for preventing bone loss. Full article
(This article belongs to the Special Issue Extracellular Vesicles for Therapeutic Applications: What’s the Story?)
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18772 KiB  
Article
Tumor Cell-Derived Microvesicles Induced Not Epithelial-Mesenchymal Transition but Apoptosis in Human Proximal Tubular (HK-2) Cells: Implications for Renal Impairment in Multiple Myeloma
by Aiqi Zhao, Fancong Kong, Chun-Jie Liu, Guoxin Yan, Fei Gao, Hao Guo, An-Yuan Guo, Zhichao Chen and Qiubai Li
Int. J. Mol. Sci. 2017, 18(3), 513; https://doi.org/10.3390/ijms18030513 - 27 Feb 2017
Cited by 7 | Viewed by 5294
Abstract
Renal impairment (RI) is one of the hallmarks of multiple myeloma (MM) and carries a poor prognosis. Microvesicles (MVs) are membrane vesicles and play an important role in disease progression. Here, we investigated the role of MVs derived from MM cells (MM-MVs) in [...] Read more.
Renal impairment (RI) is one of the hallmarks of multiple myeloma (MM) and carries a poor prognosis. Microvesicles (MVs) are membrane vesicles and play an important role in disease progression. Here, we investigated the role of MVs derived from MM cells (MM-MVs) in RI of MM. We found that MM-MVs significantly inhibited viability and induced apoptosis, but not epithelial-mesenchymal transition in human kidney-2 (HK-2), a human renal tubular epithelial cell line. The protein levels of cleaved caspase-3, 8, and 9, and E-cadherin, were increased, but vementin levels were decreased in the HK-2 cells treated with MM-MVs. Through a comparative sequencing and analysis of RNA content between the MVs from RPMI8226 MM cells (RPMI8226-MVs) and K562 leukemia cells, RPMI8226-MVs were enriched with more renal-pathogenic miRNAs, in which the selective miRNAs may participate in the up-regulation of the levels of cleaved caspase-3. Furthermore, the levels of CD138+ circulating MVs (cirMVs) in the peripheral blood were positively correlated with the severity of RI in newly-diagnosed MM. Our study supports MM-MVs representing a previously undescribed factor and playing a potential role in the development of RI of MM patients, and sheds light on the potential application of CD138+ cirMV counts in precise diagnosis of RI in MM and exploring MM-MVs as a therapeutic target. Full article
(This article belongs to the Special Issue Extracellular Vesicles for Therapeutic Applications: What’s the Story?)
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Review

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626 KiB  
Review
Mesenchymal Stem/Stromal Cell-Derived Extracellular Vesicles and Their Potential as Novel Immunomodulatory Therapeutic Agents
by Verena Börger, Michel Bremer, Rita Ferrer-Tur, Lena Gockeln, Oumaima Stambouli, Amina Becic and Bernd Giebel
Int. J. Mol. Sci. 2017, 18(7), 1450; https://doi.org/10.3390/ijms18071450 - 06 Jul 2017
Cited by 279 | Viewed by 15211
Abstract
Extracellular vesicles (EVs), such as exosomes and microvesicles, have been identified as mediators of a newly-discovered intercellular communication system. They are essential signaling mediators in various physiological and pathophysiological processes. Depending on their origin, they fulfill different functions. EVs of mesenchymal stem/stromal cells [...] Read more.
Extracellular vesicles (EVs), such as exosomes and microvesicles, have been identified as mediators of a newly-discovered intercellular communication system. They are essential signaling mediators in various physiological and pathophysiological processes. Depending on their origin, they fulfill different functions. EVs of mesenchymal stem/stromal cells (MSCs) have been found to promote comparable therapeutic activities as MSCs themselves. In a variety of in vivo models, it has been observed that they suppress pro-inflammatory processes and reduce oxidative stress and fibrosis. By switching pro-inflammatory into tolerogenic immune responses, MSC-EVs very likely promote tissue regeneration by creating a pro-regenerative environment allowing endogenous stem and progenitor cells to successfully repair affected tissues. Accordingly, MSC-EVs provide a novel, very promising therapeutic agent, which has already been successfully applied to humans. However, the MSC-EV production process has not been standardized, yet. Indeed, a collection of different protocols has been used for the MSC-EV production, characterization and application. By focusing on kidney, heart, liver and brain injuries, we have reviewed the major outcomes of published MSC-EV in vivo studies. Full article
(This article belongs to the Special Issue Extracellular Vesicles for Therapeutic Applications: What’s the Story?)
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957 KiB  
Review
The Therapeutic Benefit of Bacterial Membrane Vesicles
by Natalie J. Bitto and Maria Kaparakis-Liaskos
Int. J. Mol. Sci. 2017, 18(6), 1287; https://doi.org/10.3390/ijms18061287 - 16 Jun 2017
Cited by 94 | Viewed by 11559
Abstract
The therapeutic potential of extracellular vesicles from eukaryotes has gained strong interest in recent years. However, research into the therapeutic application of their bacterial counterparts, known as bacterial membrane vesicles, is only just beginning to be appreciated. Membrane vesicles (MVs) from both Gram-positive [...] Read more.
The therapeutic potential of extracellular vesicles from eukaryotes has gained strong interest in recent years. However, research into the therapeutic application of their bacterial counterparts, known as bacterial membrane vesicles, is only just beginning to be appreciated. Membrane vesicles (MVs) from both Gram-positive and Gram-negative bacteria offer significant advantages in therapeutic development, including large-scale, cost effective production and ease of molecular manipulation to display foreign antigens. The nanoparticle size of MVs enables their dissemination through numerous tissue types, and their natural immunogenicity and self-adjuvanting capability can be harnessed to induce both cell-mediated and humoral immunity in vaccine design. Moreover, the ability to target MVs to specific tissues through the display of surface receptors raises their potential use as targeted MV-based anti-cancer therapy. This review discusses recent advances in MV research with particular emphasis on exciting new possibilities for the application of MVs in therapeutic design. Full article
(This article belongs to the Special Issue Extracellular Vesicles for Therapeutic Applications: What’s the Story?)
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200 KiB  
Review
The Ability of Extracellular Vesicles to Induce a Pro-Inflammatory Host Response
by Maike E. Van Hezel, Rienk Nieuwland, Robin Van Bruggen and Nicole P. Juffermans
Int. J. Mol. Sci. 2017, 18(6), 1285; https://doi.org/10.3390/ijms18061285 - 16 Jun 2017
Cited by 51 | Viewed by 4740
Abstract
Extracellular vesicles (EVs) can modulate the host immune response, executing both pro- and anti-inflammatory effects. As EVs increasingly gain attention as potential carriers for targeted gene and drug delivery, knowledge on the effects of EVs on the host immune response is important. This [...] Read more.
Extracellular vesicles (EVs) can modulate the host immune response, executing both pro- and anti-inflammatory effects. As EVs increasingly gain attention as potential carriers for targeted gene and drug delivery, knowledge on the effects of EVs on the host immune response is important. This review will focus on the ability of EVs to trigger a pro-inflammatory host response by activating target cells. The overall view is that EVs can augment an inflammatory response, thereby potentially contributing to organ injury. This pro-inflammatory potential of EVs may hamper its use for therapeutic drug delivery. Whether removal of EVs as a means to reduce a pro-inflammatory or pro-coagulant response during hyper-inflammatory conditions is beneficial remains to be determined. Prior to any proposed therapeutic application, there is a need for further studies on the role of EVs in physiology and pathophysiology using improved detection and characterization methods to elucidate the roles of EVs in inflammatory conditions. Full article
(This article belongs to the Special Issue Extracellular Vesicles for Therapeutic Applications: What’s the Story?)
1697 KiB  
Review
Peptidylarginine Deiminases—Roles in Cancer and Neurodegeneration and Possible Avenues for Therapeutic Intervention via Modulation of Exosome and Microvesicle (EMV) Release?
by Sigrun Lange, Mark Gallagher, Sharad Kholia, Uchini S. Kosgodage, Mariya Hristova, John Hardy and Jameel M. Inal
Int. J. Mol. Sci. 2017, 18(6), 1196; https://doi.org/10.3390/ijms18061196 - 05 Jun 2017
Cited by 57 | Viewed by 8437
Abstract
Exosomes and microvesicles (EMVs) are lipid bilayer-enclosed structures released from cells and participate in cell-to-cell communication via transport of biological molecules. EMVs play important roles in various pathologies, including cancer and neurodegeneration. The regulation of EMV biogenesis is thus of great importance and [...] Read more.
Exosomes and microvesicles (EMVs) are lipid bilayer-enclosed structures released from cells and participate in cell-to-cell communication via transport of biological molecules. EMVs play important roles in various pathologies, including cancer and neurodegeneration. The regulation of EMV biogenesis is thus of great importance and novel ways for manipulating their release from cells have recently been highlighted. One of the pathways involved in EMV shedding is driven by peptidylarginine deiminase (PAD) mediated post-translational protein deimination, which is calcium-dependent and affects cytoskeletal rearrangement amongst other things. Increased PAD expression is observed in various cancers and neurodegeneration and may contribute to increased EMV shedding and disease progression. Here, we review the roles of PADs and EMVs in cancer and neurodegeneration. Full article
(This article belongs to the Special Issue Extracellular Vesicles for Therapeutic Applications: What’s the Story?)
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702 KiB  
Review
Extracellular Vesicles in Hematological Malignancies: From Biology to Therapy
by Antonella Caivano, Francesco La Rocca, Ilaria Laurenzana, Stefania Trino, Luciana De Luca, Daniela Lamorte, Luigi Del Vecchio and Pellegrino Musto
Int. J. Mol. Sci. 2017, 18(6), 1183; https://doi.org/10.3390/ijms18061183 - 02 Jun 2017
Cited by 32 | Viewed by 6244
Abstract
Extracellular vesicles (EVs) are a heterogeneous group of particles, between 15 nanometers and 10 microns in diameter, released by almost all cell types in physiological and pathological conditions, including tumors. EVs have recently emerged as particularly interesting informative vehicles, so that they could [...] Read more.
Extracellular vesicles (EVs) are a heterogeneous group of particles, between 15 nanometers and 10 microns in diameter, released by almost all cell types in physiological and pathological conditions, including tumors. EVs have recently emerged as particularly interesting informative vehicles, so that they could be considered a true “cell biopsy”. Indeed, EV cargo, including proteins, lipids, and nucleic acids, generally reflects the nature and status of the origin cells. In some cases, EVs are enriched of peculiar molecular cargo, thus suggesting at least a degree of specific cellular packaging. EVs are identified as important and critical players in intercellular communications in short and long distance interplays. Here, we examine the physiological role of EVs and their activity in cross-talk between bone marrow microenvironment and neoplastic cells in hematological malignancies (HMs). In these diseases, HM EVs can modify tumor and bone marrow microenvironment, making the latter “stronger” in supporting malignancy, inducing drug resistance, and suppressing the immune system. Moreover, EVs are abundant in biologic fluids and protect their molecular cargo against degradation. For these and other “natural” characteristics, EVs could be potential biomarkers in a context of HM liquid biopsy and therapeutic tools. These aspects will be also analyzed in this review. Full article
(This article belongs to the Special Issue Extracellular Vesicles for Therapeutic Applications: What’s the Story?)
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3476 KiB  
Review
The Methods of Choice for Extracellular Vesicles (EVs) Characterization
by Rafal Szatanek, Monika Baj-Krzyworzeka, Jakub Zimoch, Malgorzata Lekka, Maciej Siedlar and Jarek Baran
Int. J. Mol. Sci. 2017, 18(6), 1153; https://doi.org/10.3390/ijms18061153 - 29 May 2017
Cited by 344 | Viewed by 18355
Abstract
In recent years, extracellular vesicles (EVs) have become a subject of intense study. These membrane-enclosed spherical structures are secreted by almost every cell type and are engaged in the transport of cellular content (cargo) from parental to target cells. The impact of EVs [...] Read more.
In recent years, extracellular vesicles (EVs) have become a subject of intense study. These membrane-enclosed spherical structures are secreted by almost every cell type and are engaged in the transport of cellular content (cargo) from parental to target cells. The impact of EVs transfer has been observed in many vital cellular processes including cell-to-cell communication and immune response modulation; thus, a fast and precise characterization of EVs may be relevant for both scientific and diagnostic purposes. In this review, the most popular analytical techniques used in EVs studies are presented with the emphasis on exosomes and microvesicles characterization. Full article
(This article belongs to the Special Issue Extracellular Vesicles for Therapeutic Applications: What’s the Story?)
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215 KiB  
Review
Engineering Exosomes for Cancer Therapy
by Katie E. Gilligan and Róisín M. Dwyer
Int. J. Mol. Sci. 2017, 18(6), 1122; https://doi.org/10.3390/ijms18061122 - 24 May 2017
Cited by 209 | Viewed by 15633
Abstract
There remains an urgent need for novel therapeutic strategies to treat metastatic cancer, which results in over 8 million deaths annually worldwide. Following secretion, exosomes are naturally taken up by cells, and capable of the stable transfer of drugs, therapeutic microRNAs and proteins. [...] Read more.
There remains an urgent need for novel therapeutic strategies to treat metastatic cancer, which results in over 8 million deaths annually worldwide. Following secretion, exosomes are naturally taken up by cells, and capable of the stable transfer of drugs, therapeutic microRNAs and proteins. As knowledge of the biogenesis, release and uptake of exosomes continues to evolve, and thus also has interest in these extracellular vesicles as potential tumor-targeted vehicles for cancer therapy. The ability to engineer exosome content and migratory itinerary holds tremendous promise. Studies to date have employed viral and non-viral methods to engineer the parent cells to secrete modified exosomes, or alternatively, to directly manipulate exosome content following secretion. The majority of studies have demonstrated promising results, with decreased tumor cell invasion, migration and proliferation, along with enhanced immune response, cell death, and sensitivity to chemotherapy observed. The studies outlined in this review highlight the exciting potential for exosomes as therapeutic vehicles for cancer treatment. Successful implementation in the clinical setting will be dependent upon establishment of rigorous standards for exosome manipulation, isolation, and characterisation. Full article
(This article belongs to the Special Issue Extracellular Vesicles for Therapeutic Applications: What’s the Story?)
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1350 KiB  
Review
Mesenchymal Stem Cell Derived Extracellular Vesicles: A Role in Hematopoietic Transplantation?
by Luciana De Luca, Stefania Trino, Ilaria Laurenzana, Daniela Lamorte, Antonella Caivano, Luigi Del Vecchio and Pellegrino Musto
Int. J. Mol. Sci. 2017, 18(5), 1022; https://doi.org/10.3390/ijms18051022 - 09 May 2017
Cited by 39 | Viewed by 8025
Abstract
Mesenchymal stem cells (MSCs) are a heterogeneous cellular population containing different progenitors able to repair tissues, support hematopoiesis, and modulate immune and inflammatory responses. Several clinical trials have used MSCs in allogeneic hematopoietic stem cell transplantation (allo-HSCT) to prevent hematopoietic stem cell (HSC) [...] Read more.
Mesenchymal stem cells (MSCs) are a heterogeneous cellular population containing different progenitors able to repair tissues, support hematopoiesis, and modulate immune and inflammatory responses. Several clinical trials have used MSCs in allogeneic hematopoietic stem cell transplantation (allo-HSCT) to prevent hematopoietic stem cell (HSC) engraftment failure, reduce aplasia post chemotherapy, and to control graft versus host disease (GvHD). The efficacy of MSCs is linked to their immune suppressive and anti-inflammatory properties primarily due to the release of soluble factors. Recent studies indicate that most of these effects are mediated by extracellular vesicles (EVs). MSC-EVs have therefore therapeutic effects in regenerative medicine, tumor inhibition, and immune-regulation. MSC-EVs may offer specific advantages for patient safety, such as lower propensity to trigger innate and adaptive immune responses. It has been also shown that MSC-EVs can prevent or treat acute-GvHD by modulating the immune-response and, combined with HSCs, may contribute to the hematopoietic microenvironment reconstitution. Finally, MSC-EVs may provide a new potential therapeutic option (e.g., transplantation, gene therapy) for different diseases, particularly hematological malignancies. In this review, we will describe MSC and MSC-EVs role in improving allo-HSCT procedures and in treating GvHD. Full article
(This article belongs to the Special Issue Extracellular Vesicles for Therapeutic Applications: What’s the Story?)
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248 KiB  
Review
Pathogenic or Therapeutic Extracellular Vesicles in Rheumatic Diseases: Role of Mesenchymal Stem Cell-Derived Vesicles
by Stella Cosenza, Maxime Ruiz, Marie Maumus, Christian Jorgensen and Danièle Noël
Int. J. Mol. Sci. 2017, 18(4), 889; https://doi.org/10.3390/ijms18040889 - 22 Apr 2017
Cited by 68 | Viewed by 7900
Abstract
Extracellular vesicles (EVs) are important mediators of cell-to-cell communication pathways via the transport of proteins, mRNA, miRNA and lipids. There are three main types of EVs, exosomes, microparticles and apoptotic bodies, which are classified according to their size and biogenesis. EVs are secreted [...] Read more.
Extracellular vesicles (EVs) are important mediators of cell-to-cell communication pathways via the transport of proteins, mRNA, miRNA and lipids. There are three main types of EVs, exosomes, microparticles and apoptotic bodies, which are classified according to their size and biogenesis. EVs are secreted by all cell types and their function reproduces that of the parental cell. They are involved in many biological processes that regulate tissue homeostasis and physiopathology of diseases. In rheumatic diseases, namely osteoarthritis (OA) and rheumatoid arthritis (RA), EVs have been isolated from synovial fluid and shown to play pathogenic roles contributing to progression of both diseases. By contrast, EVs may have therapeutic effect via the delivery of molecules that may stop disease evolution. In particular, EVs derived from mesenchymal stem cells (MSCs) reproduce the main functions of the parental cells and therefore represent the ideal type of EVs for modulating the course of either disease. The aim of this review is to discuss the role of EVs in OA and RA focusing on their potential pathogenic effect and possible therapeutic options. Special attention is given to MSCs and MSC-derived EVs for modulating OA and RA progression with the perspective of developing innovative therapeutic strategies. Full article
(This article belongs to the Special Issue Extracellular Vesicles for Therapeutic Applications: What’s the Story?)
466 KiB  
Review
Extracellular Vesicles as Therapeutic Agents in Systemic Lupus Erythematosus
by Javier Perez-Hernandez, Josep Redon and Raquel Cortes
Int. J. Mol. Sci. 2017, 18(4), 717; https://doi.org/10.3390/ijms18040717 - 28 Mar 2017
Cited by 46 | Viewed by 7224
Abstract
Systemic lupus erythematosus (SLE) is a heterogeneous autoimmune disease that affects multiple organs. Currently, therapeutic molecules present adverse side effects and are only effective in some SLE patient subgroups. Extracellular vesicles (EV), including exosomes, microvesicles and apoptotic bodies, are released by most cell [...] Read more.
Systemic lupus erythematosus (SLE) is a heterogeneous autoimmune disease that affects multiple organs. Currently, therapeutic molecules present adverse side effects and are only effective in some SLE patient subgroups. Extracellular vesicles (EV), including exosomes, microvesicles and apoptotic bodies, are released by most cell types, carry nucleic acids, proteins and lipids and play a crucial role in cell-to-cell communication. EVs can stimulate or suppress the immune responses depending on the context. In SLE, EVs can work as autoadjuvants, enhance immune complex formation and maintaining inflammation state. Over the last years, EVs derived from mesenchymal stem cells and antigen presenting cells have emerged as cell-free therapeutic agents to treat autoimmune and inflammatory diseases. In this review, we summarize the current therapeutic applications of extracellular vesicles to regulate immune responses and to ameliorate disease activity in SLE and other autoimmune disorders. Full article
(This article belongs to the Special Issue Extracellular Vesicles for Therapeutic Applications: What’s the Story?)
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1277 KiB  
Review
Extracellular Vesicles Deliver Host and Virus RNA and Regulate Innate Immune Response
by Takahisa Kouwaki, Masaaki Okamoto, Hirotake Tsukamoto, Yoshimi Fukushima and Hiroyuki Oshiumi
Int. J. Mol. Sci. 2017, 18(3), 666; https://doi.org/10.3390/ijms18030666 - 20 Mar 2017
Cited by 86 | Viewed by 8250
Abstract
The innate immune system plays a crucial role in controlling viral infection. Pattern recognition receptors (PRRs), such as Toll-like receptors and RIG-I-like receptors, sense viral components called pathogen-associated molecular patterns (PAMPs) and trigger signals to induce innate immune responses. Extracellular vesicles (EVs), including [...] Read more.
The innate immune system plays a crucial role in controlling viral infection. Pattern recognition receptors (PRRs), such as Toll-like receptors and RIG-I-like receptors, sense viral components called pathogen-associated molecular patterns (PAMPs) and trigger signals to induce innate immune responses. Extracellular vesicles (EVs), including exosomes and microvesicles, deliver functional RNA and mediate intercellular communications. Recent studies have revealed that EVs released from virus-infected cells deliver viral RNA to dendritic cells and macrophages, thereby activating PRRs in recipient cells, which results in the expression of type I interferon and pro-inflammatory cytokines. On the other hand, EVs transfer not only viral RNA but also host microRNAs to recipient cells. Recently, infection of hepatocytes with hepatitis B virus (HBV) was shown to affect microRNA levels in EVs released from virus-infected cells, leading to attenuation of host innate immune response. This suggests that the virus utilizes the EVs and host microRNAs to counteract the antiviral innate immune responses. In this review, we summarize recent findings related to the role of EVs in antiviral innate immune responses. Full article
(This article belongs to the Special Issue Extracellular Vesicles for Therapeutic Applications: What’s the Story?)
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Other

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261 KiB  
Opinion
Manufacturing of Human Extracellular Vesicle-Based Therapeutics for Clinical Use
by Mario Gimona, Karin Pachler, Sandra Laner-Plamberger, Katharina Schallmoser and Eva Rohde
Int. J. Mol. Sci. 2017, 18(6), 1190; https://doi.org/10.3390/ijms18061190 - 03 Jun 2017
Cited by 208 | Viewed by 12997
Abstract
Extracellular vesicles (EVs) derived from stem and progenitor cells may have therapeutic effects comparable to their parental cells and are considered promising agents for the treatment of a variety of diseases. To this end, strategies must be designed to successfully translate EV research [...] Read more.
Extracellular vesicles (EVs) derived from stem and progenitor cells may have therapeutic effects comparable to their parental cells and are considered promising agents for the treatment of a variety of diseases. To this end, strategies must be designed to successfully translate EV research and to develop safe and efficacious therapies, whilst taking into account the applicable regulations. Here, we discuss the requirements for manufacturing, safety, and efficacy testing of EVs along their path from the laboratory to the patient. Development of EV-therapeutics is influenced by the source cell types and the target diseases. In this article, we express our view based on our experience in manufacturing biological therapeutics for routine use or clinical testing, and focus on strategies for advancing mesenchymal stromal cell (MSC)-derived EV-based therapies. We also discuss the rationale for testing MSC-EVs in selected diseases with an unmet clinical need such as critical size bone defects, epidermolysis bullosa and spinal cord injury. While the scientific community, pharmaceutical companies and clinicians are at the point of entering into clinical trials for testing the therapeutic potential of various EV-based products, the identification of the mode of action underlying the suggested potency in each therapeutic approach remains a major challenge to the translational path. Full article
(This article belongs to the Special Issue Extracellular Vesicles for Therapeutic Applications: What’s the Story?)
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