Extracellular Vesicles in Neurological Disorders: Translational Research

A special issue of Biomedicines (ISSN 2227-9059). This special issue belongs to the section "Neurobiology and Clinical Neuroscience".

Deadline for manuscript submissions: closed (31 August 2022) | Viewed by 20984

Special Issue Editors


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Guest Editor
Neurological Sciences and Cerebrovascular Research Laboratory, Department of Neurology and Stroke Centre, Paseo Castellana 261, 28046 Madrid, Spain
Interests: animal models; cell therapy: cerebral infarct; exosomes; extracellular vesicles; intracerebral hemorrhage; stroke; trophic factors; translational research

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Guest Editor
Neurological Sciences and Cerebrovascular Research Laboratory, Department of Neurology and Stroke Centre, Neuroscience Area of IdiPAZ, Hospital La Paz Institute for Health Research–IdiPAZ, La Paz University Hospital, Universidad Autónoma de Madrid, Madrid 28046, Spain
Interests: animal models; biomarkers; multiple sclerosis; extracellular vesicles; translational research; treatment

Special Issue Information

Dear Colleagues,

In the last decade, extracellular vesicles (EVs) have attracted great interest as a mode of intercellular communication in numerous biological functions and pathological processes. EVs include exosomes and microvesicles that contain proteins, lipids, mRNAs, and miRNAs. By entering biologic fluids, these vesicles are able to transport bioactive molecules between cells, either within a microenvironment or remotely. EVs are present in blood, saliva, urine, breast milk, cerebrospinal fluid, seminal fluid, and tears, reflecting the molecular fingerprint of the releasing cell type. Liquid biopsy testing can be conducted numerous times to show the dynamic changes of a disease as well as the effects of treatments. EVs can even transmit key molecules to distant recipient cells through the blood–brain barrier (BBB). This ability to cross the BBB has inspired researchers to 1) design engineered vehicles that contained personalized cargo able to reach the central nervous system as a novel therapeutic approach for treating neurological diseases and 2) to identify biomarkers that provide real-time information about the damage and repair mechanisms involved in diseases.

In this Special Issue, we will summarize the implications of EVs in neurological disorders such as stroke, multiple sclerosis, Parkinson’s disease, Alzheimer’s disease, migraine, and traumatic brain injury.

In brief, EVs can be used for diagnosis, prognosis, and treatment and as biomarkers for health and disease in the application of precision medicine to neurological diseases.

The topics of this Special Issue should be of interest not only for neurologists and neuroscientists but also for physicians in different areas of medicine.

Dr. María Gutiérrez-Fernández
Dr. Laura Otero-Ortega
Guest Editors

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Keywords

  • animal models
  • biomarkers
  • exosomes
  • extracellular vesicles
  • miRNAs
  • neurological disorders
  • proteins
  • patients
  • translational research
  • treatments

Published Papers (7 papers)

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Research

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18 pages, 3784 KiB  
Article
Phenotype and Neuronal Cytotoxic Function of Glioblastoma Extracellular Vesicles
by Wenbo Zhou, Daniel Lovasz, Zoë Zizzo, Qianbin He, Christina Coughlan, Robert G. Kowalski, Peter G. E. Kennedy, Arin N. Graner, Kevin O. Lillehei, D. Ryan Ormond, A. Samy Youssef, Michael W. Graner and Xiaoli Yu
Biomedicines 2022, 10(11), 2718; https://doi.org/10.3390/biomedicines10112718 - 27 Oct 2022
Cited by 3 | Viewed by 1963
Abstract
Glioblastoma (GBM) is the most aggressive and lethal form of brain tumor. Extracellular vesicles (EVs) released by tumor cells play a critical role in cellular communication in the tumor microenvironment promoting tumor progression and invasion. We hypothesized that GBM EVs possess unique characteristics [...] Read more.
Glioblastoma (GBM) is the most aggressive and lethal form of brain tumor. Extracellular vesicles (EVs) released by tumor cells play a critical role in cellular communication in the tumor microenvironment promoting tumor progression and invasion. We hypothesized that GBM EVs possess unique characteristics which exert effects on endogenous CNS cells including neurons, producing dose-dependent neuronal cytotoxicity. We purified EVs from the plasma of 20 GBM patients, 20 meningioma patients, and 21 healthy controls, and characterized EV phenotypes by electron microscopy, nanoparticle tracking analysis, protein concentration, and proteomics. We evaluated GBM EV functions by determining their cytotoxicity in primary neurons and the neuroblastoma cell line SH-SY5Y. In addition, we determined levels of IgG antibodies in the plasma in GBM (n = 82), MMA (n = 83), and controls (non-tumor CNS disorders and healthy donors, n = 50) with capture ELISA. We discovered that GBM plasma EVs are smaller in size and had no relationship between size and concentration. Importantly, GBM EVs purified from both plasma and tumor cell lines produced IgG-mediated, complement-dependent apoptosis and necrosis in primary human neurons, mouse brain slices, and neuroblastoma cells. The unique phenotype of GBM EVs may contribute to its neuronal cytotoxicity, providing insight into its role in tumor pathogenesis. Full article
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13 pages, 5539 KiB  
Article
Anti-Inflammatory Mesenchymal Stromal Cell-Derived Extracellular Vesicles Improve Pathology in Niemann–Pick Type C Disease
by Lien Van Hoecke, Caroline Van Cauwenberghe, Verena Börger, Arnout Bruggeman, Jonas Castelein, Griet Van Imschoot, Elien Van Wonterghem, Robin Dittrich, Wouter Claeys, Junhua Xie, Bernd Giebel and Roosmarijn E. Vandenbroucke
Biomedicines 2021, 9(12), 1864; https://doi.org/10.3390/biomedicines9121864 - 8 Dec 2021
Cited by 15 | Viewed by 3199
Abstract
Niemann–Pick type C (NPC) disease is a rare neurovisceral lipid storage disease with progressive neurodegeneration, leading to premature death. The disease is caused by loss-of-function mutations either in the NPC1 or NPC2 gene which results in lipid accumulation in the late endosomes and [...] Read more.
Niemann–Pick type C (NPC) disease is a rare neurovisceral lipid storage disease with progressive neurodegeneration, leading to premature death. The disease is caused by loss-of-function mutations either in the NPC1 or NPC2 gene which results in lipid accumulation in the late endosomes and lysosomes. The involved disease mechanisms are still incompletely understood, making the design of a rational treatment very difficult. Since the disease is characterized by peripheral inflammation and neuroinflammation and it is shown that extracellular vesicles (EVs) obtained from mesenchymal stromal cells (MSCs) provide immunomodulatory capacities, we tested the potential of MSC-EV preparations to alter NPC1 disease pathology. Here, we show that the administration of an MSC-EV preparation with in vitro and in vivo confirmed immune modulatory capabilities is able to reduce the inflammatory state of peripheral organs and different brain regions of NPC1-diseased mice almost to normal levels. Moreover, a reduction of foamy cells in different peripheral organs was observed upon MSC-EV treatment of NPC1−/− mice. Lastly, the treatment was able to decrease microgliosis and astrogliosis, typical features of NPC1 patients that lead to neurodegeneration. Altogether, our results reveal the therapeutic potential of MSC-EVs as treatment for the genetic neurovisceral lipid storage disease NPC, thereby counteracting both central and peripheral features. Full article
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10 pages, 951 KiB  
Article
Mitochondrial Electron Transport Chain Protein Abnormalities Detected in Plasma Extracellular Vesicles in Alzheimer’s Disease
by Pamela J. Yao, Erden Eren, Edward J. Goetzl and Dimitrios Kapogiannis
Biomedicines 2021, 9(11), 1587; https://doi.org/10.3390/biomedicines9111587 - 31 Oct 2021
Cited by 22 | Viewed by 3275
Abstract
Mitochondria provide energy to neurons through oxidative phosphorylation and eliminate Reactive Oxygen Species (ROS) through Superoxide Dismutase 1 (SOD1). Dysfunctional mitochondria, manifesting decreased activity of electron transport chain (ETC) complexes and high ROS levels, are involved in Alzheimer’s disease (AD) pathogenesis. We hypothesized [...] Read more.
Mitochondria provide energy to neurons through oxidative phosphorylation and eliminate Reactive Oxygen Species (ROS) through Superoxide Dismutase 1 (SOD1). Dysfunctional mitochondria, manifesting decreased activity of electron transport chain (ETC) complexes and high ROS levels, are involved in Alzheimer’s disease (AD) pathogenesis. We hypothesized that neuronal mitochondrial dysfunction in AD is reflected in ETC and SOD1 levels and activity in plasma neuron-derived extracellular vesicles (NDEVs). We immunoprecipitated NDEVs targeting neuronal marker L1CAM from two cohorts: one including 22 individuals with early AD and 29 control subjects; and another including 14 individuals with early AD and 14 control subjects. In the first cohort, we measured levels of complexes I, III, IV, ATP synthase, and SOD1; in the second cohort, we measured levels and catalytic activity of complexes IV and ATP synthase. AD individuals had lower levels of complexes I (p < 0.0001), III (p < 0.0001), IV (p = 0.0061), and V (p < 0.0001), and SOD1 (p < 0.0001) compared to controls. AD individuals also had lower levels of catalytic activity of complex IV (p = 0.0214) and ATP synthase (p < 0.0001). NDEVs confirm quantitative and functional abnormalities in ECT complexes and SOD1 previously observed in AD models and during autopsy, opening the way for using them as biomarkers for mitochondrial dysfunction in AD. Full article
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10 pages, 1073 KiB  
Article
Exosomal let-7e, miR-21-5p, miR-145, miR-146a and miR-155 in Predicting Antidepressants Response in Patients with Major Depressive Disorder
by Yi-Yung Hung, Chen-Kai Chou, Yi-Chien Yang, Hung-Chun Fu, El-Wui Loh and Hong-Yo Kang
Biomedicines 2021, 9(10), 1428; https://doi.org/10.3390/biomedicines9101428 - 9 Oct 2021
Cited by 15 | Viewed by 2465
Abstract
The intracellular microRNAs that negatively regulate Toll-like receptor 4 signaling pathways in peripheral blood mononuclear cells are associated with major depressive disorder (MDD). However, that the distribution of these microRNAs in exosomes could be a biomarker of central nervous system diseases is just [...] Read more.
The intracellular microRNAs that negatively regulate Toll-like receptor 4 signaling pathways in peripheral blood mononuclear cells are associated with major depressive disorder (MDD). However, that the distribution of these microRNAs in exosomes could be a biomarker of central nervous system diseases is just beginning to be explored. In the present study, we isolated serum exosomes from patients with MDD and healthy controls to explore the levels of exosomal microRNAs, including let-7e, miR-21-5p, miR-223, miR-145, miR-146a, and miR-155. We also investigated the changes of these exosomal microRNAs after antidepressant treatment and their association with clinical changes in scores on the Hamilton Depression Rating Scale. An ANCOVA adjusted by age, sex, BMI, and smoking showed higher expression levels of miR-146a (p = 0.006) in patients with MDD compared to controls. Patients who achieved remission showed significantly lower let-7e, miR-21-5p, miR-145, miR-146a, and miR-155 levels before treatment and increased levels after antidepressant treatment compared with the non-remission group. Through receiver operating characteristic (ROC) analysis, let-7e, miR-145, and miR-146a showed acceptable discrimination between the remission and non-remission groups, whereas miR-21-5p and miR-155 showed poor discrimination. These findings demonstrate that exosomal microRNAs may play essential roles in predicting antidepressants response. Full article
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Review

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26 pages, 1833 KiB  
Review
Neurovascular Unit-Derived Extracellular Vesicles: From Their Physiopathological Roles to Their Clinical Applications in Acute Brain Injuries
by Sandrine Reymond, Tatjana Vujić and Jean-Charles Sanchez
Biomedicines 2022, 10(9), 2147; https://doi.org/10.3390/biomedicines10092147 - 1 Sep 2022
Cited by 3 | Viewed by 2688
Abstract
Extracellular vesicles (EVs) form a heterogeneous group of membrane-enclosed structures secreted by all cell types. EVs export encapsulated materials composed of proteins, lipids, and nucleic acids, making them a key mediator in cell–cell communication. In the context of the neurovascular unit (NVU), a [...] Read more.
Extracellular vesicles (EVs) form a heterogeneous group of membrane-enclosed structures secreted by all cell types. EVs export encapsulated materials composed of proteins, lipids, and nucleic acids, making them a key mediator in cell–cell communication. In the context of the neurovascular unit (NVU), a tightly interacting multicellular brain complex, EVs play a role in intercellular communication and in maintaining NVU functionality. In addition, NVU-derived EVs can also impact peripheral tissues by crossing the blood–brain barrier (BBB) to reach the blood stream. As such, EVs have been shown to be involved in the physiopathology of numerous neurological diseases. The presence of NVU-released EVs in the systemic circulation offers an opportunity to discover new diagnostic and prognostic markers for those diseases. This review outlines the most recent studies reporting the role of NVU-derived EVs in physiological and pathological mechanisms of the NVU, focusing on neuroinflammation and neurodegenerative diseases. Then, the clinical application of EVs-containing molecules as biomarkers in acute brain injuries, such as stroke and traumatic brain injuries (TBI), is discussed. Full article
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12 pages, 660 KiB  
Review
News about Therapies of Alzheimer’s Disease: Extracellular Vesicles from Stem Cells Exhibit Advantages Compared to Other Treatments
by Jacopo Meldolesi
Biomedicines 2022, 10(1), 105; https://doi.org/10.3390/biomedicines10010105 - 5 Jan 2022
Cited by 12 | Viewed by 2762
Abstract
Upon its discovery, Alzheimer’s, the neurodegenerative disease that affects many millions of patients in the world, remained without an effective therapy. The first drugs, made available near the end of last century, induced some effects, which remained only marginal. More promising effects are [...] Read more.
Upon its discovery, Alzheimer’s, the neurodegenerative disease that affects many millions of patients in the world, remained without an effective therapy. The first drugs, made available near the end of last century, induced some effects, which remained only marginal. More promising effects are now present, induced by two approaches. Blockers of the enzyme BACE-1 induce, in neurons and glial cells, decreased levels of Aβ, the key peptide of the Alzheimer’s disease. If administered at early AD steps, the BACE-1 blockers preclude further development of the disease. However, they have no effect on established, irreversible lesions. The extracellular vesicles secreted by mesenchymal stem cells induce therapy effects analogous, but more convenient, than the effects of their original cells. After their specific fusion to target cells, the action of these vesicles depends on their ensuing release of cargo molecules, such as proteins and many miRNAs, active primarily on the cell cytoplasm. Operationally, these vesicles exhibit numerous advantages: they exclude, by their accurate selection, the heterogeneity of the original cells; exhibit molecular specificity due to their engineering and drug accumulation; and induce effective actions, mediated by variable concentrations of factors and molecules and by activation of signaling cascades. Their strength is reinforced by their combination with various factors and processes. The recent molecular and operations changes, induced especially by the stem cell target cells, result in encouraging and important improvement of the disease. Their further development is expected in the near future. Full article
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41 pages, 1673 KiB  
Review
Special delEVery: Extracellular Vesicles as Promising Delivery Platform to the Brain
by Marie J. Pauwels, Charysse Vandendriessche and Roosmarijn E. Vandenbroucke
Biomedicines 2021, 9(11), 1734; https://doi.org/10.3390/biomedicines9111734 - 20 Nov 2021
Cited by 13 | Viewed by 3369
Abstract
The treatment of central nervous system (CNS) pathologies is severely hampered by the presence of tightly regulated CNS barriers that restrict drug delivery to the brain. An increasing amount of data suggests that extracellular vesicles (EVs), i.e., membrane derived vesicles that inherently protect [...] Read more.
The treatment of central nervous system (CNS) pathologies is severely hampered by the presence of tightly regulated CNS barriers that restrict drug delivery to the brain. An increasing amount of data suggests that extracellular vesicles (EVs), i.e., membrane derived vesicles that inherently protect and transfer biological cargoes between cells, naturally cross the CNS barriers. Moreover, EVs can be engineered with targeting ligands to obtain enriched tissue targeting and delivery capacities. In this review, we provide a detailed overview of the literature describing a natural and engineered CNS targeting and therapeutic efficiency of different cell type derived EVs. Hereby, we specifically focus on peripheral administration routes in a broad range of CNS diseases. Furthermore, we underline the potential of research aimed at elucidating the vesicular transport mechanisms across the different CNS barriers. Finally, we elaborate on the practical considerations towards the application of EVs as a brain drug delivery system. Full article
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