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The role of extracellular vesicles in the physiological and pathological regulation of the blood-brain barrier.

ABSTRACT: Extracellular vesicles (EVs) are a subclass of biological nanoparticles secreted by most cell types. Once secreted, EVs can travel long distances to deliver their content to target cells thereby playing a key role in cell-to-cell communication and supporting both physiological and pathological processes. In recent years, the functional versatility of EVs has come to be more widely appreciated. Their heterogeneous structure encloses solubilized bioactive cargoes including proteins and nucleic acids. EVs mirror the secreting cell in composition therefore representing a novel source of diagnostic and prognostic biomarkers. Moreover, due to their unique structure, EVs constitute a promising class of biocompatible nanovehicles for drug delivery as well. Importantly, and of burgeoning interest, is the fact that EVs have the intrinsic ability to breach biological barriers including the complex blood-brain barrier (BBB), whose restrictive nature represents a significant therapeutic challenge. EVs have been shown to contribute to the progression of a variety of brain diseases including metastatic brain cancer, neurodegenerative diseases, and acute pathologies including infections and ischemia. In this review, the role of EVs in the maintenance and regulation of the BBB under normal physiological and pathologic conditions are discussed. Applications of EVs as therapeutic and diagnostic tools in the treatment of diseases that affect the central nervous system are presented as are limitations hindering their broad translation and potential solutions to resolve them.

SUBMITTER: Busatto S

PROVIDER: S-EPMC8409556 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Autoreactive T lymphocytes crossing the blood-brain barrier (BBB) into the central nervous system (CNS) play a crucial role in the initiation of demyelination and neurodegeneration in multiple sclerosis (MS). Recently, extracellular vesicles (EV) secreted by BBB endothelial cells (BBB-EC) have emerged as a unique form of cell-to-cell communication that contributes to cerebrovascular dysfunction. However, the precise impact of different size-based subpopulations of BBB-EC-derived EV (BBB-EV) on the early stages of MS remains unclear. Therefore, our objective was to investigate the content and function of distinct BBB-EV subpopulations in regulating BBB integrity and their role in T cell transendothelial migration, both in vitro and in vivo. Our study reveals that BBB-ECs release two distinct size based EV populations, namely small EV (sEV; 30-150 nm) and large EV (lEV; 150-300 nm), with a significantly higher secretion of sEV during inflammation. Notably, the expression patterns of cytokines and adhesion markers differ significantly between these BBB-EV subsets, indicating specific functional differences in the regulation of T cell migration. Through in vitro experiments, we demonstrate that lEV, which predominantly reflect their cellular source, play a major role in BBB integrity loss and the enhanced migration of pro-inflammatory Th1 and Th17.1 cells. Conversely, sEV appear to protect BBB function by inducing an anti-inflammatory phenotype in BBB-EC. These findings align with our in vivo data, where the administration of sEV to mice with experimental autoimmune encephalomyelitis (EAE) results in lower disease severity compared to the administration of lEV, which exacerbates disease symptoms. In conclusion, our study highlights the distinct and opposing effects of BBB-EV subpopulations on the BBB, both in vitro and in vivo. These findings underscore the need for further investigation into the diagnostic and therapeutic potential of BBB-EV in the context of MS.

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The role of extracellular vesicles in the physiological and pathological regulation of the blood-brain barrier.

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