Elucidation of Exosome Migration Across the Blood–Brain Barrier Model In Vitro

Chen, Claire C.; Liu, Linan; Ma, Fen; Wong, Chi W.; Guo, Xuning Emily; Chacko, Jenu V.; Farhoodi, Henry P.; Zhang, Shirley X.; Zimak, Jan; Ségaliny, Aude I.; Riazifar, Milad; Pham, Victor; Digman, Michelle A.; Pone, Egest J.; Zhao, Weian

doi:10.1007/s12195-016-0458-3

Cited by 423 publications

(372 citation statements)

References 76 publications

(112 reference statements)

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“…Compared to exosomes utilized in this investigation (130 nm), the Mϕ-derived extruded membrane vesicles had larger average diameter (218 nm), which may result in increased sequestration in peripheral organs causing lower brain transport. Besides, our study was consistent with the study showing that fluorescently labeled exosomes released from autologous dendritic cells was detectable in mouse brains 24 h after IV injection [55], and other recent study showing that HEK293T exosomes can penetrate the Transwell model of BBB transcellularly under inflamed conditions (TNF-α activated) [56]. …”

Section: Discussionsupporting

confidence: 92%

Macrophage exosomes as natural nanocarriers for protein delivery to inflamed brain

et al. 2017

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Recent work has stimulated interest in the use of exosomes as nanocarriers for delivery of small drugs, RNAs, and proteins to the central nervous system (CNS). To overcome the blood-brain barrier (BBB), exosomes were modified with brain homing peptides that target brain endothelium but likely to increase immune response. Here for the first time we demonstrate that there is no need for such modification to penetrate the BBB in mammals. The naïve macrophage (Mϕ) exosomes can utilize, 1) on the one hand, the integrin lymphocyte function-associated antigen 1 (LFA-1) and intercellular adhesion molecule 1 (ICAM-1), and, 2) on the other hand, the carbohydrate-binding C-type lectin receptors, to interact with brain microvessel endothelial cells comprising the BBB. Notably, upregulation of ICAM-1, a common process in inflammation, promotes Mϕ exosomes uptake in the BBB cells. We further demonstrate in vivo that naïve Mϕ exosomes, after intravenous (IV) administration, cross the BBB and deliver a cargo protein, the brain derived neurotrophic factor (BDNF), to the brain. This delivery is enhanced in the presence of brain inflammation, a condition often present in CNS diseases. Taken together, the findings are of interest to basic science and possible use of Mϕ-derived exosomes as nanocarriers for brain delivery of therapeutic proteins to treat CNS diseases.

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Section: Discussionsupporting

confidence: 92%

Macrophage exosomes as natural nanocarriers for protein delivery to inflamed brain

et al. 2017

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“…For example, several published reports have demonstrated that exosomes are capable of crossing the blood-brain barrier (BBB) when active neuroinflammation is present. [47][48][49] Neuroinflammatory cascades often result in the compromised integrity of the BBB, thereby allowing for large macromolecules and even cells to enter from the periphery. 50,51 In addition, some methods of manufacturing and labeling MEX use extended processing times, which may decrease their resulting functional properties.…”

Section: Mex Biodistributionmentioning

confidence: 99%

Preclinical translation of exosomes derived from mesenchymal stem/stromal cells

et al. 2019

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Exosomes are nanovesicles secreted by virtually all cells. Exosomes mediate the horizontal transfer of various macromolecules previously believed to be cell-autonomous in nature, including nonsecretory proteins, various classes of RNA, metabolites, and lipid membrane-associated factors. Exosomes derived from mesenchymal stem/stromal cells (MSCs) appear to be particularly beneficial for enhancing recovery in various models of disease. To date, there have been more than 200 preclinical studies of exosome-based therapies in a number of different animal models. Despite a growing number of studies reporting the therapeutic properties of MSC-derived exosomes, their underlying mechanism of action, pharmacokinetics, and scalable manufacturing remain largely outstanding questions. Here, we review the global trends associated with preclinical development of MSC-derived exosome-based therapies, including immunogenicity, source of exosomes, isolation methods, biodistribution, and disease categories tested to date. Although the in vivo data assessing the therapeutic properties of MSC-exosomes published to date are promising, several outstanding questions remain to be answered that warrant further preclinical investigation.

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“…We identified uptake of our plasma derived EVs in the hCMEC/D3 cells line (Fig 2 and 3), supporting the findings of Chen et. al 2016 who identified internalization of exosomes derived from HEK 293T cells in endothelial cells (40). The same study show that the endothelial cells internalize the EVs by endocytosis via the trans-cellular route.…”

Section: Evs Cross the Bbb And Are Retained In Endothelial Cellsmentioning

confidence: 86%

Plasma-derived exosome-like vesicles are enriched in lyso-phospholipids and pass the blood-brain barrier

Mork-Jansson

Jakubec

Mapel-Grødem

et al. 2020

Preprint

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Exosomes are vesicles involved in intercellular communication. Their membrane structure and core content is largely dependent on the cell of origin. Exosomes have been investigated both for their biological roles and their possible use as disease biomarkers and drug carriers. These potential technological applications require the rigorous characterization of exosomal blood brain barrier permeability and a description of their lipid bilayer composition. To achieve these goals, we have established a 3D static blood brain barrier system based on existing systems for liposomes and a complementary LC-MS/MS and 31 P nuclear magnetic resonance methodology for the analysis of purified human plasma-derived exosome-like vesicles. Results show that the isolated vesicles pass the blood brain barrier and are taken up in endothelial cells. The compositional analysis revealed that the isolated vesicles are enriched in lyso phospholipids and do not contain phosphatidylserine.These findings deviate significantly from the composition of exosomes originating from cell culture, and may reflect active removal by macrophages that respond to exposed phosphahtidylserine.

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Elucidation of Exosome Migration Across the Blood–Brain Barrier Model In Vitro

Cited by 423 publications

References 76 publications

Macrophage exosomes as natural nanocarriers for protein delivery to inflamed brain

Macrophage exosomes as natural nanocarriers for protein delivery to inflamed brain

Preclinical translation of exosomes derived from mesenchymal stem/stromal cells

Plasma-derived exosome-like vesicles are enriched in lyso-phospholipids and pass the blood-brain barrier

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