Zhang, L., Graf, I., Kuang, Y. et al. (10 more authors) (2021) Neural progenitor cell-derived extracellular vesicles enhance blood-brain barrier integrity by NF-κB (nuclear factor-κB)-dependent regulation of ABCB1 (ATP-binding cassette transporter B1) in stroke mice. Arteriosclerosis, Thrombosis, and Vascular Biology, 41 (3). pp. 1127-1145. ISSN 1079-5642
Abstract
Objective:
Extracellular vesicles (EVs) derived from neural progenitor cells enhance poststroke neurological recovery, albeit the underlying mechanisms remain elusive. Since previous research described an enhanced poststroke integrity of the blood-brain barrier (BBB) upon systemic transplantation of neural progenitor cells, we examined if neural progenitor cell-derived EVs affect BBB integrity and which cellular mechanisms are involved in the process.
Approach and Results:
Using in vitro models of primary brain endothelial cell (EC) cultures as well as co-cultures of brain ECs (ECs) and astrocytes exposed to oxygen glucose deprivation, we examined the effects of EVs or vehicle on microvascular integrity. In vitro data were confirmed using a mouse transient middle cerebral artery occlusion model. Cultured ECs displayed increased ABCB1 (ATP-binding cassette transporter B1) levels when exposed to oxygen glucose deprivation, which was reversed by treatment with EVs. The latter was due to an EV-induced inhibition of the NF-κB (nuclear factor-κB) pathway. Using a BBB co-culture model of ECs and astrocytes exposed to oxygen glucose deprivation, EVs stabilized the BBB and ABCB1 levels without affecting the transcellular electrical resistance of ECs. Likewise, EVs yielded reduced Evans blue extravasation, decreased ABCB1 expression as well as an inhibition of the NF-κB pathway, and downstream matrix metalloproteinase 9 (MMP-9) activity in stroke mice. The EV-induced inhibition of the NF-κB pathway resulted in a poststroke modulation of immune responses.
Conclusions:
Our findings suggest that EVs enhance poststroke BBB integrity via ABCB1 and MMP-9 regulation, attenuating inflammatory cell recruitment by inhibition of the NF-κB pathway.
Metadata
Item Type: | Article |
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Authors/Creators: |
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Copyright, Publisher and Additional Information: | © 2020 The Authors. Arteriosclerosis, Thrombosis, and Vascular Biology is published on behalf of the American Heart Association, Inc., by Wolters Kluwer Health, Inc. This is an open access article under the terms of the Creative Commons Attribution Non-Commercial-NoDerivs License, which permits use, distribution, and reproduction in any medium, provided that the original work is properly cited, the use is noncommercial, and no modifications or adaptations are made (https://creativecommons.org/licenses/by-nc-nd/4.0/). |
Keywords: | astrocytes; blood-brain barrier; endothelial cells; extracellular vesicles; matrix metalloproteinase 9 |
Dates: |
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Institution: | The University of Sheffield |
Academic Units: | The University of Sheffield > Sheffield Teaching Hospitals |
Funding Information: | Funder Grant number Medical Research Council MR/R005923/1 |
Depositing User: | Symplectic Sheffield |
Date Deposited: | 23 Mar 2022 14:02 |
Last Modified: | 25 Mar 2022 20:14 |
Status: | Published |
Publisher: | Wolters Kluwer Health |
Refereed: | Yes |
Identification Number: | 10.1161/atvbaha.120.315031 |
Related URLs: | |
Open Archives Initiative ID (OAI ID): | oai:eprints.whiterose.ac.uk:184900 |