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

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Abstract

The delivery of therapeutics to the central nervous system remains a major challenge in part due to the presence of the blood–brain barrier (BBB). Recently, cell-derived vesicles, particularly exosomes, have emerged as an attractive vehicle for targeting drugs to the brain, but whether or how they cross the BBB remains unclear. Here, we investigated the interactions between exosomes and brain microvascular endothelial cells (BMECs) in vitro under conditions that mimic the healthy and inflamed BBB in vivo. Transwell assays revealed that luciferase-carrying exosomes can cross a BMEC monolayer under stroke-like, inflamed conditions (TNF-α activated) but not under normal conditions. Confocal microscopy showed that exosomes are internalized by BMECs through endocytosis, co-localize with endosomes, in effect primarily utilizing the transcellular route of crossing. Together, these results indicate that cell-derived exosomes can cross the BBB model under stroke-like conditions in vitro. This study encourages further development of engineered exosomes as drug delivery vehicles or tracking tools for treating or monitoring neurological diseases.

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Acknowledgments

We thank Dr. W. Liao and M. Lu for discussion and technique training. We thank C. Deighan from Malvern Instruments for assistance with the use of NanoSight NS300 instrument for NTA analysis. This work was supported by the National Institute of Health (1DP2CA195763-01), American Heart Association (13BGIA17140099) and UC Irvine Academic Senate Council on Research, Computing, and Libraries (CORCL) Research Grant (SIIG-2013-2014-25). CCC was supported by National Science Foundation Graduate Research Fellowship (NSF GRFP). SXZ was supported by a Cardiovascular Applied Research and Entrepreneurship fellowship (NIH/NHLBI T32).

Conflict of Interest

The authors (Claire C. Chen, Linan Liu, Fengxia Ma, Chi W. Wong, Xuning E. Guo, Jenu V. Chacko, Henry P. Farhoodi, Shirley X. Zhang, Jan Zimak, Aude Ségaliny, Milad Riazifa, Victor Pham, Michelle A. Digman, Egest J. Pone, and Weian Zhao) declare that they have no conflicts of interest.

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Correspondence to Weian Zhao.

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Associate Editor Michael R. King oversaw the review of this article.

Claire C. Chen and Linan Liu contributed equally to this work.

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Chen, C.C., Liu, L., Ma, F. et al. Elucidation of Exosome Migration Across the Blood–Brain Barrier Model In Vitro . Cel. Mol. Bioeng. 9, 509–529 (2016). https://doi.org/10.1007/s12195-016-0458-3

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