title: Elucidation of Exosome Migration across the Blood-Brain Barrier Model In Vitro.
abstract: The delivery of therapeutics to the central nervous system (CNS) 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 vitrounder conditions that mimic the healthy and inflamed BBBin 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 conditionsin vitro. This study encourages further development of engineered exosomes as drug delivery vehicles or tracking tools for treating or monitoring neurological diseases.
authors.affiliation: Department of Pharmaceutical Sciences, Sue and Bill Gross Stem Cell Research Center, Chao Family Comprehensive Cancer Center and Edwards Life sciences Center for Advanced Cardiovascular Technology, 845 Health Sciences Road, University of California-Irvine, Irvine, California, 92697, USA; Department of Biomedical Engineering, University of California-Irvine, Irvine, California, 92697, USA.
authors.forename: Claire C
authors.initials: CC
authors.lastname: Chen
authors.affiliation: Department of Pharmaceutical Sciences, Sue and Bill Gross Stem Cell Research Center, Chao Family Comprehensive Cancer Center and Edwards Life sciences Center for Advanced Cardiovascular Technology, 845 Health Sciences Road, University of California-Irvine, Irvine, California, 92697, USA; Department of Biomedical Engineering, University of California-Irvine, Irvine, California, 92697, USA.
authors.forename: Linan
authors.initials: L
authors.lastname: Liu
authors.affiliation: Department of Pharmaceutical Sciences, Sue and Bill Gross Stem Cell Research Center, Chao Family Comprehensive Cancer Center and Edwards Life sciences Center for Advanced Cardiovascular Technology, 845 Health Sciences Road, University of California-Irvine, Irvine, California, 92697, USA; Department of Biomedical Engineering, University of California-Irvine, Irvine, California, 92697, USA; State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Disease Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin 300020, China.
authors.forename: Fengxia
authors.initials: F
authors.lastname: Ma
authors.affiliation: Department of Pharmaceutical Sciences, Sue and Bill Gross Stem Cell Research Center, Chao Family Comprehensive Cancer Center and Edwards Life sciences Center for Advanced Cardiovascular Technology, 845 Health Sciences Road, University of California-Irvine, Irvine, California, 92697, USA; Department of Biomedical Engineering, University of California-Irvine, Irvine, California, 92697, USA.
authors.forename: Chi W
authors.initials: CW
authors.lastname: Wong
authors.affiliation: Department of Pharmaceutical Sciences, Sue and Bill Gross Stem Cell Research Center, Chao Family Comprehensive Cancer Center and Edwards Life sciences Center for Advanced Cardiovascular Technology, 845 Health Sciences Road, University of California-Irvine, Irvine, California, 92697, USA; Department of Biomedical Engineering, University of California-Irvine, Irvine, California, 92697, USA.
authors.forename: Xuning E
authors.initials: XE
authors.lastname: Guo
authors.affiliation: Department of Biomedical Engineering, University of California-Irvine, Irvine, California, 92697, USA.
authors.forename: Jenu V
authors.initials: JV
authors.lastname: Chacko
authors.affiliation: Department of Pharmaceutical Sciences, Sue and Bill Gross Stem Cell Research Center, Chao Family Comprehensive Cancer Center and Edwards Life sciences Center for Advanced Cardiovascular Technology, 845 Health Sciences Road, University of California-Irvine, Irvine, California, 92697, USA; Department of Biomedical Engineering, University of California-Irvine, Irvine, California, 92697, USA; Department of Molecular Biology & Biochemistry, University of California-Irvine, Irvine, California, 92697, USA.
authors.forename: Henry P
authors.initials: HP
authors.lastname: Farhoodi
authors.affiliation: Department of Pharmaceutical Sciences, Sue and Bill Gross Stem Cell Research Center, Chao Family Comprehensive Cancer Center and Edwards Life sciences Center for Advanced Cardiovascular Technology, 845 Health Sciences Road, University of California-Irvine, Irvine, California, 92697, USA; Department of Biomedical Engineering, University of California-Irvine, Irvine, California, 92697, USA.
authors.forename: Shirley X
authors.initials: SX
authors.lastname: Zhang
authors.affiliation: Department of Pharmaceutical Sciences, Sue and Bill Gross Stem Cell Research Center, Chao Family Comprehensive Cancer Center and Edwards Life sciences Center for Advanced Cardiovascular Technology, 845 Health Sciences Road, University of California-Irvine, Irvine, California, 92697, USA; Department of Biomedical Engineering, University of California-Irvine, Irvine, California, 92697, USA.
authors.forename: Jan
authors.initials: J
authors.lastname: Zimak
authors.affiliation: Department of Pharmaceutical Sciences, Sue and Bill Gross Stem Cell Research Center, Chao Family Comprehensive Cancer Center and Edwards Life sciences Center for Advanced Cardiovascular Technology, 845 Health Sciences Road, University of California-Irvine, Irvine, California, 92697, USA; Department of Biomedical Engineering, University of California-Irvine, Irvine, California, 92697, USA.
authors.forename: Aude
authors.initials: A
authors.lastname: Ségaliny
authors.affiliation: Department of Pharmaceutical Sciences, Sue and Bill Gross Stem Cell Research Center, Chao Family Comprehensive Cancer Center and Edwards Life sciences Center for Advanced Cardiovascular Technology, 845 Health Sciences Road, University of California-Irvine, Irvine, California, 92697, USA; Department of Biomedical Engineering, University of California-Irvine, Irvine, California, 92697, USA.
authors.forename: Milad
authors.initials: M
authors.lastname: Riazifar
authors.affiliation: Department of Pharmaceutical Sciences, Sue and Bill Gross Stem Cell Research Center, Chao Family Comprehensive Cancer Center and Edwards Life sciences Center for Advanced Cardiovascular Technology, 845 Health Sciences Road, University of California-Irvine, Irvine, California, 92697, USA; Department of Biomedical Engineering, University of California-Irvine, Irvine, California, 92697, USA.
authors.forename: Victor
authors.initials: V
authors.lastname: Pham
authors.affiliation: Department of Biomedical Engineering, University of California-Irvine, Irvine, California, 92697, USA; Laboratory for Fluorescence Dynamics, University of California-Irvine, California 92697, USA; Centre for Bioactive Discovery in Health and Ageing, School of Science and Technology, University of New England, Armidale, New South Wales 2351, Australia.
authors.forename: Michelle A
authors.initials: MA
authors.lastname: Digman
authors.affiliation: Department of Pharmaceutical Sciences, Sue and Bill Gross Stem Cell Research Center, Chao Family Comprehensive Cancer Center and Edwards Life sciences Center for Advanced Cardiovascular Technology, 845 Health Sciences Road, University of California-Irvine, Irvine, California, 92697, USA; Department of Biomedical Engineering, University of California-Irvine, Irvine, California, 92697, USA.
authors.forename: Egest J
authors.initials: EJ
authors.lastname: Pone
authors.affiliation: Department of Pharmaceutical Sciences, Sue and Bill Gross Stem Cell Research Center, Chao Family Comprehensive Cancer Center and Edwards Life sciences Center for Advanced Cardiovascular Technology, 845 Health Sciences Road, University of California-Irvine, Irvine, California, 92697, USA; Department of Biomedical Engineering, University of California-Irvine, Irvine, California, 92697, USA.
authors.forename: Weian
authors.initials: W
authors.lastname: Zhao
keywords: Drug delivery; blood-brain barrier (BBB); endocytosis; exocytosis; exosome; humanized Gaussia luciferase (hGluc); inflammation; stroke; transcytosis