Cargando…

Transport of Extracellular Vesicles across the Blood-Brain Barrier: Brain Pharmacokinetics and Effects of Inflammation

Extracellular vesicles can cross the blood–brain barrier (BBB), but little is known about passage. Here, we used multiple-time regression analysis to examine the ability of 10 exosome populations derived from mouse, human, cancerous, and non-cancerous cell lines to cross the BBB. All crossed the BBB...

Descripción completa

Detalles Bibliográficos
Autores principales: Banks, William A., Sharma, Priyanka, Bullock, Kristin M., Hansen, Kim M., Ludwig, Nils, Whiteside, Theresa L.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7352415/
https://www.ncbi.nlm.nih.gov/pubmed/32575812
http://dx.doi.org/10.3390/ijms21124407
_version_ 1783557632813957120
author Banks, William A.
Sharma, Priyanka
Bullock, Kristin M.
Hansen, Kim M.
Ludwig, Nils
Whiteside, Theresa L.
author_facet Banks, William A.
Sharma, Priyanka
Bullock, Kristin M.
Hansen, Kim M.
Ludwig, Nils
Whiteside, Theresa L.
author_sort Banks, William A.
collection PubMed
description Extracellular vesicles can cross the blood–brain barrier (BBB), but little is known about passage. Here, we used multiple-time regression analysis to examine the ability of 10 exosome populations derived from mouse, human, cancerous, and non-cancerous cell lines to cross the BBB. All crossed the BBB, but rates varied over 10-fold. Lipopolysaccharide (LPS), an activator of the innate immune system, enhanced uptake independently of BBB disruption for six exosomes and decreased uptake for one. Wheatgerm agglutinin (WGA) modulated transport of five exosome populations, suggesting passage by adsorptive transcytosis. Mannose 6-phosphate inhibited uptake of J774A.1, demonstrating that its BBB transporter is the mannose 6-phosphate receptor. Uptake rates, patterns, and effects of LPS or WGA were not predicted by exosome source (mouse vs. human) or cancer status of the cell lines. The cell surface proteins CD46, AVβ6, AVβ3, and ICAM-1 were variably expressed but not predictive of transport rate nor responses to LPS or WGA. A brain-to-blood efflux mechanism variably affected CNS retention and explains how CNS-derived exosomes enter blood. In summary, all exosomes tested here readily crossed the BBB, but at varying rates and by a variety of vesicular-mediated mechanisms involving specific transporters, adsorptive transcytosis, and a brain-to-blood efflux system.
format Online
Article
Text
id pubmed-7352415
institution National Center for Biotechnology Information
language English
publishDate 2020
publisher MDPI
record_format MEDLINE/PubMed
spelling pubmed-73524152020-07-15 Transport of Extracellular Vesicles across the Blood-Brain Barrier: Brain Pharmacokinetics and Effects of Inflammation Banks, William A. Sharma, Priyanka Bullock, Kristin M. Hansen, Kim M. Ludwig, Nils Whiteside, Theresa L. Int J Mol Sci Article Extracellular vesicles can cross the blood–brain barrier (BBB), but little is known about passage. Here, we used multiple-time regression analysis to examine the ability of 10 exosome populations derived from mouse, human, cancerous, and non-cancerous cell lines to cross the BBB. All crossed the BBB, but rates varied over 10-fold. Lipopolysaccharide (LPS), an activator of the innate immune system, enhanced uptake independently of BBB disruption for six exosomes and decreased uptake for one. Wheatgerm agglutinin (WGA) modulated transport of five exosome populations, suggesting passage by adsorptive transcytosis. Mannose 6-phosphate inhibited uptake of J774A.1, demonstrating that its BBB transporter is the mannose 6-phosphate receptor. Uptake rates, patterns, and effects of LPS or WGA were not predicted by exosome source (mouse vs. human) or cancer status of the cell lines. The cell surface proteins CD46, AVβ6, AVβ3, and ICAM-1 were variably expressed but not predictive of transport rate nor responses to LPS or WGA. A brain-to-blood efflux mechanism variably affected CNS retention and explains how CNS-derived exosomes enter blood. In summary, all exosomes tested here readily crossed the BBB, but at varying rates and by a variety of vesicular-mediated mechanisms involving specific transporters, adsorptive transcytosis, and a brain-to-blood efflux system. MDPI 2020-06-21 /pmc/articles/PMC7352415/ /pubmed/32575812 http://dx.doi.org/10.3390/ijms21124407 Text en © 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Banks, William A.
Sharma, Priyanka
Bullock, Kristin M.
Hansen, Kim M.
Ludwig, Nils
Whiteside, Theresa L.
Transport of Extracellular Vesicles across the Blood-Brain Barrier: Brain Pharmacokinetics and Effects of Inflammation
title Transport of Extracellular Vesicles across the Blood-Brain Barrier: Brain Pharmacokinetics and Effects of Inflammation
title_full Transport of Extracellular Vesicles across the Blood-Brain Barrier: Brain Pharmacokinetics and Effects of Inflammation
title_fullStr Transport of Extracellular Vesicles across the Blood-Brain Barrier: Brain Pharmacokinetics and Effects of Inflammation
title_full_unstemmed Transport of Extracellular Vesicles across the Blood-Brain Barrier: Brain Pharmacokinetics and Effects of Inflammation
title_short Transport of Extracellular Vesicles across the Blood-Brain Barrier: Brain Pharmacokinetics and Effects of Inflammation
title_sort transport of extracellular vesicles across the blood-brain barrier: brain pharmacokinetics and effects of inflammation
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7352415/
https://www.ncbi.nlm.nih.gov/pubmed/32575812
http://dx.doi.org/10.3390/ijms21124407
work_keys_str_mv AT bankswilliama transportofextracellularvesiclesacrossthebloodbrainbarrierbrainpharmacokineticsandeffectsofinflammation
AT sharmapriyanka transportofextracellularvesiclesacrossthebloodbrainbarrierbrainpharmacokineticsandeffectsofinflammation
AT bullockkristinm transportofextracellularvesiclesacrossthebloodbrainbarrierbrainpharmacokineticsandeffectsofinflammation
AT hansenkimm transportofextracellularvesiclesacrossthebloodbrainbarrierbrainpharmacokineticsandeffectsofinflammation
AT ludwignils transportofextracellularvesiclesacrossthebloodbrainbarrierbrainpharmacokineticsandeffectsofinflammation
AT whitesidetheresal transportofextracellularvesiclesacrossthebloodbrainbarrierbrainpharmacokineticsandeffectsofinflammation