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dc.contributor.author
Schaffenrath, Johanna
dc.contributor.author
Huang, Sheng-Fu
dc.contributor.author
Wyss, Tania
dc.contributor.author
Delorenzi, Mauro
dc.contributor.author
Keller, Annika
dc.date.accessioned
2021-08-06T12:12:09Z
dc.date.available
2021-08-06T02:51:19Z
dc.date.available
2021-08-06T12:12:09Z
dc.date.issued
2021-07-28
dc.identifier.issn
2045-8118
dc.identifier.other
10.1186/s12987-021-00269-w
en_US
dc.identifier.uri
http://hdl.handle.net/20.500.11850/499764
dc.identifier.doi
10.3929/ethz-b-000499764
dc.description.abstract
Background Genetic variation in a population has an influence on the manifestation of monogenic as well as multifactorial disorders, with the underlying genetic contribution dependent on several interacting variants. Common laboratory mouse strains used for modelling human disease lack the genetic variability of the human population. Therefore, outcomes of rodent studies show limited relevance to human disease. The functionality of brain vasculature is an important modifier of brain diseases. Importantly, the restrictive interface between blood and brain—the blood–brain barrier (BBB) serves as a major obstacle for the drug delivery into the central nervous system (CNS). Using genetically diverse mouse strains, we aimed to investigate the phenotypic and transcriptomic variation of the healthy BBB in different inbred mouse strains. Methods We investigated the heterogeneity of brain vasculature in recently wild-derived mouse strains (CAST/EiJ, WSB/EiJ, PWK/PhJ) and long-inbred mouse strains (129S1/SvImJ, A/J, C57BL/6J, DBA/2J, NOD/ShiLtJ) using different phenotypic arms. We used immunohistochemistry and confocal laser microscopy followed by quantitative image analysis to determine vascular density and pericyte coverage in two brain regions—cortex and hippocampus. Using a low molecular weight fluorescence tracer, sodium fluorescein and spectrophotometry analysis, we assessed BBB permeability in young and aged mice of selected strains. For further phenotypic characterization of endothelial cells in inbred mouse strains, we performed bulk RNA sequencing of sorted endothelial cells isolated from cortex and hippocampus. Results Cortical vessel density and pericyte coverage did not differ among the investigated strains, except in the cortex, where PWK/PhJ showed lower vessel density compared to NOD/ShiLtJ, and a higher pericyte coverage than DBA/2J. The vascular density in the hippocampus differed among analyzed strains but not the pericyte coverage. The staining patterns of endothelial arteriovenous zonation markers were similar in different strains. BBB permeability to a small fluorescent tracer, sodium fluorescein, was also similar in different strains, except in the hippocampus where the CAST/EiJ showed higher permeability than NOD/ShiLtJ. Transcriptomic analysis of endothelial cells revealed that sex of the animal was a major determinant of gene expression differences. In addition, the expression level of several genes implicated in endothelial function and BBB biology differed between wild-derived and long-inbred mouse strains. In aged mice of three investigated strains (DBA/2J, A/J, C57BL/6J) vascular density and pericyte coverage did not change—expect for DBA/2J, whereas vascular permeability to sodium fluorescein increased in all three strains. Conclusions Our analysis shows that although there were no major differences in parenchymal vascular morphology and paracellular BBB permeability for small molecular weight tracer between investigated mouse strains or sexes, transcriptomic differences of brain endothelial cells point to variation in gene expression of the intact BBB. These baseline variances might be confounding factors in pathological conditions that may lead to a differential functional outcome dependent on the sex or genetic polymorphism.
en_US
dc.format
application/pdf
en_US
dc.language.iso
en
en_US
dc.publisher
BioMed Central Ltd
en_US
dc.rights.uri
http://creativecommons.org/licenses/by/4.0/
dc.subject
Blood–brain barrier
en_US
dc.subject
Brain endothelial cells
en_US
dc.subject
Vascular zonation
en_US
dc.subject
Vascular permeability
en_US
dc.subject
Inbred mouse strains
en_US
dc.title
Characterization of the blood–brain barrier in genetically diverse laboratory mouse strains
en_US
dc.type
Journal Article
dc.rights.license
Creative Commons Attribution 4.0 International
ethz.journal.title
Fluids and Barriers of the CNS
ethz.journal.volume
18
en_US
ethz.journal.issue
1
en_US
ethz.journal.abbreviated
Fluids Barriers CNS
ethz.pages.start
34
en_US
ethz.size
15 p.
en_US
ethz.version.deposit
publishedVersion
en_US
ethz.identifier.wos
ethz.identifier.scopus
ethz.publication.place
London
en_US
ethz.publication.status
published
en_US
ethz.date.deposited
2021-08-06T02:51:21Z
ethz.source
SCOPUS
ethz.eth
yes
en_US
ethz.availability
Open access
en_US
ethz.rosetta.installDate
2021-08-06T12:12:16Z
ethz.rosetta.lastUpdated
2022-03-29T10:58:33Z
ethz.rosetta.versionExported
true
ethz.COinS
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