Nishihara, Hideaki; Perriot, Sylvain; Gastfriend, Benjamin D; Steinfort, Marel; Cibien, Celine; Soldati, Sasha; Matsuo, Kinya; Guimbal, Sarah; Mathias, Amandine; Palecek, Sean P; Shusta, Eric V; Du Pasquier, Renaud; Engelhardt, Britta (2022). Intrinsic blood-brain barrier dysfunction contributes to multiple sclerosis pathogenesis. Brain : a journal of neurology, 145(12), pp. 4334-4348. Oxford University Press 10.1093/brain/awac019
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Intrinsic_blood-brain_barrier_dysfunction_contributes_to_multiple_sclerosis_pathogenesis.pdf - Accepted Version Available under License Publisher holds Copyright. Download (2MB) | Preview |
Blood-brain barrier (BBB) breakdown and immune cell infiltration into the central nervous system (CNS) are early hallmarks of multiple sclerosis (MS). The mechanisms leading to BBB dysfunction are incompletely understood and generally thought to be a consequence of neuroinflammation. Here, we have challenged this view and asked if intrinsic alterations in the BBB of MS patients contribute to MS pathogenesis. To this end, we made use of human induced pluripotent stem cells (hiPSCs) derived from healthy controls (HC) and MS patients and differentiated them into brain microvascular endothelial cell (BMEC)-like cells as in vitro model of the BBB. MS-derived BMEC-like cells showed impaired junctional integrity, barrier properties and efflux pump activity when compared to HC. Also, MS-derived BMEC-like cells displayed an inflammatory phenotype with increased adhesion molecule expression and immune cell interactions. Activation of Wnt/β-catenin signaling in MS-derived endothelial progenitor cells enhanced barrier characteristics and reduced the inflammatory phenotype. Our study provides evidence for an intrinsic impairment of BBB function in MS patients that can be modeled in vitro. Human iPSC-derived BMEC-like cells are thus suitable to explore the molecular underpinnings of BBB dysfunction in MS and will assist in the identification of potential novel therapeutic targets for BBB stabilization.
Item Type: |
Journal Article (Original Article) |
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Division/Institute: |
09 Interdisciplinary Units > Microscopy Imaging Center (MIC) 04 Faculty of Medicine > Pre-clinic Human Medicine > Theodor Kocher Institute |
UniBE Contributor: |
Nishihara, Hideaki, Soldati, Sasha Giulio Natale, Matsuo, Kinya, Guimbal, Sarah Daniela Amandine, Engelhardt, Britta |
Subjects: |
600 Technology > 610 Medicine & health |
ISSN: |
1460-2156 |
Publisher: |
Oxford University Press |
Language: |
English |
Submitter: |
Sibylle Manuela Floquet |
Date Deposited: |
01 Feb 2022 09:12 |
Last Modified: |
29 Jan 2023 00:25 |
Publisher DOI: |
10.1093/brain/awac019 |
PubMed ID: |
35085379 |
Uncontrolled Keywords: |
blood-brain barrier human induced pluripotent stem cells immune cell migration multiple sclerosis permeability |
BORIS DOI: |
10.48350/165022 |
URI: |
https://boris.unibe.ch/id/eprint/165022 |
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