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González-Gallego, J.* ; Todorov-Völgyi, K.* ; Müller, S.A.* ; Antesberger, S.* ; Todorov, M.I. ; Malik, R.* ; Grimalt-Mirada, R.* ; Gonçalves, C.C.* ; Schifferer, M.* ; Kislinger, G.* ; Weisheit, I.* ; Lindner, B.* ; Crusius, D.* ; Kroeger, J.* ; Borri, M.* ; Ertürk, A. ; Nelson, M.C.* ; Misgeld, T.* ; Lichtenthaler, S.F.* ; Dichgans, M.* ; Paquet, D.*

A fully iPS-cell-derived 3D model of the human blood-brain barrier for exploring neurovascular disease mechanisms and therapeutic interventions.

Nat. Neurosci., DOI: 10.1038/s41593-025-02123-w (2025)
Publ. Version/Full Text Research data DOI PMC
Open Access Hybrid
Creative Commons Lizenzvertrag
Blood-brain barrier (BBB) integrity is critical for brain homeostasis, with malfunctions contributing to neurovascular and neurodegenerative disorders. Mechanistic studies on BBB function have been mostly conducted in rodent and in vitro models, which recapitulate some disease features, but have limited translatability to humans and pose challenges for drug discovery. Here we report on a fully human induced pluripotent stem (iPS)-cell-derived, microfluidic three-dimensional (3D) BBB model consisting of endothelial cells (ECs), mural cells and astrocytes. Our model expresses typical fate markers, forms a barrier in vessel-like tubes and enables perfusion, including with human blood. Deletion of FOXF2 in ECs, a major risk gene for cerebral small vessel disease, induced key features of BBB dysfunction, including compromised cell junction integrity and enhanced caveolae formation. Proteomic analysis revealed dysregulated endocytosis and cell junction pathways. Disease features phenocopied those seen in mice with EC-specific Foxf2 deficiency. Moreover, lipid-nanoparticle-based treatment with Foxf2 mRNA rescued BBB deficits, demonstrating the potential for drug development.
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Publication type Article: Journal article
Document type Scientific Article
Keywords Pluripotent Stem-cells; Endothelial-cells; Pericytes; Proteins; Vessels; Health; Atlas; Unit
ISSN (print) / ISBN 1097-6256
e-ISSN 1546-1726
Journal Nature Neuroscience
Publisher Nature Publishing Group
Publishing Place Heidelberger Platz 3, Berlin, 14197, Germany
Reviewing status Peer reviewed
Institute(s) Institute for Intelligent Biotechnologies (IBIO)
Grants EC | Horizon 2020 Framework Programme (EU Framework Programme for Research and Innovation H2020)
Fondation Leducq
DI 722/16-1, BE 6169/1-1]
Deutsche Forschungsgemeinschaft (German Research Foundation)