TY  - JOUR
AU  - González-Gallego, Judit
AU  - Todorov-Völgyi, Katalin
AU  - Müller, Stephan A
AU  - Antesberger, Sophie
AU  - Todorov, Mihail Ivilinov
AU  - Malik, Rainer
AU  - Grimalt-Mirada, Rita
AU  - Gonçalves, Carolina Cardoso
AU  - Schifferer, Martina
AU  - Kislinger, Georg
AU  - Weisheit, Isabel
AU  - Lindner, Barbara
AU  - Crusius, Dennis
AU  - Kroeger, Joseph
AU  - Borri, Mila
AU  - Erturk, Ali
AU  - Nelson, Mark
AU  - Misgeld, Thomas
AU  - Lichtenthaler, Stefan F
AU  - Dichgans, Martin
AU  - Paquet, Dominik
TI  - A fully iPS-cell-derived 3D model of the human blood-brain barrier for exploring neurovascular disease mechanisms and therapeutic interventions.
JO  - Nature neuroscience
VL  - 29
IS  - 2
SN  - 1097-6256
CY  - New York, NY
PB  - Nature America
M1  - DZNE-2026-00173
SP  - 479 - 492
PY  - 2026
AB  - 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.
KW  - Blood-Brain Barrier: physiology
KW  - Humans
KW  - Induced Pluripotent Stem Cells: physiology
KW  - Animals
KW  - Forkhead Transcription Factors: genetics
KW  - Endothelial Cells: physiology
KW  - Mice
KW  - Astrocytes: physiology
KW  - Cells, Cultured
KW  - Forkhead Transcription Factors (NLM Chemicals)
LB  - PUB:(DE-HGF)16
C6  - pmid:41398476
C2  - pmc:PMC12880921
DO  - DOI:10.1038/s41593-025-02123-w
UR  - https://pub.dzne.de/record/285049
ER  -