TY - JOUR
KW - Blood–brain barrier
KW - Experimental models of disease
KW - Stem-cell differentiation
KW - Stroke
AU - Judit González-Gallego
AU - Katalin Todorov-Völgyi
AU - Stephan A. Müller
AU - Sophie Antesberger
AU - Mihail Ivilinov Todorov
AU - Rainer Malik
AU - Rita Grimalt-Mirada
AU - Carolina Cardoso Gonçalves
AU - Martina Schifferer
AU - Georg Kislinger
AU - Isabel Weisheit
AU - Barbara Lindner
AU - Dennis Crusius
AU - Joseph Kroeger
AU - Mila Borri
AU - Ali Erturk
AU - Mark Nelson
AU - Thomas Misgeld
AU - Stefan F. Lichtenthaler
AU - Martin Dichgans
AU - Dominik Paquet
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.
BT - Nature Neuroscience
DA - 2025-12-15
DO - 10.1038/s41593-025-02123-w
LA - en
N2 - 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.
PY - 2025
SP - 1
EP - 14
T2 - Nature Neuroscience
TI - A fully iPS-cell-derived 3D model of the human blood–brain barrier for exploring neurovascular disease mechanisms and therapeutic interventions
UR - https://www.nature.com/articles/s41593-025-02123-w
Y2 - 2026-01-14
SN - 1546-1726
ER -