02471nas a2200433   4500000000100000000000100001008004100002260001500043653002600058653003500084653003000119653001100149100002800160700002800188700002300216700002300239700002800262700001700290700002400307700003200331700002300363700002000386700002000406700002000426700001900446700001900465700001500484700001500499700001600514700001900530700002800549700002000577700001900597245015000616856005500766300000900821520119300830022001402023       2025                            d  c2025-12-1510aBlood–brain barrier10aExperimental models of disease10aStem-cell differentiation10aStroke1 aJudit González-Gallego1 aKatalin Todorov-Völgyi1 aStephan A. Müller1 aSophie Antesberger1 aMihail Ivilinov Todorov1 aRainer Malik1 aRita Grimalt-Mirada1 aCarolina Cardoso Gonçalves1 aMartina Schifferer1 aGeorg Kislinger1 aIsabel Weisheit1 aBarbara Lindner1 aDennis Crusius1 aJoseph Kroeger1 aMila Borri1 aAli Erturk1 aMark Nelson1 aThomas Misgeld1 aStefan F. Lichtenthaler1 aMartin Dichgans1 aDominik Paquet00aA fully iPS-cell-derived 3D model of the human blood–brain barrier for exploring neurovascular disease mechanisms and therapeutic interventions  uhttps://www.nature.com/articles/s41593-025-02123-w  a1-143 aBlood–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.  a1546-1726