@article{6901,
  keywords = {Blood–brain barrier, Experimental models of disease, Stem-cell differentiation, Stroke},
  author = {Judit González-Gallego and Katalin Todorov-Völgyi and Stephan A. Müller and Sophie Antesberger and Mihail Ivilinov Todorov and Rainer Malik and Rita Grimalt-Mirada and Carolina Cardoso Gonçalves and Martina Schifferer and Georg Kislinger and Isabel Weisheit and Barbara Lindner and Dennis Crusius and Joseph Kroeger and Mila Borri and Ali Erturk and Mark Nelson and Thomas Misgeld and Stefan F. Lichtenthaler and Martin Dichgans and Dominik Paquet},
  title = {A fully iPS-cell-derived 3D model of the human blood–brain barrier for exploring neurovascular disease mechanisms and therapeutic interventions},
  abstract = {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.},
  year = {2025},
  journal = {Nature Neuroscience},
  pages = {1-14},
  month = {2025-12-15},
  issn = {1546-1726},
  url = {https://www.nature.com/articles/s41593-025-02123-w},
  doi = {10.1038/s41593-025-02123-w},
  language = {en},
}