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

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

  • Nat Neurosci. 2025 Dec 15. doi: 10.1038/s41593-025-02123-w.
Judit González-Gallego # 1 2,  Katalin Todorov-Völgyi # 1,  Stephan A Müller 3 4,  Sophie Antesberger 1 2,  Mihail Ivilinov Todorov 1 5,  Rainer Malik 1,  Rita Grimalt-Mirada 1,  Carolina Cardoso Gonçalves 1 2,  Martina Schifferer 3 6,  Georg Kislinger 7,  Isabel Weisheit 1 2,  Barbara Lindner 1,  Dennis Crusius 1,  Joseph Kroeger 1 2,  Mila Borri 1,  Ali Erturk 1 6 8 9 10,  Mark Nelson 11 12,  Thomas Misgeld 3 6 7,  Stefan F Lichtenthaler 3 4 6,  Martin Dichgans 13 14 15 16 17,  Dominik Paquet 18 19 20
Affiliations

Affiliations

  • 1 Institute for Stroke and Dementia Research (ISD), University Hospital, LMU Munich, Munich, Germany.
  • 2 Graduate School of Systemic Neuroscience (GSN), LMU Munich, Munich, Germany.
  • 3 German Center for Neurodegenerative Diseases (DZNE) Munich, Munich, Germany.
  • 4 Neuroproteomics, School of Medicine and Health, Klinikum rechts der Isar, Technical University of Munich, Munich, Germany.
  • 5 Institute for Tissue Engineering and Regenerative Medicine (iTERM), Helmholtz Center Munich, Neuherberg, Germany.
  • 6 Munich Cluster for Systems Neurology (SyNergy), Munich, Germany.
  • 7 Institute of Neuronal Cell Biology, Technical University of Munich, Munich, Germany.
  • 8 Institute for Intelligent Biotechnologies (iBIO), Helmholtz Center Munich, Neuherberg, Germany.
  • 9 Deep Piction, Munich, Germany.
  • 10 School of Medicine, Koç University, Istanbul, Turkey.
  • 11 Department of Pharmacology, University of Vermont, Burlington, VT, USA.
  • 12 Division of Cardiovascular Sciences, University of Manchester, Manchester, UK.
  • 13 Institute for Stroke and Dementia Research (ISD), University Hospital, LMU Munich, Munich, Germany. Martin.Dichgans@med.uni-muenchen.de.
  • 14 Graduate School of Systemic Neuroscience (GSN), LMU Munich, Munich, Germany. Martin.Dichgans@med.uni-muenchen.de.
  • 15 German Center for Neurodegenerative Diseases (DZNE) Munich, Munich, Germany. Martin.Dichgans@med.uni-muenchen.de.
  • 16 Munich Cluster for Systems Neurology (SyNergy), Munich, Germany. Martin.Dichgans@med.uni-muenchen.de.
  • 17 German Centre for Cardiovascular Research (DZHK), Munich, Germany. Martin.Dichgans@med.uni-muenchen.de.
  • 18 Institute for Stroke and Dementia Research (ISD), University Hospital, LMU Munich, Munich, Germany. dominik.paquet@med.uni-muenchen.de.
  • 19 Graduate School of Systemic Neuroscience (GSN), LMU Munich, Munich, Germany. dominik.paquet@med.uni-muenchen.de.
  • 20 Munich Cluster for Systems Neurology (SyNergy), Munich, Germany. dominik.paquet@med.uni-muenchen.de.
  • # Contributed equally.
PMID: 41398476 DOI: 10.1038/s41593-025-02123-w
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.

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