Journal Article

DZNE-2026-00173

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png A fully iPS-cell-derived 3D model of the human blood-brain barrier for exploring neurovascular disease mechanisms and therapeutic interventions.

González-Gallego, J. ; Todorov-Völgyi, K. ; Müller, S. A.DZNE* ; Antesberger, S. ; Todorov, M. I. ; Malik, R. ; Grimalt-Mirada, R. ; Gonçalves, C. C. ; Schifferer, M.DZNE* ; Kislinger, G.Extern* ; Weisheit, I. ; Lindner, B. ; Crusius, D. ; Kroeger, J. ; Borri, M. ; Erturk, A. ; Nelson, M. ; Misgeld, T.DZNE* ; Lichtenthaler, S. F.DZNE* ; Dichgans, M.DZNE* ; Paquet, D.

2026
Nature America New York, NY

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Please use a persistent id in citations: 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.

Keyword(s): Blood-Brain Barrier: physiology (MeSH) ; Humans (MeSH) ; Induced Pluripotent Stem Cells: physiology (MeSH) ; Animals (MeSH) ; Forkhead Transcription Factors: genetics (MeSH) ; Endothelial Cells: physiology (MeSH) ; Mice (MeSH) ; Astrocytes: physiology (MeSH) ; Cells, Cultured (MeSH) ; Forkhead Transcription Factors

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Contributing Institute(s):

1. Neuroproteomics (AG Lichtenthaler)
2. Neuronal Cell Biology (AG Misgeld)
3. Vascular Cognitive Impairment & Post-Stroke Dementia (AG Dichgans)

Research Program(s):

1. 352 - Disease Mechanisms (POF4-352) (POF4-352)
2. 351 - Brain Function (POF4-351) (POF4-351)
3. 353 - Clinical and Health Care Research (POF4-353) (POF4-353)

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Database coverage:
; BIOSIS Previews ; Biological Abstracts ; Clarivate Analytics Master Journal List ; Current Contents - Life Sciences ; DEAL Nature ; Ebsco Academic Search ; Essential Science Indicators ; IF >= 25 ; JCR ; National-Konsortium ; SCOPUS ; Science Citation Index Expanded ; Web of Science Core Collection

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