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

ABSTRACT: Integrity of the blood-brain barrier (BBB) is critical for brain homeostasis, and its malfunction contributes to neurovascular and neurodegenerative disorders. So far, mechanistic studies on BBB function have been mostly conducted in rodent and non-physiological 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 iPSC-derived, microfluidic 3D BBB model consisting of endothelial cells (EC), mural cells, and astrocytes. Our model expresses typical cell fate markers, forms a barrier in vessel-like tubes, and enables perfusion, including with human blood. We optimized iPSC differentiations and validated cellular fates by comparison to published datasets and extensive benchmarking vs. primary cells with proteomic profiles provided in an online database. To demonstrate suitability for translational research, we applied the model to investigate deficiency of FOXF2, a major risk gene for cerebral small vessel disease. Deletion of FOXF2 in EC induced key features of BBB dysfunction, including compromised cell junction integrity and enhanced caveolae formation. Proteomic analysis further revealed dysregulation of endocytosis and cell junction pathways. Disease features phenocopied those seen in mice with endothelial cell-specific Foxf2 deficiency, validating the relevance of our in vitro model to investigate in vivo phenotypes of neurovascular disease. Moreover, lipid-nanoparticle-based treatment with Foxf2 mRNA rescued BBB deficits in our FOXF2 KO model, demonstrating its potential for drug development.

ORGANISM(S): Homo sapiens

PROVIDER: GSE302761 | GEO | 2025/08/26

REPOSITORIES: GEO

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Project description:With advances in single-cell genomics, molecular signatures of cells comprising the brain vasculature are revealed in unprecedented detail, yet the ageing-associated cell subtype transcriptomic changes which may contribute to neurovascular dysfunction in neurodegenerative diseases remain elusive. Here, we performed single-cell transcriptomic profiling of brain endothelial cells (EC) in young adult and aged mice to characterize their ageing-associated genome-wide expression changes. We identified zonation-dependent transcriptomic changes in aged brain EC subtypes, with capillary ECs exhibiting the most transcriptomic alterations. Pathway enrichment analysis revealed altered immune/cytokine signaling in ECs of all vascular segments, while functional changes impacting the blood-brain barrier (BBB) and glucose/energy metabolism were most prominently implicated in ECs of the capillary bed – the primary site where ECs and other neurovascular unit (NVU) cell types closely interact and coordinate to regulate BBB and cerebral blood flow in health and diseased conditions. Furthermore, an overrepresentation of Alzheimer’s disease (AD)-associated genes identified from GWAS studies was evident among the human orthologs of differentially expressed genes of aged capillary ECs but not other EC subtypes. Importantly, for numerous EC-enriched differentially expressed genes with important functional roles at the BBB and/or association with AD, we found concordant expression changes in human aged or AD brains. Finally, we demonstrated that treatment with exenatide, a glucagon-like peptide-1 receptor (GLP-1R) agonist, strongly reverses transcriptomic changes in ECs and largely reduces BBB leakage in the aged brain. Thus, our study revealed novel vascular ageing-associations of AD in the brain capillary endothelium, and provides insights into detailed transcriptomic alterations underlying brain EC ageing that are complex with subtype specificity yet amenable to pharmacological interventions.

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

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