ArticleProceedings of the National Academy of Sciences of the United States of America2024
Synergistic induction of blood-brain barrier properties.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 16 papers, 1 of them a synthesis that pooled it.
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The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
16 citing papers in PubMed, 1 synthesis or guideline pooled it.
- Acupuncture improves blood-brain barrier integrity through multi-targeted mechanisms: a preclinical meta-analysis.Frontiers in neurology · 2025Pooled it
- Cellular and signalling mechanisms that regulate the blood-brain barrier.Nature reviews. Molecular cell biology · 2026Review
- Synthetic Cyclic CAntioxidants (Basel, Switzerland) · 2026Article
- EHD4 and ASAP2 are critical negative regulators of the claudin-5-based endothelial barrier.The FEBS journal · 2026Article
- Nanoscopic analysis of tight junction organization in in vitro blood-brain barrier models.Fluids and barriers of the CNS · 2026Article
- Development of the blood-brain barrier.Development (Cambridge, England) · 2026Review
- Brain Endothelial Glycocalyx as a Blood-Facing Translational Interface in Alzheimer's Disease: Beyond "Leaky" Barriers Toward Repair-First Stratification.Drug design, development and therapy · 2026Review
- Generation of hiPSC-Derived Brain Microvascular Endothelial Cells Using Directed Differentiation and Transcriptional Reprogramming.Arteriosclerosis, thrombosis, and vascular biology · 2026Article
- Role of transforming growth factorβ in neurovascular unit during cerebral small vessel disease.Fluids and barriers of the CNS · 2025Review
- Metabolites associated with type 2 diabetes and Alzheimer's disease trigger differential intracellular signaling responses in mouse primary neurons.Brain research · 2025Article
- ApoE4 disrupts intracellular trafficking and iron homeostasis in a reproducible iPSC-based model of human brain endothelial cells.Stem cell reports · 2025Article
- Article
- Much More than Nutrients: The Protective Effects of Nutraceuticals on the Blood-Brain Barrier in Diseases.Nutrients · 2025Review
- Alanine and glutathione targeting of dopamine- or ibuprofen-coupled polypeptide nanocarriers increases both crossing and protective effects on a blood-brain barrier model.Fluids and barriers of the CNS · 2025Article
- Molecular mechanisms of streptococcal disruption of the blood-brain barrier and their pathogenic role in bacterial meningitis.Frontiers in immunology · 2025Review
- Using a brain-like endothelial cell differentiation to characterize the CS79iBRCA-n2 BRCA1 mutated patient derived stem cell line.Frontiers in cell and developmental biology · 2025Article
Corrections and comments
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Authors and funding
18 authors.
Funding
Abstract
Blood-brain barrier (BBB) models derived from human stem cells are powerful tools to improve our understanding of cerebrovascular diseases and to facilitate drug development for the human brain. Yet providing stem cell-derived endothelial cells with the right signaling cues to acquire BBB characteristics while also retaining their vascular identity remains challenging. Here, we show that the simultaneous activation of cyclic AMP and Wnt/β-catenin signaling and inhibition of the TGF-β pathway in endothelial cells robustly induce BBB properties in vitro. To target this interaction, we present a small-molecule cocktail named cARLA, which synergistically enhances barrier tightness in a range of BBB models across species. Mechanistically, we reveal that the three pathways converge on Wnt/β-catenin signaling to mediate the effect of cARLA via the tight junction protein claudin-5. We demonstrate that cARLA shifts the gene expressional profile of human stem cell-derived endothelial cells toward the in vivo brain endothelial signature, with a higher glycocalyx density and efflux pump activity, lower rates of endocytosis, and a characteristic endothelial response to proinflammatory cytokines. Finally, we illustrate how cARLA can improve the predictive value of human BBB models regarding the brain penetration of drugs and targeted nanoparticles. Due to its synergistic effect, high reproducibility, and ease of use, cARLA has the potential to advance drug development for the human brain by improving BBB models across laboratories.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.