ArticleFluids and barriers of the CNS2022
Prolonged culturing of iPSC-derived brain endothelial-like cells is associated with quiescence, downregulation of glycolysis, and resistance to disruption by an Alzheimer's brain milieu.
Article in Fluids and barriers of the CNS, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 11 papers.
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Who cites it
11 citing papers in PubMed, 19 citations in OpenAlex.
- Comparative permeability of the blood-brain barrier to albumin, DTPA, and sucrose: effects of inflammation-induced disruption.Fluids and barriers of the CNS · 2025Article
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- The Rise of Pluripotent Stem Cell-Derived Glia Models of Neuroinflammation.Neurology international · 2025Review
- Article
- Amyloid beta peptides (Aβ) from Alzheimer's disease neuronal secretome induce endothelial activation in a human cerebral microvessel model.Neurobiology of disease · 2023Article
- Cellular senescence and the blood-brain barrier: Implications for aging and age-related diseases.Experimental biology and medicine (Maywood, N.J.) · 2023Review
- The role of platelets in the blood-brain barrier during brain pathology.Frontiers in cellular neuroscience · 2023Review
- Human-Induced Pluripotent Stem Cell-Based Model of the Blood-Brain at 10 Years: A Retrospective on Past and Current Disease Models.Handbook of experimental pharmacology · 2023Review
- Human mini-blood-brain barrier models for biomedical neuroscience research: a review.Biomaterials research · 2022Review
- Induced pluripotent stem cell-derived cells model brain microvascular endothelial cell glucose metabolism.Fluids and barriers of the CNS · 2022Article
- P450 oxidoreductase regulates barrier maturation by mediating retinoic acid metabolism in a model of the human BBB.Stem cell reports · 2022Article
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Authors and funding
8 authors at 2 institutions in 2 countries.
Funding
Abstract
backgroundHuman induced pluripotent stem cell (hiPSC)-derived brain endothelial-like cells (iBECs) are a robust, scalable, and translatable model of the human blood-brain barrier (BBB). Prior works have shown that high transendothelial electrical resistance (TEER) persists in iBECs for at least 2 weeks, emphasizing the utility of the model for longer term studies. However, most studies evaluate iBECs within the first few days of subculture, and little is known about their proliferative state, which could influence their functions. In this study, we characterized iBEC proliferative state in relation to key BBB properties at early (2 days) and late (9 days) post-subculture time points.
methodshiPSCs were differentiated into iBECs using fully defined, serum-free medium. The proportion of proliferating cells was determined by BrdU assays. We evaluated TEER, expression of glycolysis enzymes and tight and adherens junction proteins (TJP and AJP), and glucose transporter-1 (GLUT1) function by immunoblotting, immunofluorescence, and quantifying radiolabeled tracer permeabilities. We also compared barrier disruption in response to TNF-α and conditioned medium (CM) from hiPSC-derived neurons harboring the Alzheimer's disease (AD)-causing Swedish mutation (APP
resultsA significant decline in iBEC proliferation over time in culture was accompanied by adoption of a more quiescent endothelial metabolic state, indicated by downregulation of glycolysis-related proteins and upregulation GLUT1. Interestingly, upregulation of GLUT1 was associated with reduced glucose transport rates in more quiescent iBECs. We also found significant decreases in claudin-5 (CLDN5) and vascular endothelial-cadherin (VE-Cad) and a trend toward a decrease in platelet endothelial cell adhesion molecule-1 (PECAM-1), whereas zona occludens-1 (ZO-1) increased and occludin (OCLN) remained unchanged. Despite differences in TJP and AJP expression, there was no difference in mean TEER on day 2 vs. day 9. TNF-α induced disruption irrespective of iBEC proliferative state. Conversely, APP
conclusioniBECs can be used to study responses to disease-relevant stimuli in proliferating vs. more quiescent endothelial cell states, which may provide insight into BBB vulnerabilities in contexts of development, brain injury, and neurodegenerative disease.
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