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An isogenic blood–brain barrier model comprising brain endothelial cells, astrocytes, and neurons derived from human induced pluripotent stem cells

2016; Wiley; Volume: 140; Issue: 6 Linguagem: Inglês

10.1111/jnc.13923

1471-4159

Scott G. Canfield, Matthew J. Stebbins, Bethsymarie Soto Morales, Shusaku Asai, Gad D. Vatine, Clive N. Svendsen, Sean P. Palecek, Eric V. Shusta,

Hedgehog Signaling Pathway Studies

Abstract The blood–brain barrier ( BBB ) is critical in maintaining a physical and metabolic barrier between the blood and the brain. The BBB consists of brain microvascular endothelial cells ( BMEC s) that line the brain vasculature and combine with astrocytes, neurons and pericytes to form the neurovascular unit. We hypothesized that astrocytes and neurons generated from human‐induced pluripotent stem cells ( iPSC s) could induce BBB phenotypes in iPSC ‐derived BMEC s, creating a robust multicellular human BBB model. To this end, iPSC s were used to form neural progenitor‐like EZ ‐spheres, which were in turn differentiated to neurons and astrocytes, enabling facile neural cell generation. The iPSC ‐derived astrocytes and neurons induced barrier tightening in primary rat BMEC s indicating their BBB inductive capacity. When co‐cultured with human iPSC ‐derived BMEC s, the iPSC ‐derived neurons and astrocytes significantly elevated trans‐endothelial electrical resistance, reduced passive permeability, and improved tight junction continuity in the BMEC cell population, while p ‐glycoprotein efflux transporter activity was unchanged. A physiologically relevant neural cell mixture of one neuron: three astrocytes yielded optimal BMEC induction properties. Finally, an isogenic multicellular BBB model was successfully demonstrated employing BMEC s, astrocytes, and neurons from the same donor iPSC source. It is anticipated that such an isogenic facsimile of the human BBB could have applications in furthering understanding the cellular interplay of the neurovascular unit in both healthy and diseased humans. image Read the Editorial Highlight for this article on page 843 .