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An isogenic blood–brain barrier model comprising brain endothelial cells, astrocytes, and neurons derived from human induced pluripotent stem cells
Author(s) -
Canfield Scott G.,
Stebbins Matthew J.,
Morales Bethsymarie Soto,
Asai Shusaku W.,
Vatine Gad D.,
Svendsen Clive N.,
Palecek Sean P.,
Shusta Eric V.
Publication year - 2017
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1111/jnc.13923
Subject(s) - induced pluripotent stem cell , blood–brain barrier , biology , neuroscience , microbiology and biotechnology , astrocyte , neuron , neural stem cell , progenitor cell , endothelial stem cell , tight junction , human brain , population , stem cell , embryonic stem cell , central nervous system , medicine , biochemistry , in vitro , gene , environmental health
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.Read the Editorial Highlight for this article on page 843.