title: A retinoic acid-enhanced, multicellular human blood-brain barrier model derived from stem cell sources.
abstract: Blood-brain barrier (BBB) models are often used to investigate BBB function and screen brain-penetrating therapeutics, but it has been difficult to construct a human model that possesses an optimal BBB phenotype and is readily scalable. To address this challenge, we developed a human in vitro BBB model comprising brain microvascular endothelial cells (BMECs), pericytes, astrocytes and neurons derived from renewable cell sources. First, retinoic acid (RA) was used to substantially enhance BBB phenotypes in human pluripotent stem cell (hPSC)-derived BMECs, particularly through adherens junction, tight junction, and multidrug resistance protein regulation. RA-treated hPSC-derived BMECs were subsequently co-cultured with primary human brain pericytes and human astrocytes and neurons derived from human neural progenitor cells (NPCs) to yield a fully human BBB model that possessed significant tightness as measured by transendothelial electrical resistance (~5,000 Ωxcm(2)). Overall, this scalable human BBB model may enable a wide range of neuroscience studies.
authors.affiliation: Department of Chemical and Biological Engineering, University of Wisconsin-Madison, Madison, WI, USA.
authors.forename: Ethan S
authors.initials: ES
authors.lastname: Lippmann
authors.affiliation: Department of Chemical and Biological Engineering, University of Wisconsin-Madison, Madison, WI, USA.
authors.forename: Abraham
authors.initials: A
authors.lastname: Al-Ahmad
authors.affiliation: Department of Chemical and Biological Engineering, University of Wisconsin-Madison, Madison, WI, USA.
authors.forename: Samira M
authors.initials: SM
authors.lastname: Azarin
authors.affiliation: Department of Chemical and Biological Engineering, University of Wisconsin-Madison, Madison, WI, USA.
authors.forename: Sean P
authors.initials: SP
authors.lastname: Palecek
authors.affiliation: Department of Chemical and Biological Engineering, University of Wisconsin-Madison, Madison, WI, USA.
authors.forename: Eric V
authors.initials: EV
authors.lastname: Shusta
mesh_terms: D001253:Astrocytes / Q000166:cytology; D001812:Blood-Brain Barrier / Q000737:chemistry / Q000378:metabolism*; D001921:Brain / Q000166:cytology; D002454:Cell Differentiation / Q000187:drug effects; D002478:Cells, Cultured; D018920:Coculture Techniques; D004553:Electric Conductivity; D004730:Endothelium, Vascular / Q000166:cytology; D006801:Humans; D008954:Models, Biological; D058953:Neural Stem Cells / Q000166:cytology; D009474:Neurons / Q000166:cytology; D020286:Pericytes / Q000166:cytology; D039904:Pluripotent Stem Cells / Q000166:cytology / Q000187:drug effects*; D014212:Tretinoin / Q000494:pharmacology*
chemical_list: D014212:Tretinoin