Establishment of a Human iPSC- and Nanofiber-Based Microphysiological Blood–Brain Barrier System

Authors

Dianjun Qi, University of Nebraska Medical Center
Shaohua Wu, University of Nebraska Medical CenterFollow
Haishuang Lin, University of Nebraska - LincolnFollow
Mitchell A. Kuss, University of Nebraska Medical Center
Yuguo Lei, University of Nebraska - LincolnFollow
Alexey Krasnoslobodtsev, University of Nebraska at OmahaFollow
Shaheen Ahmed, University of Nebraska Medical CenterFollow
Chi Zhang, University of Nebraska Medical CenterFollow
Hyung Joon Kim, University of Nebraska Medical Center
Peng Jiang, Rutgers University - New Brunswick/PiscatawayFollow
Bin Duan, University of Nebraska Medical CenterFollow

ORCID IDs

0000-0002-7682-6912

0000-0002-5647-3793

Date of this Version

2018

Document Type

Article

Citation

ACS Appl Mater Interfaces. 2018 July 05; 10(26): 21825–21835

Comments

Copyright 2018 American Chemical Society

doi:10.1021/acsami.8b03962

Abstract

The blood–brain barrier (BBB) is an active and complex diffusion barrier that separates the circulating blood from the brain and extracellular fluid, regulates nutrient transportation, and provides protection against various toxic compounds and pathogens. Creating an in vitro microphysiological BBB system, particularly with relevant human cell types, will significantly facilitate the research of neuropharmaceutical drug delivery, screening, and transport, as well as improve our understanding of pathologies that are due to BBB damage. Currently, most of the in vitro BBB models are generated by culturing rodent astrocytes and endothelial cells, using commercially available transwell membranes. Those membranes are made of plastic biopolymers that are nonbiodegradable, porous, and stiff. In addition, distinct from rodent astrocytes, human astrocytes possess unique cell complexity and physiology, which are among the few characteristics that differentiate human brains from rodent brains. In this study, we established a novel human BBB microphysiologocal system, consisting of a three-dimensionally printed holder with a electrospun poly(lactic-co-glycolic) acid (PLGA) nanofibrous mesh, a bilayer coculture of human astrocytes, and endothelial cells, derived from human induced pluripotent stem cells (hiPSCs), on the electrospun PLGA mesh. This human BBB model achieved significant barrier integrity with tight junction protein expression, an effective permeability to sodium fluorescein, and higher transendothelial electrical resistance (TEER) comparing to electrospun mesh-based counterparts. Moreover, the coculture of hiPSC-derived astrocytes and endothielial cells promoted the tight junction protein expression and the TEER value. We further verified the barrier functions of our BBB model with antibrain tumor drugs (paclitaxel and bortezomib) and a neurotoxic peptide (amyloid β 1–42). The human microphysiological system generated in this study will potentially provide a new, powerful tool for research on human BBB physiology and pathology.