TY - JOUR
T1 - Establishment of a Human iPSC- and Nanofiber-Based Microphysiological Blood-Brain Barrier System
AU - Qi, Dianjun
AU - Wu, Shaohua
AU - Lin, Haishuang
AU - Kuss, Mitchell A.
AU - Lei, Yuguo
AU - Krasnoslobodtsev, Alexey
AU - Ahmed, Shaheen
AU - Zhang, Chi
AU - Kim, Hyung Joon
AU - Jiang, Peng
AU - Duan, Bin
N1 - Funding Information:
This work has been supported by Mary & Dick Holland Regenerative Medicine Program start-up grant, Mary & Dick Holland Regenerative Medicine Program pilot project grant, and Nebraska Research Initiative funding to B.D. and grants from the NIH (R21HD091512 and R01NS102382) to P.J. Nebraska Stem Cell Research Project Grant to B.D., Y.L., and H.J.K. We would like to thank Jane DeVasure and Dr. Todd Wyatt for the assistance of TEER measurement. We would like to thank Dr. Linxia Gu and Pengfei Dong for the assistance of tensile tests. We would like to thank Janice A. Taylor and James R. Talaska of the Advanced Microscopy Core Facility at the University of Nebraska Medical Center (UNMC) for providing assistance with confocal microscopy. Support for the UNMC Advanced Microscopy Core Facility was provided by the Nebraska Research Initiative, the Fred and Pamela Buffett Cancer Center Support Grant (P30CA036727), and an Institutional Development Award (IDeA) from the NIGMS of the NIH (P30GM106397). We would also like to thank the Nanoimaging Core Facility at UNMC for providing access to the Force Robot 300 instrument (JPK, Berlin, Germany).
Publisher Copyright:
© Copyright 2018 American Chemical Society.
PY - 2018/7/5
Y1 - 2018/7/5
N2 - 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.
AB - 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.
KW - 3D printing
KW - drug screening
KW - electrospinning
KW - human induced pluripotent stem cells
KW - transepithelial electrical resistance
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U2 - 10.1021/acsami.8b03962
DO - 10.1021/acsami.8b03962
M3 - Article
C2 - 29897225
AN - SCOPUS:85048719821
VL - 10
SP - 21825
EP - 21835
JO - ACS applied materials & interfaces
JF - ACS applied materials & interfaces
SN - 1944-8244
IS - 26
ER -