iPSC-Derived Brain Endothelium Exhibits Stable, Long-Term Barrier Function in Perfused Hydrogel Scaffolds

Summary: There is a profound need for functional, biomimetic in vitro tissue constructs of the human blood-brain barrier and neurovascular unit (NVU) to model diseases and identify therapeutic interventions. Here, we show that induced pluripotent stem cell (iPSC)-derived human brain microvascular en...

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Main Authors:	Shannon L. Faley, Emma H. Neal, Jason X. Wang, Allison M. Bosworth, Callie M. Weber, Kylie M. Balotin, Ethan S. Lippmann, Leon M. Bellan
Format:	Article
Language:	English
Published:	Elsevier 2019-03-01
Series:	Stem Cell Reports
Online Access:	http://www.sciencedirect.com/science/article/pii/S2213671119300116

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spelling	doaj-ceeb8e1c612240c494e9beedd647b37e2020-11-25T01:20:23ZengElsevierStem Cell Reports2213-67112019-03-01123474487iPSC-Derived Brain Endothelium Exhibits Stable, Long-Term Barrier Function in Perfused Hydrogel ScaffoldsShannon L. Faley0Emma H. Neal1Jason X. Wang2Allison M. Bosworth3Callie M. Weber4Kylie M. Balotin5Ethan S. Lippmann6Leon M. Bellan7Department of Mechanical Engineering, Vanderbilt University, Nashville, TN 37212, USADepartment of Chemical and Biomolecular Engineering, Vanderbilt University, Nashville, TN 37212, USADepartment of Biomedical Engineering, Vanderbilt University, Nashville, TN 37232, USADepartment of Biomedical Engineering, Vanderbilt University, Nashville, TN 37232, USADepartment of Biomedical Engineering, Vanderbilt University, Nashville, TN 37232, USADepartment of Biomedical Engineering, Vanderbilt University, Nashville, TN 37232, USADepartment of Chemical and Biomolecular Engineering, Vanderbilt University, Nashville, TN 37212, USA; Department of Biomedical Engineering, Vanderbilt University, Nashville, TN 37232, USA; Vanderbilt Brain Institute, Vanderbilt University Medical School, Nashville, TN 37232, USA; Chemical and Physical Biology Program, Vanderbilt University, Nashville, TN 37232, USA; Corresponding authorDepartment of Mechanical Engineering, Vanderbilt University, Nashville, TN 37212, USA; Department of Biomedical Engineering, Vanderbilt University, Nashville, TN 37232, USA; Corresponding authorSummary: There is a profound need for functional, biomimetic in vitro tissue constructs of the human blood-brain barrier and neurovascular unit (NVU) to model diseases and identify therapeutic interventions. Here, we show that induced pluripotent stem cell (iPSC)-derived human brain microvascular endothelial cells (BMECs) exhibit robust barrier functionality when cultured in 3D channels within gelatin hydrogels. We determined that BMECs cultured in 3D under perfusion conditions were 10–100 times less permeable to sodium fluorescein, 3 kDa dextran, and albumin relative to human umbilical vein endothelial cell and human dermal microvascular endothelial cell controls, and the BMECs maintained barrier function for up to 21 days. Analysis of cell-cell junctions revealed expression patterns supporting barrier formation. Finally, efflux transporter activity was maintained over 3 weeks of perfused culture. Taken together, this work lays the foundation for development of a representative 3D in vitro model of the human NVU constructed from iPSCs. : Faley et al. present a 3D in vitro model of the blood-brain barrier constructed using induced pluripotent stem cell-derived human brain microvascular endothelial cells cultured in 3D channels in gelatin hydrogels. The model displays robust tight junction protein expression, restricted paracellular permeability, and active efflux transporter activity, and represents an important step toward a representative human in vitro neurovascular model. Keywords: induced pluripotent stem cell, blood-brain barrier, neurovascular unit, three dimensional model, tissue engineeringhttp://www.sciencedirect.com/science/article/pii/S2213671119300116
collection	DOAJ
language	English
format	Article
sources	DOAJ
author	Shannon L. Faley Emma H. Neal Jason X. Wang Allison M. Bosworth Callie M. Weber Kylie M. Balotin Ethan S. Lippmann Leon M. Bellan
spellingShingle	Shannon L. Faley Emma H. Neal Jason X. Wang Allison M. Bosworth Callie M. Weber Kylie M. Balotin Ethan S. Lippmann Leon M. Bellan iPSC-Derived Brain Endothelium Exhibits Stable, Long-Term Barrier Function in Perfused Hydrogel Scaffolds Stem Cell Reports
author_facet	Shannon L. Faley Emma H. Neal Jason X. Wang Allison M. Bosworth Callie M. Weber Kylie M. Balotin Ethan S. Lippmann Leon M. Bellan
author_sort	Shannon L. Faley
title	iPSC-Derived Brain Endothelium Exhibits Stable, Long-Term Barrier Function in Perfused Hydrogel Scaffolds
title_short	iPSC-Derived Brain Endothelium Exhibits Stable, Long-Term Barrier Function in Perfused Hydrogel Scaffolds
title_full	iPSC-Derived Brain Endothelium Exhibits Stable, Long-Term Barrier Function in Perfused Hydrogel Scaffolds
title_fullStr	iPSC-Derived Brain Endothelium Exhibits Stable, Long-Term Barrier Function in Perfused Hydrogel Scaffolds
title_full_unstemmed	iPSC-Derived Brain Endothelium Exhibits Stable, Long-Term Barrier Function in Perfused Hydrogel Scaffolds
title_sort	ipsc-derived brain endothelium exhibits stable, long-term barrier function in perfused hydrogel scaffolds
publisher	Elsevier
series	Stem Cell Reports
issn	2213-6711
publishDate	2019-03-01
description	Summary: There is a profound need for functional, biomimetic in vitro tissue constructs of the human blood-brain barrier and neurovascular unit (NVU) to model diseases and identify therapeutic interventions. Here, we show that induced pluripotent stem cell (iPSC)-derived human brain microvascular endothelial cells (BMECs) exhibit robust barrier functionality when cultured in 3D channels within gelatin hydrogels. We determined that BMECs cultured in 3D under perfusion conditions were 10–100 times less permeable to sodium fluorescein, 3 kDa dextran, and albumin relative to human umbilical vein endothelial cell and human dermal microvascular endothelial cell controls, and the BMECs maintained barrier function for up to 21 days. Analysis of cell-cell junctions revealed expression patterns supporting barrier formation. Finally, efflux transporter activity was maintained over 3 weeks of perfused culture. Taken together, this work lays the foundation for development of a representative 3D in vitro model of the human NVU constructed from iPSCs. : Faley et al. present a 3D in vitro model of the blood-brain barrier constructed using induced pluripotent stem cell-derived human brain microvascular endothelial cells cultured in 3D channels in gelatin hydrogels. The model displays robust tight junction protein expression, restricted paracellular permeability, and active efflux transporter activity, and represents an important step toward a representative human in vitro neurovascular model. Keywords: induced pluripotent stem cell, blood-brain barrier, neurovascular unit, three dimensional model, tissue engineering
url	http://www.sciencedirect.com/science/article/pii/S2213671119300116
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iPSC-Derived Brain Endothelium Exhibits Stable, Long-Term Barrier Function in Perfused Hydrogel Scaffolds

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