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      Neurovascular Organotypic Culture Models Using Induced Pluripotent Stem Cells to Assess Adverse Chemical Exposure Outcomes

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          Abstract

          Introduction: Human-induced pluripotent stem cells (iPSCs) represent a promising cell source for the construction of organotypic culture models for chemical toxicity screening and characterization.

          Materials and Methods: To characterize the effects of chemical exposure on the human neurovasculature, we constructed neurovascular unit (NVU) models consisting of endothelial cells (ECs) and astrocytes (ACs) derived from human-iPSCs, as well as human brain-derived pericytes (PCs). The cells were cocultured on synthetic poly(ethylene glycol) (PEG) hydrogels that guided the self-assembly of capillary-like vascular networks. High-content epifluorescence microscopy evaluated dose-dependent changes to multiple aspects of NVU morphology.

          Results: Cultured vascular networks underwent quantifiable morphological changes when incubated with vascular disrupting chemicals. The activity of predicted vascular disrupting chemicals from a panel of 38 compounds (U.S. Environmental Protection Agency) was ranked based on morphological features detected in the NVU model. In addition, unique morphological neurovascular disruption signatures were detected per chemical. A comparison of PEG-based NVU and Matrigel -based NVU models found greater sensitivity and consistency in chemical detection by the PEG-based NVU models.

          Discussion: We suspect that specific morphological changes may be used for discerning adverse outcome pathways initiated by chemical exposure and rapid mechanistic characterization of chemical exposure to neurovascular function.

          Conclusion: The use of human stem cell-derived vascular tissue and PEG hydrogels in the construction of NVU models leads to rapid detection of adverse chemical effects on neurovascular stability. The use of multiple cell types in coculture elucidates potential mechanisms of action by chemicals applied to the model.

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          Author and article information

          Journal
          Appl In Vitro Toxicol
          Appl In Vitro Toxicol
          aivt
          Applied in Vitro Toxicology
          Mary Ann Liebert, Inc., publishers (140 Huguenot Street, 3rd FloorNew Rochelle, NY 10801USA )
          2332-1512
          2332-1539
          01 June 2019
          17 June 2019
          : 5
          : 2
          : 92-110
          Affiliations
          [ 1 ]Human Models for Analysis of Pathways Center, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin.
          [ 2 ]Department of Ophthalmology and Visual Sciences, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin.
          [ 3 ]School of Pharmacy, University of Wisconsin-Madison, Madison, Wisconsin.
          [ 4 ]Department of Biomedical Engineering, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin.
          [ 5 ]Department of Orthopedics and Rehabilitation, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin.
          [ 6 ]Department of Pediatrics, and University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin.
          [ 7 ]Department of Cell and Regenerative Biology, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin.
          Author notes
          [*]Address correspondence to: Dr. Nader Sheibani, Department of Ophthalmology and Visual Sciences, University of Wisconsin School of Medicine and Public Health, 1111 Highland Avenue, 9453 WIMR, Madison, WI 53705 nsehaibanikar@ 123456wisc.edu
          Article
          PMC6594538 PMC6594538 6594538 10.1089/aivt.2018.0025
          10.1089/aivt.2018.0025
          6594538
          32292797
          d75dafe9-c594-4374-a51e-e82dfc3d5499
          Copyright 2019, Mary Ann Liebert, Inc., publishers
          History
          Page count
          Figures: 5, Tables: 1, References: 59, Pages: 19
          Categories
          Original Articles

          stem cells,ocular toxicity,neurotoxicity,high throughput,cardiotoxicity,acute toxicity

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