PMID- 32292797 OWN - NLM STAT- PubMed-not-MEDLINE LR - 20210727 IS - 2332-1512 (Print) IS - 2332-1539 (Electronic) IS - 2332-1512 (Linking) VI - 5 IP - 2 DP - 2019 Jun 1 TI - Neurovascular Organotypic Culture Models Using Induced Pluripotent Stem Cells to Assess Adverse Chemical Exposure Outcomes. PG - 92-110 LID - 10.1089/aivt.2018.0025 [doi] AB - 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. CI - Copyright 2019, Mary Ann Liebert, Inc., publishers. FAU - Nguyen, Eric H AU - Nguyen EH AD - Human Models for Analysis of Pathways Center, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin. AD - Department of Ophthalmology and Visual Sciences, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin. FAU - Dombroe, Micah J AU - Dombroe MJ AD - School of Pharmacy, University of Wisconsin-Madison, Madison, Wisconsin. FAU - Fisk, Debra L AU - Fisk DL AD - Human Models for Analysis of Pathways Center, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin. AD - Department of Ophthalmology and Visual Sciences, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin. FAU - Daly, William T AU - Daly WT AD - Human Models for Analysis of Pathways Center, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin. AD - Department of Biomedical Engineering, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin. AD - Department of Orthopedics and Rehabilitation, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin. FAU - Sorenson, Christine M AU - Sorenson CM AD - Department of Pediatrics, and University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin. FAU - Murphy, William L AU - Murphy WL AD - Human Models for Analysis of Pathways Center, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin. AD - Department of Biomedical Engineering, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin. AD - Department of Orthopedics and Rehabilitation, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin. FAU - Sheibani, Nader AU - Sheibani N AD - Human Models for Analysis of Pathways Center, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin. AD - Department of Ophthalmology and Visual Sciences, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin. AD - Department of Biomedical Engineering, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin. AD - Department of Cell and Regenerative Biology, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin. LA - eng GR - P41 RR002301/RR/NCRR NIH HHS/United States GR - S10 RR025062/RR/NCRR NIH HHS/United States GR - S10 RR029220/RR/NCRR NIH HHS/United States GR - T32 GM008349/GM/NIGMS NIH HHS/United States GR - R01 HL093282/HL/NHLBI NIH HHS/United States GR - R24 EY022883/EY/NEI NIH HHS/United States GR - P30 EY016665/EY/NEI NIH HHS/United States GR - R01 EY026078/EY/NEI NIH HHS/United States GR - R21 EB016381/EB/NIBIB NIH HHS/United States GR - S10 RR002781/RR/NCRR NIH HHS/United States GR - P41 GM103399/GM/NIGMS NIH HHS/United States GR - S10 RR008438/RR/NCRR NIH HHS/United States GR - S10 RR023438/RR/NCRR NIH HHS/United States GR - T32 ES007015/ES/NIEHS NIH HHS/United States GR - R01 EB010039/EB/NIBIB NIH HHS/United States PT - Journal Article DEP - 20190617 PL - United States TA - Appl In Vitro Toxicol JT - Applied in vitro toxicology JID - 101692723 PMC - PMC6594538 OTO - NOTNLM OT - acute toxicity OT - cardiotoxicity OT - high throughput OT - neurotoxicity OT - ocular toxicity OT - stem cells COIS- W.L.M. is a founder and stockholder for StemPharm, Inc. All other authors have no competing financial interests. EDAT- 2020/04/16 06:00 MHDA- 2020/04/16 06:01 PMCR- 2020/06/26 CRDT- 2020/04/16 06:00 PHST- 2020/04/16 06:00 [entrez] PHST- 2020/04/16 06:00 [pubmed] PHST- 2020/04/16 06:01 [medline] PHST- 2020/06/26 00:00 [pmc-release] AID - 10.1089/aivt.2018.0025 [pii] AID - 10.1089/aivt.2018.0025 [doi] PST - ppublish SO - Appl In Vitro Toxicol. 2019 Jun 1;5(2):92-110. doi: 10.1089/aivt.2018.0025. Epub 2019 Jun 17.