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

PubMed ID: 32292797

Author(s): Nguyen EH, Dombroe MJ, Fisk DL, Daly WT, Sorenson CM, Murphy WL, Sheibani N. Neurovascular organotypic culture models using induced pluripotent stem cells to assess adverse chemical exposure outcomes. Appl In Vitro Toxicol. 2019 Jun 1;5(2):92-110. doi: 10.1089/aivt.2018.0025. Epub 2019 Jun 17. PMID 32292797

Journal: Applied In Vitro Toxicology, Volume 5, Issue 2, Jun 2019

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.