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

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.

SUBMITTER: Nguyen EH

PROVIDER: S-EPMC6594538 | biostudies-literature | 2019 Jun

REPOSITORIES: biostudies-literature

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

Nguyen Eric H EH Dombroe Micah J MJ Fisk Debra L DL Daly William T WT Sorenson Christine M CM Murphy William L WL Sheibani Nader N

Applied in vitro toxicology 20190617 2

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 pericyte ...[more]

PMID: 32292797

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Project description:Cigarette smoke (CS) has a major impact on lung biology and may result in the development of lung diseases such as chronic obstructive pulmonary disease or lung cancer. To understand the underlying mechanisms of disease development, it would be important to examine the impact of CS exposure directly on lung tissues. However, this approach is difficult to implement in epidemiological studies because lung tissue sampling is complex and invasive. Alternatively, tissue culture models can facilitate the assessment of exposure impacts on the lung tissue. Submerged 2D cell cultures, such as normal human bronchial epithelial (NHBE) cell cultures, have traditionally been used for this purpose. However, they cannot be exposed directly to smoke in a similar manner to the in vivo exposure situation. Recently developed 3D tissue culture models better reflect the in vivo situation because they can be cultured at the air-liquid interface (ALI). Their basal sides are immersed in the culture medium; whereas, their apical sides are exposed to air. Moreover, organotypic tissue cultures that contain different type of cells, better represent the physiology of the tissue in vivo. In this work, the utilization of an in vitro exposure system to expose human organotypic bronchial and nasal tissue models to mainstream CS is demonstrated. Ciliary beating frequency and the activity of cytochrome P450s (CYP) 1A1/1B1 were measured to assess functional impacts of CS on the tissues. Furthermore, to examine CS-induced alterations at the molecular level, gene expression profiles were generated from the tissues following exposure. A slight increase in CYP1A1/1B1 activity was observed in CS-exposed tissues compared with air-exposed tissues. A network-and transcriptomics-based systems biology approach was sufficiently robust to demonstrate CS-induced alterations of xenobiotic metabolism that were similar to those observed in the bronchial and nasal epithelial cells obtained from smokers.

Dataset Information

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

Publications

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

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