Unknown,Transcriptomics,Genomics,Proteomics

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3D vasculature-on-a-chip model of perfused human coronary artery endothelial microvessels for studying monocyte-to-endothelium adhesion in vitro: Use case application in systems toxicology

ABSTRACT: Lifestyle and genetic factors can lead to the development of atherosclerosis and, ultimately, cardiovascular adverse events. Rodent models are commonly used to investigate mechanism(s) of atherogenesis. However, the 3Rs principles, aiming to limit animal testing, encourage the scientific community to develop new physiologically relevant in vitro alternatives. Leveraging the 96-chip OrganoPlate®, a microfluidic platform, we have established a three-dimensional (3D) model of endothelial microvessels-on-a-chip under flow using primary human coronary arterial endothelial cells. As functional readout, we have set up an assay to measure the adhesion of monocytes to the lumen of perfused microvessels. For monitoring molecular changes in microvessels, we have established the staining and quantification of specific protein markers of inflammation and oxidative stress using high content imaging, as well as analyzed transcriptome changes using microarrays. To demonstrate its usefulness in systems toxicology, we leveraged our 3D vasculature-on-a-chip model to assess the impact of the Tobacco Heating System (THS) 2.2, a candidate modified risk tobacco product, and the 3R4F reference cigarette on the adhesion of monocytic cells to endothelial microvessels. Our results show that THS 2.2 aerosol-conditioned medium had a reduced effect on monocyte-endothelium adhesion compared with 3R4F smoke-conditioned medium. In conclusion, we have established a relevant 3D vasculature-on-a-chip model for investigating leukocyte-endothelial microvessel adhesion. A case study illustrates how the model can be used for product testing in the context of systems toxicology-based risk assessment. The current model and its potential further development options also open perspectives of applications in vascular disease research and drug discovery.

ORGANISM(S): Homo sapiens

SUBMITTER: Alain Sewer

PROVIDER: E-MTAB-7555 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Project description:Adverse outcome pathways (AOP) contain summarizing sequences of key events (KE) relating toxicant exposures to specific adverse outcomes (AO) observed in exposed populations. Quantitative AOPs (qAOP) provide frameworks to assess AO risks based on KE quantification and the modeling of their relationships. This work aimed to develop the quantitative component of AOP 411 <Oxidative stress leading to decreased lung function>. To examine the pertinence of the resulting qAOP-based risk assessment approach, we applied it to predict the medium-term lung function evolution after switching from combustible cigarettes (CC) to heated tobacco products (HTP). We used publicly available data for oxidative stress (in vitro), ciliary beating frequency (in vitro), mucociliary clearance (human), and lung function (human). Following the course of smoking-related lung function decline (Fletcher and Peto, 1977, PMID 871704), we assumed a non-monotonic time evolution where the risk of the AO <decreased lung function> begins to decline after quitting smoking CC or switching to HTP use. Consequently, we designed our qAOP to evaluate the relative reduction (RR) of AO risk for HTP switching compared to the two scenarios of continuing or quitting CC consumption. We developed both data- and physiology-based KE relationship (KER) models. Despite sparse data with respect to dose- and time-response relationships, we successfully connected the measured KEs through in silico KER models. We then used the resulting qAOP to evaluate the exposure effects of switching from CC smoking to HTP use along AOP 411. This approach enabled in silico prediction of the AO RR for which in vivo data were not yet available. In summary, our qAOP provides a multiscale mechanistic approach to evaluate medium-term lung function evolution for the use case of switching from CC smoking to HTP use. The presented approach demonstrates how 21st Century Toxicology principles such as in vitro testing and in silico predictions can be integrated to achieve a meaningful risk assessment approach. It also represents a starting point for integrating additional AOP into an extended AOP network that includes other mechanisms leading to decreased lung function.

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3D vasculature-on-a-chip model of perfused human coronary artery endothelial microvessels for studying monocyte-to-endothelium adhesion in vitro: Use case application in systems toxicology

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