Liver-on-a-chip bioengineering to model systemic health responses to pollution exposure

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Background: Air pollution aggravates chronic diseases of the lung, blood vessels, heart and brain. Current regulations aim to limit particulate matter up to 2.5 micron (PM2.5). However, this fraction varies in composition of particles and chemicals, and the causal agents and toxicity pathways have yet to be determined. We are developing a novel pollution hazard identification platform to determine the toxicological responses to environmental pollutants using mouse stress reporter models (Dundee) and associated epigenetic and transcription changes (Edinburgh, CMVM). Defined exposures in an animal model permit more sensitive detection of molecular mechanisms than population-based studies, but are less adaptable to many pollution sources. In collaboration with Engineering (CSE), we will design an organ tissue culture on-a-chip as a novel assay for environmental cell stress and epigenetic changes. The liver plays a key role in metabol- ising environmental pollutants and can be a major determinant in outcomes. Our Aim is to develop and evaluate a liver cell-based approach to predict human exposure adverse outcomes. Project Proposal (Tangible interaction between CSE, MVM and external funder (if any) must be evident): Our Interaction will combine unique cell stress reporter cell lines developed based on stem cell and epigenetics expertise (Pennings (CS), Meehan (MGPH), CMVM) and mouse genetics and toxicology (Wolf, Dundee), with microfluidic organ-on-a-chip technology and optical spectroscopy in bioengineering (Elfick, CSE). Joint research will develop components to adapt the cells to 3D culture, and adapt the device to environmental exposure studies. NERC NE/W002086/1 (tinyurl.com/2p8m7y5n) is funding identification of exposure stress pathways and epigenetic changes in our mouse reporter models with luminescence detection of oxidative stress, DNA damage, and CAR or AhR mediated xenobiotic exposures. Objective 1 will derive embryonic stem cell lines that carry the same reporters as the parental animals. These stem cells will be a renewable source for derivation of other cell types, with Objective 2 adopting a liver cell differentiation protocol. Horizon is funding organ-on-a-chip studies with 3D co-culture of liver cell lines. The technology was tested as a model for liver predictive toxicology (PMID36473994). Objective 3 will integrate the reporter cells into this design, live-image cells, and collect cells for epigenetics and transcriptomics studies with or without pollutant exposure, and data analysis. The PhD study will inform liver-chip research regarding cell stress and epigenetic changes. Outcomes will be compared to NERC consortium data to address the Research Question whether 3D liver cell-based autonomous responses can model the liver in systemic health responses to pollution.