Abstract
The potential for nanomaterial (NM) translocation to secondary organs is a realistic prospect, with the liver one of the most important target organs. Traditional in vitro or ex vivo hepatic toxicology models are often limiting and/or troublesome (i.e. short life-span reduced metabolic activity, lacking important cell populations, high inter-individual variability, etc.). Building on previous work, this study utilises a 3D human liver microtissue (MT) model (MT composed of mono-culture of hepatocytes or two different co-culture MT systems with non-parenchymal cell (NPC) fraction sourced from different donors) to investigate the importance of inter-donor variability of the non-parenchymal cell population in the overall governance of toxicological response following exposure to a panel of NMs. To the best of our knowledge, this is the first study of its kind to investigate inter-donor variability in hepatic NPC population. The data showed that the Kupffer cells were crucial in dictating the overall hepatic toxicity following exposure to the materials. Furthermore, a statistically significant difference was noted between the two co-culture MT models. However, the trend for particle-induced biological responses was similar between the co-cultures (cytotoxicity, cytokine production and caspase activity). Therefore, despite the recognition of some discrepancies in the absolute values between the co-culture models, the fact that the trends and patterns of biological responses were comparable between the multi-cellular models we propose the 3D liver MT to be a valuable tool in particle toxicology.
Highlights
The liver is the bodies’ main detoxification centre, removing xenobiotics and waste products[11]
In an attempt to address this issue, this study was designed to scrutinize a scaffold free 3D liver microtissue (MT) model composed of primary human hepatocytes and primary human liver-derived non-parenchymal cell (NPC)
Three different MT models were utilized: (1) MT composed of mono-culture of hepatocytes (2) co-culture MT composed of multi-donor primary human hepatocytes and NPC fraction from donor 1, while (3) co-culture MT is composed of multi-donor primary human hepatocytes and NPC fraction from donor 2
Summary
The liver is the bodies’ main detoxification centre, removing xenobiotics and waste products[11]. Understanding the patterns and the nature of biological responses from the immune cells (KCs in the liver) sourced from different individuals is critical for good experimental design and more accurate in vitro to in vivo data extrapolation. In an attempt to address this issue, this study was designed to scrutinize a scaffold free 3D liver microtissue (MT) model composed of primary human hepatocytes and primary human liver-derived NPC (particular attention on inter-individual variability in the NPC population). To best of our knowledge, this is the first study, to investigate the importance of the role of KCs in the particle-induced hepatic inflammatory response in vitro, as well ascertaining the significance of inter-donor NPC sub-population variability in the toxicological response from the liver. Increased knowledge of the biological capabilities of the test model systems will no doubt be critical for better understanding the outcome of experiments intended to evaluate liver-specific function and toxicity and prove invaluable in future study design
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