Abstract
The ability of the liver to simultaneously carry out multiple functions is dependent on the metabolic heterogeneity of hepatocytes spatially located within a liver lobule spanning from the portal triad to the central vein. This complex zonal architecture of the liver, however, makes accurate in vitro modeling a challenge and often standard culture systems assume a homogenous model which may lead to inaccurate translatability of results. Here, we use a combination of mathematical modeling and experimental data to demonstrate a readily constructible in vitro flow system capable of liver zonation in primary rat hepatocytes. We show the differential expression of zonation markers, enhanced functionality when compared to standard static cultures and zone-specific metabolism and cell damage in the presence of paracetamol, a known zone-specific toxin. This type of advanced system provides a more in-depth and essential understanding of liver physiology and pathophysiology as well as the accurate evaluation of pharmacological interventions at a zone-specific level.
Highlights
Drug-induced liver injury (DILI) represents a major global human health concern and is one of the most common side effects of many therapeutic compounds, leading to a high incidence of patient morbidity and mortality (Gaskell et al, 2016)
By using primary rat hepatocytes (PRH), we have shown that the cells exhibit differential protein expression and toxicity profiles when exposed to known hepatotoxins, mimicking a response more like that seen in vivo
Accurate in vitro modeling is essential to data translatability in vivo
Summary
Drug-induced liver injury (DILI) represents a major global human health concern and is one of the most common side effects of many therapeutic compounds, leading to a high incidence of patient morbidity and mortality (Gaskell et al, 2016). Further complexity arises since it has previously been determined that hepatocytes in the liver are a heterogeneous population and, that in order to cope with an immense spectrum of functions which are performed simultaneously, liver cells show a considerable heterogeneity and functional plasticity known as metabolic zonation (Colnot and Perret, 2011). Hepatocytes within the liver sinusoid are exposed to varying gradients of oxygen, nutrients, hormones, and metabolites giving rise to zonation whereby cells along the sinusoid have vastly different levels of gene expression and metabolic competence (Kietzmann, 2017). The 3 main zones (Figure 1) along a sinusoidal unit, namely periportal (PP), central lobular (CL) and perivenous (PV), are functionally and biochemically different affecting key functions such as ammonia detoxification, glucose/energy
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