In vitro and in silico liver models: Current trends, challenges and opportunities

Abstract

Most common drug development failures originate from either bioavailability problems, or unexpected toxic effects. The culprit is often the liver, which is responsible for biotransformation of a majority of xenobiotics. Liver may be modeled using "liver on a chip" devices, which may include established cell lines, primary human cells, and stem cell-derived hepatocyte-like cells. The choice of biological material along with its processing and maintenance greatly influence both the device performance and the resultant toxicity predictions. Impediments to the development of "liver on a chip" technology include the problems with standardization of cells, limitations imposed by culturing and the necessity to develop more complicated fluidic contours. Fortunately, recent breakthroughs in the development of cell-based reporters, including ones with fluorescent label, permits monitoring of the behavior of the cells embed into the "liver on a chip" devices. Finally, a set of computational approaches has been developed to model both particular toxic response and the homeostasis of human liver as a whole; these approaches pave a way to enhance the in silico stage of assessment for a potential toxicity.

Human Liver Spheroids as a Model to Study Aetiology and Treatment of Hepatic Fibrosis

“…Hepatic stellate cells (HSCs) undergo differentiation to a pro-fibrotic phenotype which is associated with liver fibrosis [12][13][14], making these NPCs integral to evaluating pharmaceutical interventions. Advances in tissue engineering support increased cellular longevity in vitro, which is achieved by a three-dimensional (3D) spatial arrangement of cells, and where applied to liver tissue, demonstrate improved hepatocyte viability and functionality [15][16][17]. Primary human hepatocytes (PHH) cultured as 3D spheroids maintain tissue-like architecture, cell-cell interactions, and hepatocyte phenotype [18,19], and have therefore successfully been used to model hepatotoxicity [20][21][22], cholestasis [23], steatosis and insulin resistance [24,25], as well as the impact of genetic variants on lipid biosynthesis [26].…”

The application of omics-based human liver platforms for investigating the mechanism of drug-induced hepatotoxicity in vitro

“…HepG2 cells, due to their high mitochondrial DNA and organelles contents, remain a model of choice for the study of compound-induced mitochondrial dysfunction (Poloznikov et al 2018). Applied transcriptomic and proteomic analyses to this cell model, Jiang et al (2015a) and Paemanee et al (2017) explained the mechanisms of mitochondrial dysfunction associated with APAP and nevirapine (NVP) administrations.…”

“…BSEP, NTCP and OCT-1) and phase I/II enzymes (e.g. GSTA 1/2 and GSTM1) in HepG2 cells (Poloznikov et al 2018;Van den Hof et al 2015) challenge the relevance of HepG2-based in vitro models in DILI research (Zeilinger et al 2016).…”

“…Hepatocytes represent around 60% of the total liver cell population (Poloznikov et al 2018). Due to their physiological relevance, PHH (freshly isolated or stably cryopreserved) are commonly accepted as the 'gold standard' for constructing liver models for in vitro drug testing and DILI mechanistic research (Gerets et al 2012).…”

“…However, PHH maintained in quiescent monolayer cultures rapidly dedifferentiate (4-6 h when kept in suspension and 24-48 h when cultured on plates), resulting in a loss of morphological integrity, liver-specific enzyme activities, hepatic functions and cell viability within days (Bell et al 2016;Soldatow et al 2013). Thus, when maintained in suspension or directly seeded onto (collagen-coated) culture plates, the lifespan for PHH is limited and preservation of an in vivo like phenotype of these cells is challenging (Poloznikov et al 2018).…”