Human stem cell-derived hepatocytes: breakthrough of an expedient tool for preclinical assessment of drug-induced liver injury?

Steatosis, also known as fatty liver disease (FLD), is a disorder in which the lipid metabolism of the liver is disturbed, leading to the abnormal retention of lipids in hepatocytes. FLD can be induced by several drugs, and although it is mostly asymptomatic, it can lead to steatohepatitis, which is associated with liver inflammation and damage. Drug-induced liver injury is currently the major cause of postmarketing withdrawal of pharmaceuticals and discontinuation of the development of new chemical entities. Therefore, the potential induction of steatosis must be evaluated during preclinical drug development. However, robust human-relevant in vitro models are lacking. In the present study, we explore the applicability of hepatic cells (hSKP-HPCs) derived from postnatal skin precursors, a stem cell population residing in human dermis, to investigate the steatosis-inducing effects of sodium valproate (Na-VPA). Exposure of hSKP-HPC to sub-cytotoxic concentrations of this reference steatogenic compound showed an increased intracellular accumulation of lipid droplets, and the modulation of key factors involved in lipid metabolism. Using a toxicogenomics approach, we further compared Na-VPA-treated hSKP-HPC and Na-VPA-treated primary human hepatocytes to liver samples from patients suffering from mild and advanced steatosis. Our data show that in hSKP-HPC exposed to Na-VPA and liver samples of patients suffering from mild steatosis, but not in primary human hepatocytes, "liver steatosis" was efficiently identified as a toxicological response. These findings illustrate the potential of hSKP-HPC as a human-relevant in vitro model to identify hepatosteatotic effects of chemical compounds.

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In vitro assessment of drug-induced liver steatosis based on human dermal stem cell-derived hepatic cells

Rodrigues

Branson

Boe

et al. 2015

Arch Toxicol

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Identification of potential biomarkers of hepatitis B-induced acute liver failure using hepatic cells derived from human skin precursors

Rodrigues

Sachinidis

Boe

et al. 2015

Toxicology in Vitro

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Toxicogenomics-based prediction of acetaminophen-induced liver injury using human hepatic cell systems

et al. 2016

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Human stem cell-derived hepatocytes: breakthrough of an expedient tool for preclinical assessment of drug-induced liver injury?

Cited by 4 publications

References 15 publications

In vitro assessment of drug-induced liver steatosis based on human dermal stem cell-derived hepatic cells

In vitro assessment of drug-induced liver steatosis based on human dermal stem cell-derived hepatic cells

Identification of potential biomarkers of hepatitis B-induced acute liver failure using hepatic cells derived from human skin precursors

Toxicogenomics-based prediction of acetaminophen-induced liver injury using human hepatic cell systems

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