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

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• 作者：Robim M. Rodrigues ; Steven Branson ; Veerle De Boe…
• 关键词：Postnatal stem cells ; hSKP ; Steatosis ; In vitro toxicology
• 刊名：Archives of Toxicology
• 出版年：2016
• 出版时间：March 2016
• 年：2016
• 卷：90
• 期：3
• 页码：677-689
• 全文大小：4,037 KB
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• 作者单位：Robim M. Rodrigues (1)
  Steven Branson (1)
  Veerle De Boe (2)
  Agapios Sachinidis (3)
  Vera Rogiers (1)
  Joery De Kock (1)
  Tamara Vanhaecke (1)
  
  1. Department of In Vitro Toxicology and Dermato-Cosmetology, Faculty of Medicine and Pharmacy, Center for Pharmaceutical Research, Vrije Universiteit Brussel, Brussels, Belgium
  2. Department of Urology, UZ Brussel, Brussels, Belgium
  3. Institute of Neurophysiology, Center of Physiology, University of Cologne, Cologne, Germany
  
• 刊物主题：Pharmacology/Toxicology; Occupational Medicine/Industrial Medicine; Environmental Health; Biomedicine general;
• 出版者：Springer Berlin Heidelberg
• ISSN：1432-0738

文摘

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.