Technological advancements for the development of stem cell-based models for hepatotoxicity testing

Arch Toxicol. 2019 Jul;93(7):1789-1805. doi: 10.1007/s00204-019-02465-y. Epub 2019 Apr 29.

Abstract

Stem cells are characterized by their self-renewal capacity and their ability to differentiate into multiple cell types of the human body. Using directed differentiation strategies, stem cells can now be converted into hepatocyte-like cells (HLCs) and therefore, represent a unique cell source for toxicological applications in vitro. However, the acquired hepatic functionality of stem cell-derived HLCs is still significantly inferior to primary human hepatocytes. One of the main reasons for this is that most in vitro models use traditional two-dimensional (2D) setups where the flat substrata cannot properly mimic the physiology of the human liver. Therefore, 2D-setups are progressively being replaced by more advanced culture systems, which attempt to replicate the natural liver microenvironment, in which stem cells can better differentiate towards HLCs. This review highlights the most recent cell culture systems, including scaffold-free and scaffold-based three-dimensional (3D) technologies and microfluidics that can be employed for culture and hepatic differentiation of stem cells intended for hepatotoxicity testing. These methodologies have shown to improve in vitro liver cell functionality according to the in vivo liver physiology and allow to establish stem cell-based hepatic in vitro platforms for the accurate evaluation of xenobiotics.

Keywords: 2D- and 3D-culture systems; Drug screening; Hepatocyte-like cells; In vitro toxicity; Microfluidics; Stem cells.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Animal Testing Alternatives / methods*
  • Cell Culture Techniques
  • Cell Differentiation / drug effects*
  • Chemical and Drug Induced Liver Injury / etiology*
  • Hepatocytes / cytology
  • Hepatocytes / drug effects*
  • Humans
  • Liver / drug effects*
  • Stem Cells / cytology
  • Stem Cells / drug effects*
  • Xenobiotics / toxicity*

Substances

  • Xenobiotics