Archives of Toxicology

, Volume 93, Issue 7, pp 1789–1805 | Cite as

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

  • Alessandra Natale
  • Koen Vanmol
  • Aysu Arslan
  • Sandra Van Vlierberghe
  • Peter Dubruel
  • Jürgen Van Erps
  • Hugo Thienpont
  • Matij Buzgo
  • Joost Boeckmans
  • Joery De Kock
  • Tamara Vanhaecke
  • Vera Rogiers
  • Robim M. RodriguesEmail author
Review Article


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.


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





Two-photon polymerization




Adipose-derived mesenchymal stem cells


Adult human stem cells


Bone marrow mesenchymal stem cells


Bone morphogenetic protein


Bile salt export pump


Proto-oncogene c-fos


Cytochrome P450


Extracellular matrix


Early growth response


Fibroblast growth factor








Human embryonic stem cells


Hepatic growth factor


Human induced pluripotent stem cells


Hepatocyte-like cells


Human mesenchymal stem/stromal cells


Human skin-derived precursors


Immediate early genes


Menstrual blood stem cells


Micropatterned co-cultures


Sodium-taurocholate cotransporting polypeptide


Oncostatin M


Plasminogen activator inhibitor


Placenta-derived mesenchymal stem cells


Primary human hepatocytes


Phosphatase of regenerating liver


Umbilical cord mesenchymal stem cells


Wingless-type MMTV integration site



This work was supported by grants from the ‘Chair Mireille Aerens for alternative methods development’, the Research Foundation-Vlaanderen (FWO) (G030217N and 12H2216N) and Leef milieu Brussel (BIM, SUB/2017/BEA/VUB).


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Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  • Alessandra Natale
    • 1
  • Koen Vanmol
    • 2
  • Aysu Arslan
    • 3
  • Sandra Van Vlierberghe
    • 2
    • 3
  • Peter Dubruel
    • 3
  • Jürgen Van Erps
    • 2
  • Hugo Thienpont
    • 2
  • Matij Buzgo
    • 4
  • Joost Boeckmans
    • 1
  • Joery De Kock
    • 1
  • Tamara Vanhaecke
    • 1
  • Vera Rogiers
    • 1
  • Robim M. Rodrigues
    • 1
    Email author
  1. 1.Department of In Vitro Toxicology and Dermato-Cosmetology (IVTD)Vrije Universiteit BrusselBrusselsBelgium
  2. 2.Brussels Photonics (B-PHOT)Vrije Universiteit Brussel and Flanders MakeBrusselsBelgium
  3. 3.Polymer Chemistry and Biomaterials Group (PBM), Centre of Macromolecular ChemistryGhent UniversityGhentBelgium
  4. 4.InocurePragueCzech Republic

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