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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

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

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

Abbreviations

2D

Two-dimensional

2PP

Two-photon polymerization

3D

Three-dimensional

ADMSCs

Adipose-derived mesenchymal stem cells

ASCs

Adult human stem cells

BMMSCs

Bone marrow mesenchymal stem cells

BMP

Bone morphogenetic protein

BSEP

Bile salt export pump

CFOS

Proto-oncogene c-fos

CYP

Cytochrome P450

ECM

Extracellular matrix

EGR

Early growth response

FGF

Fibroblast growth factor

Gel-MOD

Methacrylamide-gelatin

Gel-MOD-AEMA

Gelatin-methacrylamide-aminoethylmethacrylate

Gel-NB

Gel-Norbornene

hESCs

Human embryonic stem cells

HGF

Hepatic growth factor

hiPSCs

Human induced pluripotent stem cells

HLCs

Hepatocyte-like cells

hMSCs

Human mesenchymal stem/stromal cells

hSKP

Human skin-derived precursors

IEG

Immediate early genes

MenSCs

Menstrual blood stem cells

MPCCs

Micropatterned co-cultures

NTCP

Sodium-taurocholate cotransporting polypeptide

OSM

Oncostatin M

PAI

Plasminogen activator inhibitor

PDMSCs

Placenta-derived mesenchymal stem cells

PHH

Primary human hepatocytes

PRL

Phosphatase of regenerating liver

UCMSCs

Umbilical cord mesenchymal stem cells

Wnt

Wingless-type MMTV integration site

Notes

Acknowledgements

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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