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Int J Mol Med. 2017 Dec;40(6):1759-1771. doi: 10.3892/ijmm.2017.3190. Epub 2017 Oct 16.

Hepatic differentiation of human iPSCs in different 3D models: A comparative study.

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Boehringer Ingelheim Pharma GmbH and Co.KG, Nonclinical Drug Safety Germany, D-88397 Biberach an der Riss, Germany.
Bioreactor Group, Berlin Brandenburg Center for Regenerative Therapies (BCRT), Charité-Universitätsmedizin Berlin, Campus Virchow-Klinikum, D-13353 Berlin, Germany.
Tissue Injury and Repair Group, Chancellor's Building, Edinburgh Medical School, University of Edinburgh, EH164SB Edinburgh, UK.
Institute of Genetic Medicine, University of Newcastle upon Tyne, NE13BZ Newcastle upon Tyne, UK.
Department of Hepatobiliary Surgery and Visceral Transplantation, University of Leipzig, D-04103 Leipzig, Germany.
Boehringer Ingelheim Pharma GmbH and Co.KG, Drug Metabolism and Pharmacokinetics Germany, D-88397 Biberach an der Riss, Germany.


Human induced pluripotent stem cells (hiPSCs) are a promising source from which to derive distinct somatic cell types for in vitro or clinical use. Existent protocols for hepatic differentiation of hiPSCs are primarily based on 2D cultivation of the cells. In the present study, the authors investigated the generation of hiPSC-derived hepatocyte-like cells using two different 3D culture systems: A 3D scaffold-free microspheroid culture system and a 3D hollow-fiber perfusion bioreactor. The differentiation outcome in these 3D systems was compared with that in conventional 2D cultures, using primary human hepatocytes as a control. The evaluation was made based on specific mRNA expression, protein secretion, antigen expression and metabolic activity. The expression of α-fetoprotein was lower, while cytochrome P450 1A2 or 3A4 activities were higher in the 3D culture systems as compared with the 2D differentiation system. Cells differentiated in the 3D bioreactor showed an increased expression of albumin and hepatocyte nuclear factor 4α, as well as secretion of α-1-antitrypsin as compared with the 2D differentiation system, suggesting a higher degree of maturation. In contrast, the 3D scaffold-free microspheroid culture provides an easy and robust method to generate spheroids of a defined size for screening applications, while the bioreactor culture model provides an instrument for complex investigations under physiological-like conditions. In conclusion, the present study introduces two 3D culture systems for stem cell derived hepatic differentiation each demonstrating advantages for individual applications as well as benefits in comparison with 2D cultures.

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