Characterization of Human Induced Pluripotent Stem Cell-Derived Hepatocytes with Mature Features and Potential for Modeling Metabolic Diseases
by
Gustav Holmgren 1,†
, Benjamin Ulfenborg 1,*,†, Annika Asplund 2, Karin Toet 3, Christian X Andersson 2, Ann Hammarstedt 4,‡, Roeland Hanemaaijer 3, Barbara Küppers-Munther 2,* and Jane Synnergren 1
Gustav Holmgren 1,†, Benjamin Ulfenborg 1,*,†, Annika Asplund 2, Karin Toet 3, Christian X Andersson 2, Ann Hammarstedt 4,‡, Roeland Hanemaaijer 3, Barbara Küppers-Munther 2,* and Jane Synnergren 1
1
Systems biology research center, School of Bioscience, University of Skövde, 54128 Skövde, Sweden
2
R&D, Hepatocyte Product Development, Takara Bio Europe AB, 41346 Gothenburg, Sweden
3
Department of Metabolic Health Research, TNO, 2333 Leiden, The Netherlands
4
The Lundberg Laboratory for Diabetes Research, Departments of Molecular and Clinical Medicine, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, 41345 Gothenburg, Sweden
*
Authors to whom correspondence should be addressed.
†
These authors contributed equally to this work.
‡
Present address: AstraZeneca Gothenburg, BioPharmaceuticals R&D, Late-stage Development, 43183 Mölndal, Sweden.
Int. J. Mol. Sci. 2020, 21(2), 469; https://doi.org/10.3390/ijms21020469
Received: 13 November 2019 / Revised: 6 January 2020 / Accepted: 7 January 2020 / Published: 11 January 2020
(This article belongs to the Special Issue From hIPSCs to Adult Cells in a Dish: Promises and Pitfalls)
There is a strong anticipated future for human induced pluripotent stem cell-derived hepatocytes (hiPS-HEP), but so far, their use has been limited due to insufficient functionality. We investigated the potential of hiPS-HEP as an in vitro model for metabolic diseases by combining transcriptomics with multiple functional assays. The transcriptomics analysis revealed that 86% of the genes were expressed at similar levels in hiPS-HEP as in human primary hepatocytes (hphep). Adult characteristics of the hiPS-HEP were confirmed by the presence of important hepatocyte features, e.g., Albumin secretion and expression of major drug metabolizing genes. Normal energy metabolism is crucial for modeling metabolic diseases, and both transcriptomics data and functional assays showed that hiPS-HEP were similar to hphep regarding uptake of glucose, low-density lipoproteins (LDL), and fatty acids. Importantly, the inflammatory state of the hiPS-HEP was low under standard conditions, but in response to lipid accumulation and ER stress the inflammation marker tumor necrosis factor α (TNFα) was upregulated. Furthermore, hiPS-HEP could be co-cultured with primary hepatic stellate cells both in 2D and in 3D spheroids, paving the way for using these co-cultures for modeling non-alcoholic steatohepatitis (NASH). Taken together, hiPS-HEP have the potential to serve as an in vitro model for metabolic diseases. Furthermore, differently expressed genes identified in this study can serve as targets for future improvements of the hiPS-HEP.
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Keywords:
human induced pluripotent stem cells; human stem cell-derived hepatocytes; in vitro; metabolic diseases; transcriptomics; maturation; characterization
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MDPI and ACS Style
Holmgren, G.; Ulfenborg, B.; Asplund, A.; Toet, K.; Andersson, C.X.; Hammarstedt, A.; Hanemaaijer, R.; Küppers-Munther, B.; Synnergren, J. Characterization of Human Induced Pluripotent Stem Cell-Derived Hepatocytes with Mature Features and Potential for Modeling Metabolic Diseases. Int. J. Mol. Sci. 2020, 21, 469.
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