title: One Standardized Differentiation Procedure Robustly Generates Homogenous Hepatocyte Cultures Displaying Metabolic Diversity from a Large Panel of Human Pluripotent Stem Cells.
abstract: Human hepatocytes display substantial functional inter-individual variation regarding drug metabolizing functions. In order to investigate if this diversity is mirrored in hepatocytes derived from different human pluripotent stem cell (hPSC) lines, we evaluated 25 hPSC lines originating from 24 different donors for hepatic differentiation and functionality. Homogenous hepatocyte cultures could be derived from all hPSC lines using one standardized differentiation procedure. To the best of our knowledge this is the first report of a standardized hepatic differentiation procedure that is generally applicable across a large panel of hPSC lines without any adaptations to individual lines. Importantly, with regard to functional aspects, such as Cytochrome P450 activities, we observed that hepatocytes derived from different hPSC lines displayed inter-individual variation characteristic for primary hepatocytes obtained from different donors, while these activities were highly reproducible between repeated experiments using the same line. Taken together, these data demonstrate the emerging possibility to compile panels of hPSC-derived hepatocytes of particular phenotypes/genotypes relevant for drug metabolism and toxicity studies. Moreover, these findings are of significance for applications within the regenerative medicine field, since our stringent differentiation procedure allows the derivation of homogenous hepatocyte cultures from multiple donors which is a prerequisite for the realization of future personalized stem cell based therapies.
authors.affiliation: Takara Bio Europe AB (former Cellartis AB), Arvid Wallgrens Backe 20, 413 46, Gothenburg, Sweden.|Systems Biology Research Center, School of Bioscience, University of Skövde, Skövde, Sweden.
authors.forename: Annika
authors.initials: A
authors.lastname: Asplund
authors.affiliation: Takara Bio Europe AB (former Cellartis AB), Arvid Wallgrens Backe 20, 413 46, Gothenburg, Sweden.|Novo Nordisk A/S, Bagsværd, Denmark.
authors.forename: Arvind
authors.initials: A
authors.lastname: Pradip
authors.affiliation: Takara Bio Europe AB (former Cellartis AB), Arvid Wallgrens Backe 20, 413 46, Gothenburg, Sweden.
authors.forename: Mariska
authors.initials: M
authors.lastname: van Giezen
authors.affiliation: Takara Bio Europe AB (former Cellartis AB), Arvid Wallgrens Backe 20, 413 46, Gothenburg, Sweden.
authors.forename: Anders
authors.initials: A
authors.lastname: Aspegren
authors.affiliation: Takara Bio Europe AB (former Cellartis AB), Arvid Wallgrens Backe 20, 413 46, Gothenburg, Sweden.
authors.forename: Helena
authors.initials: H
authors.lastname: Choukair
authors.affiliation: Takara Bio Europe AB (former Cellartis AB), Arvid Wallgrens Backe 20, 413 46, Gothenburg, Sweden.
authors.forename: Marie
authors.initials: M
authors.lastname: Rehnström
authors.affiliation: Takara Bio Europe AB (former Cellartis AB), Arvid Wallgrens Backe 20, 413 46, Gothenburg, Sweden.
authors.forename: Susanna
authors.initials: S
authors.lastname: Jacobsson
authors.affiliation: Systems Biology Research Center, School of Bioscience, University of Skövde, Skövde, Sweden.
authors.forename: Nidal
authors.initials: N
authors.lastname: Ghosheh
authors.affiliation: Takara Bio Europe AB (former Cellartis AB), Arvid Wallgrens Backe 20, 413 46, Gothenburg, Sweden.
authors.forename: Dorra
authors.initials: D
authors.lastname: El Hajjam
authors.affiliation: Takara Bio Europe AB (former Cellartis AB), Arvid Wallgrens Backe 20, 413 46, Gothenburg, Sweden.|Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
authors.forename: Sandra
authors.initials: S
authors.lastname: Holmgren
authors.affiliation: Takara Bio Europe AB (former Cellartis AB), Arvid Wallgrens Backe 20, 413 46, Gothenburg, Sweden.
authors.forename: Susanna
authors.initials: S
authors.lastname: Larsson
authors.affiliation: Takara Bio Europe AB (former Cellartis AB), Arvid Wallgrens Backe 20, 413 46, Gothenburg, Sweden.
authors.forename: Jörg
authors.initials: J
authors.lastname: Benecke
authors.affiliation: Takara Bio Europe AB (former Cellartis AB), Arvid Wallgrens Backe 20, 413 46, Gothenburg, Sweden.
authors.forename: Mariela
authors.initials: M
authors.lastname: Butron
authors.affiliation: Takara Bio Europe AB (former Cellartis AB), Arvid Wallgrens Backe 20, 413 46, Gothenburg, Sweden.
authors.forename: Annelie
authors.initials: A
authors.lastname: Wigander
authors.affiliation: Takara Bio Europe AB (former Cellartis AB), Arvid Wallgrens Backe 20, 413 46, Gothenburg, Sweden.
authors.forename: Karin
authors.initials: K
authors.lastname: Noaksson
authors.affiliation: Systems Biology Research Center, School of Bioscience, University of Skövde, Skövde, Sweden.|AstraZeneca R&D, GMD CVMD GMed, Mölndal, Sweden.
authors.forename: Peter
authors.initials: P
authors.lastname: Sartipy
authors.affiliation: Takara Bio Europe AB (former Cellartis AB), Arvid Wallgrens Backe 20, 413 46, Gothenburg, Sweden.|NovaHep AB, Arvid Wallgrens Backe 20, Gothenburg, Sweden.
authors.forename: Petter
authors.initials: P
authors.lastname: Björquist
authors.affiliation: Takara Bio Europe AB (former Cellartis AB), Arvid Wallgrens Backe 20, 413 46, Gothenburg, Sweden.
authors.forename: Josefina
authors.initials: J
authors.lastname: Edsbagge
authors.affiliation: Takara Bio Europe AB (former Cellartis AB), Arvid Wallgrens Backe 20, 413 46, Gothenburg, Sweden. barbara.kuppers_munther@takara-clontech.eu.|Systems Biology Research Center, School of Bioscience, University of Skövde, Skövde, Sweden. barbara.kuppers_munther@takara-clontech.eu.
authors.forename: Barbara
authors.identifier: http://orcid.org/0000-0003-4217-9355
authors.initials: B
authors.lastname: Küppers-Munther
mesh_terms: D018929:Cell Culture Techniques / Q000592:standards*; D002454:Cell Differentiation / Q000187:drug effects; D002460:Cell Line; D003470:Culture Media / Q000494:pharmacology*; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics* / Q000378:metabolism; D015870:Gene Expression; D022781:Hepatocytes / Q000166:cytology / Q000187:drug effects* / Q000201:enzymology; D006801:Humans; D008658:Inactivation, Metabolic / Q000235:genetics; D007527:Isoenzymes / Q000235:genetics / Q000378:metabolism; D007621:Karyotyping; D009928:Organ Specificity; D039904:Pluripotent Stem Cells / Q000166:cytology / Q000187:drug effects* / Q000201:enzymology; D061251:Primary Cell Culture; D015203:Reproducibility of Results
chemical_list: D003470:Culture Media; D007527:Isoenzymes; D003577:Cytochrome P-450 Enzyme System
keywords: Cellular therapy; Hepatocyte differentiation; Human embyronic stem cells; Human induced pluripotent stem cells; Liver; Toxicity