title: Prediction of Differentiation Tendency Toward Hepatocytes from Gene Expression in Undifferentiated Human Pluripotent Stem Cells.
abstract: Functional hepatocytes derived from human pluripotent stem cells (hPSCs) have potential as tools for predicting drug-induced hepatotoxicity in the early phases of drug development. However, the propensity of hPSC lines to differentiate into specific lineages is reported to differ. The ability to predict low propensity of hPSCs to differentiate into hepatocytes would facilitate the selection of useful hPSC clones and substantially accelerate development of hPSC-derived hepatocytes for pharmaceutical research. In this study, we compared the expression of genes associated with hepatic differentiation in five hPSC lines including human ES cell line, H9, which is known to differentiate into hepatocytes, and an hPSC line reported with a poor propensity for hepatic differentiation. Genes distinguishing between undifferentiated hPSCs, hPSC-derived hepatoblast-like differentiated cells, and primary human hepatocytes were drawn by two-way cluster analysis. The order of expression levels of genes in undifferentiated hPSCs was compared with that in hPSC-derived hepatoblast-like cells. Three genes were selected as predictors of low propensity for hepatic differentiation. Expression of these genes was investigated in 23 hPSC clones. Review of representative cells by induction of hepatic differentiation suggested that low prediction scores were linked with low hepatic differentiation. Thus, our model using gene expression ranking and bioinformatic analysis could reasonably predict poor differentiation propensity of hPSC lines.
authors.affiliation: 1 Laboratory of Stem Cell Cultures, National Institutes of Biomedical Innovation , Health and Nutrition, Osaka, Japan .
authors.forename: Kana
authors.initials: K
authors.lastname: Yanagihara
authors.affiliation: 1 Laboratory of Stem Cell Cultures, National Institutes of Biomedical Innovation , Health and Nutrition, Osaka, Japan .
authors.forename: Yujung
authors.initials: Y
authors.lastname: Liu
authors.affiliation: 2 Department of Basic Medicinal Sciences, Graduate School of Pharmaceutical Sciences, Nagoya University , Nagoya, Japan .
authors.forename: Kei
authors.initials: K
authors.lastname: Kanie
authors.affiliation: 3 Laboratory of Biochemistry and Molecular Biology, Graduate School of Pharmaceutical Sciences, Osaka University , Osaka, Japan .|4 The Keihanshin Consortium for Fostering the Next Generation of Global Leaders in Research (K-CONNEX), Kyoto University , Kyoto, Japan .|5 Laboratory of Hepatocyte Regulation, National Institutes of Biomedical Innovation , Health and Nutrition, Osaka, Japan .
authors.forename: Kazuo
authors.initials: K
authors.lastname: Takayama
authors.affiliation: 1 Laboratory of Stem Cell Cultures, National Institutes of Biomedical Innovation , Health and Nutrition, Osaka, Japan .|6 Department of Oral Biology & Engineering Integrated Health Sciences, Institute of Biomedical and Health Sciences, Hiroshima University , Hiroshima, Japan .
authors.forename: Minako
authors.initials: M
authors.lastname: Kokunugi
authors.affiliation: 1 Laboratory of Stem Cell Cultures, National Institutes of Biomedical Innovation , Health and Nutrition, Osaka, Japan .
authors.forename: Mitsuhi
authors.initials: M
authors.lastname: Hirata
authors.affiliation: 1 Laboratory of Stem Cell Cultures, National Institutes of Biomedical Innovation , Health and Nutrition, Osaka, Japan .
authors.forename: Takayuki
authors.initials: T
authors.lastname: Fukuda
authors.affiliation: 1 Laboratory of Stem Cell Cultures, National Institutes of Biomedical Innovation , Health and Nutrition, Osaka, Japan .
authors.forename: Mika
authors.initials: M
authors.lastname: Suga
authors.affiliation: 6 Department of Oral Biology & Engineering Integrated Health Sciences, Institute of Biomedical and Health Sciences, Hiroshima University , Hiroshima, Japan .
authors.forename: Hiroki
authors.initials: H
authors.lastname: Nikawa
authors.affiliation: 3 Laboratory of Biochemistry and Molecular Biology, Graduate School of Pharmaceutical Sciences, Osaka University , Osaka, Japan .|5 Laboratory of Hepatocyte Regulation, National Institutes of Biomedical Innovation , Health and Nutrition, Osaka, Japan .|7 Global Center for Medical Engineering and Informatics, Osaka University , Osaka, Japan .
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Mizuguchi
authors.affiliation: 2 Department of Basic Medicinal Sciences, Graduate School of Pharmaceutical Sciences, Nagoya University , Nagoya, Japan .
authors.forename: Ryuji
authors.initials: R
authors.lastname: Kato
authors.affiliation: 1 Laboratory of Stem Cell Cultures, National Institutes of Biomedical Innovation , Health and Nutrition, Osaka, Japan .
authors.forename: Miho K
authors.initials: MK
authors.lastname: Furue
mesh_terms: D002454:Cell Differentiation / Q000235:genetics*; D002460:Cell Line; D019070:Cell Lineage / Q000235:genetics; D016000:Cluster Analysis; D004707:Endoderm / Q000166:cytology; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D056726:Genetic Association Studies; D022781:Hepatocytes / Q000166:cytology* / Q000378:metabolism; D006801:Humans; D039904:Pluripotent Stem Cells / Q000166:cytology* / Q000378:metabolism
keywords: cell differentiation; endoderm; hepatocyte; human embryonic stem cells; human induced pluripotent stem cells