title: Comparison of a teratogenic transcriptome-based predictive test based on human embryonic versus inducible pluripotent stem cells.
abstract: Human embryonic stem cells (hESCs) partially recapitulate early embryonic three germ layer development, allowing testing of potential teratogenic hazards. Because use of hESCs is ethically debated, we investigated the potential for human induced pluripotent stem cells (hiPSCs) to replace hESCs in such tests.
  
  
  
  Three cell lines, comprising hiPSCs (foreskin and IMR90) and hESCs (H9) were differentiated for 14 days. Their transcriptome profiles were obtained on day 0 and day 14 and analyzed by comprehensive bioinformatics tools.
  
  
  
  The transcriptomes on day 14 showed that more than 70% of the "developmental genes" (regulated genes with > 2-fold change on day 14 compared to day 0) exhibited variability among cell lines. The developmental genes belonging to all three cell lines captured biological processes and KEGG pathways related to all three germ layer embryonic development. In addition, transcriptome profiles were obtained after 14 days of exposure to teratogenic valproic acid (VPA) during differentiation. Although the differentially regulated genes between treated and untreated samples showed more than 90% variability among cell lines, VPA clearly antagonized the expression of developmental genes in all cell lines: suppressing upregulated developmental genes, while inducing downregulated ones. To quantify VPA-disturbed development based on developmental genes, we estimated the "developmental potency" (Dp) and "developmental index" (Di).
  
  
  
  Despite differences in genes deregulated by VPA, uniform Divalues were obtained for all three cell lines. Given that the Divalues for VPA were similar for hESCs and hiPSCs, Dican be used for robust hazard identification, irrespective of whether hESCs or hiPSCs are used in the test systems.
authors.affiliation: Institute of Neurophysiology and Center for Molecular Medicine Cologne (CMMC), University of Cologne (UKK), Robert-Koch-Str. 39, 50931, Cologne, Germany.
authors.forename: Vaibhav
authors.initials: V
authors.lastname: Shinde
authors.affiliation: Institute of Neurophysiology and Center for Molecular Medicine Cologne (CMMC), University of Cologne (UKK), Robert-Koch-Str. 39, 50931, Cologne, Germany.
authors.forename: Sureshkumar
authors.initials: S
authors.lastname: Perumal Srinivasan
authors.affiliation: Institute of Neurophysiology and Center for Molecular Medicine Cologne (CMMC), University of Cologne (UKK), Robert-Koch-Str. 39, 50931, Cologne, Germany.
authors.forename: Margit
authors.initials: M
authors.lastname: Henry
authors.affiliation: Institute of Neurophysiology and Center for Molecular Medicine Cologne (CMMC), University of Cologne (UKK), Robert-Koch-Str. 39, 50931, Cologne, Germany.
authors.forename: Tamara
authors.initials: T
authors.lastname: Rotshteyn
authors.affiliation: Institute of Neurophysiology and Center for Molecular Medicine Cologne (CMMC), University of Cologne (UKK), Robert-Koch-Str. 39, 50931, Cologne, Germany.
authors.forename: Jürgen
authors.initials: J
authors.lastname: Hescheler
authors.affiliation: Department of Statistics, Technical University of Dortmund University, 44227, Dortmund, Germany.
authors.forename: Jörg
authors.initials: J
authors.lastname: Rahnenführer
authors.affiliation: Department of Statistics, Technical University of Dortmund University, 44227, Dortmund, Germany.
authors.forename: Marianna
authors.initials: M
authors.lastname: Grinberg
authors.affiliation: Integrative Research Institute for the Life Sciences, Institute for Theoretical Biology, Humboldt University, 10115, Berlin, Germany.
authors.forename: Johannes
authors.initials: J
authors.lastname: Meisig
authors.affiliation: Integrative Research Institute for the Life Sciences, Institute for Theoretical Biology, Humboldt University, 10115, Berlin, Germany.
authors.forename: Nils
authors.initials: N
authors.lastname: Blüthgen
authors.affiliation: Doerenkamp-Zbinden Chair for In Vitro Toxicology and Biomedicine, University of Konstanz, Box: M657, 78457, Konstanz, Germany.
authors.forename: Tanja
authors.initials: T
authors.lastname: Waldmann
authors.affiliation: Doerenkamp-Zbinden Chair for In Vitro Toxicology and Biomedicine, University of Konstanz, Box: M657, 78457, Konstanz, Germany.
authors.forename: Marcel
authors.initials: M
authors.lastname: Leist
authors.affiliation: Leibniz Research Centre for Working Environment and Human Factors at the Technical University of Dortmund (IfADo), 44139, Dortmund, Germany.
authors.forename: Jan Georg
authors.initials: JG
authors.lastname: Hengstler
authors.affiliation: Institute of Neurophysiology and Center for Molecular Medicine Cologne (CMMC), University of Cologne (UKK), Robert-Koch-Str. 39, 50931, Cologne, Germany. a.sachinidis@uni-koeln.de.
authors.forename: Agapios
authors.initials: A
authors.lastname: Sachinidis
mesh_terms: D002454:Cell Differentiation / Q000187:drug effects; D002460:Cell Line; D015536:Down-Regulation / Q000187:drug effects; D053595:Embryonic Stem Cells / Q000166:cytology* / Q000187:drug effects*; D005855:Germ Layers / Q000166:cytology / Q000187:drug effects; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000166:cytology* / Q000187:drug effects*; D013723:Teratogens / Q000494:pharmacology*; D059467:Transcriptome / Q000187:drug effects*; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D013723:Teratogens
keywords: Cytotoxic agents; Differentiation; Embryoid bodies; Embryonic stem cells; Genomics; Induced pluripotent stem cells