Abstract
BackgroundHuman 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.MethodsThree 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.ResultsThe 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” (D p) and “developmental index” (D i).ConclusionsDespite differences in genes deregulated by VPA, uniform D i values were obtained for all three cell lines. Given that the D i values for VPA were similar for hESCs and hiPSCs, D i can be used for robust hazard identification, irrespective of whether hESCs or hiPSCs are used in the test systems.Electronic supplementary materialThe online version of this article (doi:10.1186/s13287-016-0449-2) contains supplementary material, which is available to authorized users.
Highlights
Human embryonic stem cells partially recapitulate early embryonic three germ layer development, allowing testing of potential teratogenic hazards
Given that a conclusion as to whether human induced pluripotent stem cells (hiPSCs) can replace human embryonic stem cells (hESCs) for developmental toxicity testing based on a gene ontology categories (GOs) analysis is not possible, we proposed the use of two indices: developmental potency” (Dp) and developmental index” (Di) based on valproic acid (VPA) deregulated developmental genes
Our results suggest that even though hESCs and hiPSCs show common and distinct differentiation transcriptomic profiles, the developmental hazard of the test compounds can be determined by estimating Di, irrespective of whether hESCs or hiPSCs are used in the test system
Summary
Human embryonic stem cells (hESCs) partially recapitulate early embryonic three germ layer development, allowing testing of potential teratogenic hazards. The present transitional teratogenicity assessment methods are limited because: (1) interspecies differences in both in vitro and in vivo animal-based test systems do not optimally predict human relevant teratogenic drug candidates; (2) traditional methodologies involve extensive animal studies, making tests costly and timeconsuming; and (3) traditional approaches are not efficient given that they only allow testing of a limited number of compounds at a time, even though the number of the drug candidates increases markedly each year (http://cen.acs.org/articles/94/i5/Year-New-Drugs.html) Such limitations have resulted in several drugs being withdrawn from the market because of toxic effects to humans [1]. These systems have already been applied in numerous studies to identify and characterize developmental toxicants [12,13,14,15]
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