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      Definition of transcriptome-based indices for quantitative characterization of chemically disturbed stem cell development: introduction of the STOP-Tox ukn and STOP-Tox ukk tests

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          Abstract

          Stem cell-based in vitro test systems can recapitulate specific phases of human development. In the UKK test system, human pluripotent stem cells (hPSCs) randomly differentiate into cells of the three germ layers and their derivatives. In the UKN1 test system, hPSCs differentiate into early neural precursor cells. During the normal differentiation period (14 days) of the UKK system, 570 genes [849 probe sets (PSs)] were regulated >fivefold; in the UKN1 system (6 days), 879 genes (1238 PSs) were regulated. We refer to these genes as ‘developmental genes’. In the present study, we used genome-wide expression data of 12 test substances in the UKK and UKN1 test systems to understand the basic principles of how chemicals interfere with the spontaneous transcriptional development in both test systems. The set of test compounds included six histone deacetylase inhibitors (HDACis), six mercury-containing compounds (‘mercurials’) and thalidomide. All compounds were tested at the maximum non-cytotoxic concentration, while valproic acid and thalidomide were additionally tested over a wide range of concentrations. In total, 242 genes (252 PSs) in the UKK test system and 793 genes (1092 PSs) in the UKN1 test system were deregulated by the 12 test compounds. We identified sets of ‘diagnostic genes’ appropriate for the identification of the influence of HDACis or mercurials. Test compounds that interfered with the expression of developmental genes usually antagonized their spontaneous development, meaning that up-regulated developmental genes were suppressed and developmental genes whose expression normally decreases were induced. The fraction of compromised developmental genes varied widely between the test compounds, and it reached up to 60 %. To quantitatively describe disturbed development on a genome-wide basis, we recommend a concept of two indices, ‘developmental potency’ ( D p) and ‘developmental index’ ( D i), whereby D p is the fraction of all developmental genes that are up- or down-regulated by a test compound, and D i is the ratio of overrepresentation of developmental genes among all genes deregulated by a test compound. The use of D i makes hazard identification more sensitive because some compounds compromise the expression of only a relatively small number of genes but have a high propensity to deregulate developmental genes specifically, resulting in a low D p but a high D i. In conclusion, the concept based on the indices D p and D i offers the possibility to quantitatively express the propensity of test compounds to interfere with normal development.

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          The online version of this article (doi:10.1007/s00204-016-1741-8) contains supplementary material, which is available to authorized users.

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          Most cited references 77

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          CellNet: network biology applied to stem cell engineering.

          Somatic cell reprogramming, directed differentiation of pluripotent stem cells, and direct conversions between differentiated cell lineages represent powerful approaches to engineer cells for research and regenerative medicine. We have developed CellNet, a network biology platform that more accurately assesses the fidelity of cellular engineering than existing methodologies and generates hypotheses for improving cell derivations. Analyzing expression data from 56 published reports, we found that cells derived via directed differentiation more closely resemble their in vivo counterparts than products of direct conversion, as reflected by the establishment of target cell-type gene regulatory networks (GRNs). Furthermore, we discovered that directly converted cells fail to adequately silence expression programs of the starting population and that the establishment of unintended GRNs is common to virtually every cellular engineering paradigm. CellNet provides a platform for quantifying how closely engineered cell populations resemble their target cell type and a rational strategy to guide enhanced cellular engineering.
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            The influence of the proinflammatory cytokine, osteopontin, on autoimmune demyelinating disease.

            Multiple sclerosis is a demyelinating disease, characterized by inflammation in the brain and spinal cord, possibly due to autoimmunity. Large-scale sequencing of cDNA libraries, derived from plaques dissected from brains of patients with multiple sclerosis (MS), indicated an abundance of transcripts for osteopontin (OPN). Microarray analysis of spinal cords from rats paralyzed by experimental autoimmune encephalomyelitis (EAE), a model of MS, also revealed increased OPN transcripts. Osteopontin-deficient mice were resistant to progressive EAE and had frequent remissions, and myelin-reactive T cells in OPN-/- mice produced more interleukin 10 and less interferon-gamma than in OPN+/+ mice. Osteopontin thus appears to regulate T helper cell-1 (TH1)-mediated demyelinating disease, and it may offer a potential target in blocking development of progressive MS.
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              Alternative (non-animal) methods for cosmetics testing: current status and future prospects-2010.

              The 7th amendment to the EU Cosmetics Directive prohibits to put animal-tested cosmetics on the market in Europe after 2013. In that context, the European Commission invited stakeholder bodies (industry, non-governmental organisations, EU Member States, and the Commission's Scientific Committee on Consumer Safety) to identify scientific experts in five toxicological areas, i.e. toxicokinetics, repeated dose toxicity, carcinogenicity, skin sensitisation, and reproductive toxicity for which the Directive foresees that the 2013 deadline could be further extended in case alternative and validated methods would not be available in time. The selected experts were asked to analyse the status and prospects of alternative methods and to provide a scientifically sound estimate of the time necessary to achieve full replacement of animal testing. In summary, the experts confirmed that it will take at least another 7-9 years for the replacement of the current in vivo animal tests used for the safety assessment of cosmetic ingredients for skin sensitisation. However, the experts were also of the opinion that alternative methods may be able to give hazard information, i.e. to differentiate between sensitisers and non-sensitisers, ahead of 2017. This would, however, not provide the complete picture of what is a safe exposure because the relative potency of a sensitiser would not be known. For toxicokinetics, the timeframe was 5-7 years to develop the models still lacking to predict lung absorption and renal/biliary excretion, and even longer to integrate the methods to fully replace the animal toxicokinetic models. For the systemic toxicological endpoints of repeated dose toxicity, carcinogenicity and reproductive toxicity, the time horizon for full replacement could not be estimated.
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                Author and article information

                Contributors
                xx49 231 1084 348 , hengstler@ifado.de
                marcel.leist@uni-konstanz.de
                a.sachinidis@uni-koeln.de
                Journal
                Arch Toxicol
                Arch. Toxicol
                Archives of Toxicology
                Springer Berlin Heidelberg (Berlin/Heidelberg )
                0340-5761
                1432-0738
                17 May 2016
                17 May 2016
                2017
                : 91
                : 2
                : 839-864
                Affiliations
                [1 ]ISNI 0000 0000 8580 3777, GRID grid.6190.e, Institute of Neurophysiology and Centre for Molecular Medicine Cologne (CMMC), , University of Cologne (UKK), ; Robert-Koch-Str. 39, 50931 Cologne, Germany
                [2 ]ISNI 0000 0001 0658 7699, GRID grid.9811.1, Doerenkamp-Zbinden Chair for In Vitro Toxicology and Biomedicine, , University of Konstanz, ; Box: M657, 78457 Constance, Germany
                [3 ]ISNI 0000 0001 0658 7699, GRID grid.9811.1, Konstanz Graduate School Chemical Biology KORS-CB, , University of Konstanz, ; 78457 Constance, Germany
                [4 ]ISNI 0000 0001 0416 9637, GRID grid.5675.1, Department of Statistics, , TU Dortmund University, ; Dortmund, Germany
                [5 ]ISNI 0000 0001 0416 9637, GRID grid.5675.1, Leibniz Research Centre for Working Environment and Human Factors at the Technical, , University of Dortmund (IfADo), ; Ardeystrasse 67, 44139 Dortmund, Germany
                [6 ]ISNI 0000 0001 2218 4662, GRID grid.6363.0, Institute of Pathology, , Charité Universitätsmedizin, ; 10117 Berlin, Germany
                [7 ]ISNI 0000 0001 2248 7639, GRID grid.7468.d, Integrative Research Institute for the Life Sciences, Institute for Theoretical Biology, , Humboldt Universität, ; 10115 Berlin, Germany
                [8 ]ISNI 0000 0001 2190 4373, GRID grid.7700.0, Centre for Organismal Studies, , Heidelberg University, ; 69120 Heidelberg, Germany
                Article
                1741
                10.1007/s00204-016-1741-8
                5306084
                27188386
                © The Author(s) 2016

                Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.

                Funding
                Funded by: FundRef http://dx.doi.org/10.13039/501100002347, Bundesministerium für Bildung und Forschung;
                Award ID: SysDT
                Award ID: SysDT
                Award Recipient :
                Categories
                In vitro Systems
                Custom metadata
                © Springer-Verlag Berlin Heidelberg 2017

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