Title: Development of a pluripotent stem cell derived neuronal model to identify chemically induced pathway perturbations in relation to neurotoxicity: effects of CREB pathway inhibition
Authors: PISTOLLATO FRANCESCALOUISSE JOCHEMSCELFO BIBIANAMENNECOZZI MILENAACCORDI BenedettaBASSO GiuseppeGASPAR John AntonydasZAGOURA DIMITRABARILARI MANUELAPALOSAARI TainaSACHINIDIS AgapiosBREMER Susanne
Citation: TOXICOLOGY AND APPLIED PHARMACOLOGY vol. 280 no. 2 p. 378-388
Publisher: ACADEMIC PRESS INC ELSEVIER SCIENCE
Publication Year: 2014
JRC N°: JRC86778
ISSN: 0041-008X
URI: http://www.sciencedirect.com/science/article/pii/S0041008X14002993
http://publications.jrc.ec.europa.eu/repository/handle/JRC86778
DOI: 10.1016/j.taap.2014.08.007
Type: Articles in periodicals and books
Abstract: According to the new paradigm shift in toxicity testing, acquisition of knowledge on the mechanisms underlying the toxicity of chemicals, such as perturbations of biological pathways, is of primary interest. Moreover, pluripotent stem cells (PSCs), such as human embryonic stem cells (hESCs) and human induced pluripotent stem cells (hiPSCs), offer a unique opportunity to derive physiologically relevant human cell types to be used in these mechanistic studies. In the present study, we compared the neuronal differentiation propensity of hESCs and hiPSCs aiming to develop tolls for mechanistic neurotoxicity testing. The gene expression and signaling pathway analyses demonstrate the activation of a similar neuronal signature in the two cellular models, particularly indicating that the neuronal survival related cAMP responsive element binding protein (CREB) pathway gets activated upon differentiation. Furthermore, analysis of CREB pathway inhibition, using 2-naphthol-AS-E-phosphate, shows a decrease in neuronal cells as well as an inhibition of neurite outgrowth, synaptogenesis and impairment of electrical activity. These data indicate that inhibition of the CREB pathway can be related to relevant endpoints for neurotoxicity testing in our in vitro cell model, and, as such, qualify the use of this cellular model for mechanism-based toxicity testing
JRC Directorate:Institute for Health and Consumer Protection Historical Collection

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