Development of a pluripotent stem cell derived neuronal model to identify chemically induced pathway perturbations in relation to neurotoxicity: effects of CREB pathway inhibition

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

PISTOLLATO Francesca;  LOUISSE Jochem;  SCELFO Bibiana;  MENNECOZZI Milena;  ACCORDI Benedetta;  BASSO Giuseppe;  GASPAR John Antonydas;  ZAGOURA Dimitra;  BARILARI Manuela;  PALOSAARI Taina;  SACHINIDIS Agapios;  BREMER Susanne; 

2014-10-14

ACADEMIC PRESS INC ELSEVIER SCIENCE

JRC86778

0041-008X,   

http://www.sciencedirect.com/science/article/pii/S0041008X14002993,    https://publications.jrc.ec.europa.eu/repository/handle/JRC86778,   

10.1016/j.taap.2014.08.007,