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

According to the advocated paradigm shift in toxicology, acquisition of knowledge on the mechanisms underlying the toxicity of chemicals, such as perturbations of biological pathways, is of primary interest. Pluripotent stem cells (PSCs), such as human embryonic stem cells (hESCs) and human induced...

Full description

Saved in:
Bibliographic Details
Published in:Toxicology and applied pharmacology 2014, Vol.280 (2)
Main Authors: Pistollato, F, Louisse, J, Scelfo, B, Mennecozzi, M, Accordi, B, Basso, B, Gaspar, J.A, Zagoura, D, Barilari, M, Palosaari, T, Sachinidis, A, Bremer, S
Format: Article
Language:
Subjects:
c-fos
contributes
differentiation
expression
identification
in-vitro
mechanisms
response element
toxicity
x-inactivation
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary:According to the advocated paradigm shift in toxicology, acquisition of knowledge on the mechanisms underlying the toxicity of chemicals, such as perturbations of biological pathways, is of primary interest. 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 measure molecular and cellular effects of such pathway modulations. Here we compared the neuronal differentiation propensity of hESCs and hiPSCs with the aim to develop novel hiPSC-based tools for measuring pathway perturbation in relation to molecular and cellular effects in vitro. Among other fundamental pathways, also, the cAMP responsive element binding protein (CREB) pathway was activated in our neuronal models and gave us the opportunity to study time-dependent effects elicited by chemical perturbations of the CREB pathway in relation to cellular effects. We show that the inhibition of the CREB pathway, using 2-naphthol-AS-E-phosphate (KG-501), induced an inhibition of neurite outgrowth and synaptogenesis, as well as a decrease of MAP2+ neuronal cells. These data indicate that a CREB pathway inhibition can be related to molecular and cellular effects that may be relevant for neurotoxicity testing, and, thus, qualify the use of our hiPSC-derived neuronal model for studying chemical-induced neurotoxicity resulting from pathway perturbations.
ISSN:0041-008X
1096-0333