Distinct gene expression responses of two anticonvulsant drugs in a novel human embryonic stem cell based neural differentiation assay protocol

Sjors H. W. Schulpen*, Esther de Jong, Liset J. J. de la Fonteyne, Arja de Klerk, Aldert H. Piersma

*Corresponding author for this work

    Research output: Contribution to journalArticleAcademicpeer-review

    Abstract

    Hazard assessment of chemicals and pharmaceuticals is increasingly gaining from knowledge about molecular mechanisms of toxic action acquired in dedicated in vitro assays. We have developed an efficient human embryonic stem cell neural differentiation test (hESTn) that allows the study of the molecular interaction of compounds with the neural differentiation process. Within the 11-day differentiation protocol of the assay, embryonic stem cells lost their pluripotency, evidenced by the reduced expression of stem cell markers Pou5F1 and Nanog. Moreover, stem cells differentiated into neural cells, with morphologically visible neural structures together with increased expression of neural differentiation-related genes such as beta III-tubulin, Map2, Neurogin1, Mapt and Reelin. Valproic acid (VPA) and carbamazepine (CBZ) exposure during hESTn differentiation led to concentration-dependent reduced expression of beta III-tubulin, Neurogin1 and Reelin. In parallel VPA caused an increased gene expression of Map2 and Mapt which is possibly related to the neural protective effect of VPA. These findings illustrate the added value of gene expression analysis for detecting compound specific effects in hESTn. Our findings were in line with and could explain effects observed in animal studies. This study demonstrates the potential of this assay protocol for mechanistic analysis of specific compound-induced inhibition of human neural cell differentiation. (c) 2014 Elsevier Ltd. All rights reserved.

    Original languageEnglish
    Pages (from-to)449-457
    Number of pages9
    JournalToxicology in Vitro
    Volume29
    Issue number3
    DOIs
    Publication statusPublished - Apr 2015

    Keywords

    • Human embryonic stem cells
    • Neural differentiation
    • Neurodevelopmental toxicity
    • Valproic acid
    • Carbamazepine
    • VITRO EMBRYOTOXICITY TEST
    • VALPROIC ACID
    • IN-VITRO
    • DEVELOPMENTAL TOXICITY
    • ANTIEPILEPTIC DRUGS
    • HUMAN ESCS
    • TEST ESTN
    • CARBAMAZEPINE
    • TERATOGENICITY
    • NEUROGENESIS

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