A novel dual reporter embryonic stem cell line for toxicological assessment of teratogen-induced perturbation of anterior-posterior patterning of the heart

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http://hdl.handle.net/10138/314169

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Leigh , R S , Ruskoaho , H J & Kaynak , B L 2020 , ' A novel dual reporter embryonic stem cell line for toxicological assessment of teratogen-induced perturbation of anterior-posterior patterning of the heart ' , Archives of Toxicology , vol. 94 , no. 2 , pp. 631-645 . https://doi.org/10.1007/s00204-019-02632-1

Title: A novel dual reporter embryonic stem cell line for toxicological assessment of teratogen-induced perturbation of anterior-posterior patterning of the heart
Author: Leigh, Robert S.; Ruskoaho, Heikki J.; Kaynak, Bogac L.
Contributor: University of Helsinki, Division of Pharmacology and Pharmacotherapy
University of Helsinki, Division of Pharmacology and Pharmacotherapy
University of Helsinki, Division of Pharmacology and Pharmacotherapy
Date: 2020-02
Language: eng
Number of pages: 15
Belongs to series: Archives of Toxicology
ISSN: 0340-5761
URI: http://hdl.handle.net/10138/314169
Abstract: Reliable in vitro models to assess developmental toxicity of drugs and chemicals would lead to improvement in fetal safety and a reduced cost of drug development. The validated embryonic stem cell test (EST) uses cardiac differentiation of mouse embryonic stem cells (mESCs) to predict in vivo developmental toxicity, but does not take into account the stage-specific patterning of progenitor populations into anterior (ventricular) and posterior (atrial) compartments. In this study, we generated a novel dual reporter mESC line with fluorescent reporters under the control of anterior and posterior cardiac promoters. Reporter expression was observed in nascent compartments in transgenic mouse embryos, and mESCs were used to develop differentiation assays in which chemical modulators of Wnt (XAV939: 3, 10 mu M), retinoic acid (all-trans retinoic acid: 0.1, 1, 10 mu M; 9-cis retinoic acid: 0.1, 1, 10 mu M; bexarotene 0.1, 1, 10 mu M), and Tgf-beta (SB431542: 3, 10 mu M) pathways were tested for stage- and dose-dependent effects on in vitro anterior-posterior patterning. Our results suggest that with further development, the inclusion of anterior-posterior reporter expression could be part of a battery of high-throughput tests used to identify and characterize teratogens.
Subject: Teratogen
Cardiogenesis
Atrial cardiomyocyte
Ventricular cardiomyocyte
Stem cells
Anterior-posterior patterning
3R
Developmental toxicity
Embryotoxicity
1ST-TRIMESTER EXPOSURE
MOUSE
EXPRESSION
DIFFERENTIATION
CARDIOMYOCYTES
MALFORMATIONS
DISEASE
MICE
317 Pharmacy
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