Markers of murine embryonic and neural stem cells, neurons and astrocytes: Reference points for developmental neurotoxicity testing

University of Konstanz, Germany.
ALTEX 01/2010; 27(1):17-42.
Source: PubMed


Developmental neurotoxicity (DNT) is a serious concern for environmental chemicals, as well as for food and drug constituents. Animal-based DNT models have relatively low sensitivity, and they are burdened by high work-load, cost and animal ethics. Murine embryonic stem cells (mESC) recapitulate several critical processes involved in the development of the nervous system if they are induced to differentiate into neural cells. They therefore represent an alternative toxicological model to predict human hazard. In this review, we discuss how mESC can be used for DNT assays. We have compiled a list of mRNA markers that define undifferentiated mESC (n = 42), neural stem cells (n = 73), astrocytes (n = 25) and the pattern of different neuronal and non-neuronal cell types generated (n = 57). We propose that transcriptional profiling can be used as a sensitive endpoint in toxicity assays to distinguish neural differentiation states during normal and disturbed development. Importantly, we believe that it can be scaled up to relatively high throughput whilst still providing rich information on disturbances affecting small cell subpopulations. Moreover, this approach can provide insight into underlying mechanisms and pathways of toxicity. We broadly discuss the methodological basis of marker lists and DNT assay design. The discussion is put in the context of a new generation of alternative assays (embryonic stem cell based DNT testing = ESDNT V2.0), that may later include human induced pluripotent stem cells, and that are not designed for 1:1 replacement of animal experiments, but are rather intended to improve human risk assessment by using independent scientific principles.

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Available from: Bastian Zimmer,
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    • "Other cell identifier genes are upregulated during the cellular maturation phase. Such waves of transcriptional changes are also found in differentiating embryonic stem cells (ESC) [1]. They are guided and controlled by chromatin structure, which regulates the accessibility of the underlying DNA to sequence-specific regulator proteins such as transcription factors (TFs) or the transcriptional initiation complex [2]. "
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    • "Systems are used to a limited extent for prescreens Breier et al. (2010); Moser (2011) Neurons from embryonal carcinoma stem cells and ESCs -Stem-cell-based protocols are the focus of current industrial initiatives Kuegler et al. (2010); Coyne et al. (2011) V. Ahuja and S. Sharma "
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    • "While there is no deus ex machina to solve all these challenges for the experimental toxicologist , the advent of pluripotent stem cells (PSCs) provides significant improvements (Baquié et al. 2012; Leist et al. 2008), enabling the impact of potentially toxic pesticides to be studied on virtually all types of cells without recourse to immortalized cell lines. Within the last 5 years, the European ESNATS consortium has been developing pluripotent stem cell-based toxicity tests, and first results demonstrate that such test systems may indeed become powerful tools (Krug et al. 2013; Bolt 2013; Vojnits et al. 2012; Kern et al. 2013; Meganathan et al. 2012; Kuegler et al. 2010; Zimmer et al. 2011a, b; Balmer et al. 2012). "

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