Neural progenitor cells as models for high-throughput screens of developmental neurotoxicity: State of the science

Breier, Joseph M.; Gaßmann, Kathrin; Kayser, Reinier; Stegeman, Hanneke; Groot, Didima de; Fritsche, Ellen; Shafer, Timothy J.

doi:10.1016/j.ntt.2009.06.005

Cited by 101 publications

(66 citation statements)

References 107 publications

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“…Moreover, hNPCs are able to integrate into the host tissue and to differentiate into different neuronal subtypes (Cossetti et al, 2012;Ryu et al, 2009). Therefore, hNPCs have been used as a new model system in screening assays for the effects of compounds on the development of the nervous system (Breier et al, 2008(Breier et al, , 2010Qin et al, 2012). Our previous study about effects of thalidomide on the neural differentiation in hNPCs also demonstrated a promising model for neuronal development toxicity testing in vitro (Qin et al, 2012).…”

Section: Introductionmentioning

confidence: 99%

Effects of PAMAM dendrimers with various surface functional groups and multiple generations on cytotoxicity and neuronal differentiation using human neural progenitor cells

et al. 2016

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-Polyamidoamine (PAMAM) dendrimers have potential for biological applications as delivery systems for genes, drugs, and imaging agents into the brain, but their developmental neurotoxicity remains unknown. We investigated the effects of PAMAM dendrimers with various surface functional groups and multiple generations on neuronal differentiation using human neural progenitor cells at an equal mass concentration. Only PAMAM dendrimers containing amine (NH 2 ) surface groups at concentrations of 10 μg/mL significantly reduced cell viability and neuronal differentiation, compared with non-amine-terminated dendrimers. PAMAM-NH 2 with generation (G)3, G4, G5 G6, and G7 significantly decreased cell viability and inhibited neuronal differentiation from a concentration of 5 μg/mL, but G0, G1, and G2 dendrimers did not have any effect at this concentration. Cytotoxicity indices of PAMAM-NH 2 dendrimers at 10 μg/mL correlated well with the zeta potentials of the particles. Surface group density and particle number in unit volume is more important characteristic than particle size to influence cytotoxicity for positive changed dendrimers. PAMAM-50% C 12 at 1 μg/mL altered the expression level of the oxidative stress-related genes, ROR1, CYP26A1, and TGFB1, which is a DNA damage response gene. Our results indicate that PAMAM dendrimer exposure may have a surface charge-dependent adverse effect on neuronal differentiation, and that the effect may be associated with oxidative stress and DNA damage during development of neural cells.

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Section: Introductionmentioning

confidence: 99%

Effects of PAMAM dendrimers with various surface functional groups and multiple generations on cytotoxicity and neuronal differentiation using human neural progenitor cells

et al. 2016

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“…To date, there are no validated alternative in vitro DNT assays available, but within the last years significant effort has been made to develop cell-based testing strategies for DNT hazard characterization of toxicants (Bal-Price et al 2012;Breier et al 2010;Coecke et al 2007;Crofton et al 2011;Lein et al 2005Lein et al , 2007. In parallel, toxicological testing principles have been subjected to a paradigm shift, proposing that chemical testing should move toward higherthroughput, mechanism-oriented, preferably human-based methods to circumvent species-specific effects in responses to compound exposure (Krewski et al 2010;NRC 2007;Seidle and Stephens 2009).…”

Section: Introductionmentioning

confidence: 99%

Comparative human and rat neurospheres reveal species differences in chemical effects on neurodevelopmental key events

et al. 2015

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The developing brain is highly vulnerable to the adverse effects of chemicals, resulting in neurodevelopmental disorders in humans. Currently, animal experiments in the rat are the gold standard for developmental neurotoxicity (DNT) testing; however, these guideline studies are insufficient in terms of animal use, time and costs and bear the issue of species extrapolation. Therefore, the necessity for alternative methods that predict DNT of chemicals faster, cheaper and with a high predictivity for humans is internationally agreed on. In this respect, we developed an in vitro model for DNT key event screening, which is based on primary human and rat neural progenitor cells grown as neurospheres. They are able to mimic basic processes of early fetal brain development and enable an investigation of species differences between humans and rodents in corresponding cellular models. The goal of this study was to investigate to what extent human and rat neurospheres were able to correctly predict the DNT potential of a well-characterized training set of nine chemicals by investigating effects on progenitor cell proliferation, migration and neuronal differentiation in parallel to cell viability, and to compare these chemical responses between human and rat neurospheres. We demonstrate that (1) by correlating these human and rat in vitro results to existing in vivo data, human and rat neurospheres classified most compounds correctly and thus may serve as a valuable component of a modular DNT testing strategy and (2) human and rat neurospheres differed in their sensitivity to most chemicals, reflecting toxicodynamic species differences of chemicals.

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“…31 ReNcell VM is an immortalized human neuroprogenitor cell line and can be differentiated into astrocytic glial cells and neuronal cells. 18,32 Consistent with these studies, we had found that after withdrawal of growth factors from the growth media, the ReN cells were differentiated into a neuronal cell system consisting of astrocytes, neurons, and oligodendrocytes (Fig.…”

Section: Discussionmentioning

confidence: 99%

Dynamic Mass Redistribution Assay Decodes Differentiation of a Neural Progenitor Stem Cell

et al. 2012

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Stem cells hold great potential in drug discovery and development. However, challenges remain to quantitatively measure the functions of stem cells and their differentiated products. Here, we applied fluorescent imaging, quantitative real-time PCR, and label-free dynamic mass redistribution (DMR) assays to characterize the differentiation process of the ReNcell VM human neural progenitor stem cell. Immunofluorescence imaging showed that after growth factor withdrawal, the neuroprogenitor stem cell was differentiated into dopaminergic neurons, astrocytes, and oligodendrocytes, thus creating a neuronal cell system. High-performance liquid chromatography analysis showed that the differentiated cell system released dopamine upon depolarization with KCl. In conjunction with quantitative real-time PCR, DMR assays using a G-proteincoupled receptor agonist library revealed that a subset of receptors, including dopamine D 1 and D 4 receptors, underwent marked alterations in both receptor expression and signaling pathway during the differentiation process. These findings suggest that DMR assays can decode the differentiation process of stem cells at the cell system level.

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Neural progenitor cells as models for high-throughput screens of developmental neurotoxicity: State of the science

Cited by 101 publications

References 107 publications

Effects of PAMAM dendrimers with various surface functional groups and multiple generations on cytotoxicity and neuronal differentiation using human neural progenitor cells

Effects of PAMAM dendrimers with various surface functional groups and multiple generations on cytotoxicity and neuronal differentiation using human neural progenitor cells

Comparative human and rat neurospheres reveal species differences in chemical effects on neurodevelopmental key events

Dynamic Mass Redistribution Assay Decodes Differentiation of a Neural Progenitor Stem Cell

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