Design of a high-throughput human neural crest cell migration assay to indicate potential developmental toxicants

Nyffeler, Johanna; Karreman, Christiaan; Leisner, Heidrun; Kim, Yong Jun; Lee, Gabsang; Waldmann, Tanja; Leist, Marcel

doi:10.14573/altex.1605031

Cited by 29 publications

(57 citation statements)

References 43 publications

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“…Differentiation to NCCs was performed exactly as described earlier (Nyffeler et al 2016;Zimmer et al 2012). Briefly, the protocol involves differentiation of hESC to rosettes, manual picking of rosettes and FACS-sorting for positive expression of the NCC marker HNK-1 and negative expression of Dll1.…”

Section: Ncc Differentiationmentioning

confidence: 99%

“…Initial results of the MINC assay showed that some exemplary compounds specifically affect NCC function (Dreser et al 2015;Zimmer et al 2014). Subsequently, a modified version of the assay (cMINC) was adapted for higher throughput by making it experimenter-independent and enabling automated image acquisition (Nyffeler et al 2016). In the present study, we explored the suitability of the cMINC assay for screening purposes.…”

Section: Introductionmentioning

confidence: 99%

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Combination of multiple neural crest migration assays to identify environmental toxicants from a proof-of-concept chemical library

et al. 2017

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Many in vitro tests have been developed to screen for potential neurotoxicity. However, only few cell function-based tests have been used for comparative screening, and thus experience is scarce on how to confirm and evaluate screening hits. We addressed these questions for the neural crest cell migration test (cMINC). After an initial screen, a hit follow-up strategy was devised. A library of 75 compounds plus internal controls (NTP80-list), assembled by the National Toxicology Program of the USA (NTP) was used. It contained some known classes of (developmental) neurotoxic compounds. The primary screen yielded 23 confirmed hits, which comprised ten flame retardants, seven pesticides and six drug-like compounds. Comparison of concentration-response curves for migration and viability showed that all hits were specific. The extent to which migration was inhibited was 25-90%, and two organochlorine pesticides (DDT, heptachlor) were most efficient. In the second part of this study, (1) the cMINC assay was repeated under conditions that prevent proliferation; (2) a transwell migration assay was used as a different type of migration assay; (3) cells were traced to assess cell speed. Some toxicants had largely varying effects between assays, but each hit was confirmed in at least one additional test. This comparative study allows an estimate on how confidently the primary hits from a cell function-based screen can be considered as toxicants disturbing a key neurodevelopmental process. Testing of the NTP80-list in more assays will be highly interesting to assemble a test battery and to build prediction models for developmental toxicity.

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Section: Ncc Differentiationmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Combination of multiple neural crest migration assays to identify environmental toxicants from a proof-of-concept chemical library

et al. 2017

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“…Many of these human cell-based assays have been used to study small numbers of chemicals (n < 15; e.g., Harrill et al, 2011;He et al, 2012;Rempel et al, 2015;Baumann et al, 2016;Brown et al, 2016) or to derive mechanistic information for limited numbers of chemicals (e.g., Gassmann et al, 2010;Balmer et al, 2012;Balmer and Leist, 2014;Barenys et al, 2016). Only a few have been utilized to screen larger numbers (n > 15) of compounds (e.g., Stiegler et al, 2011;Zimmer et al, 2012;Culbreth et al, 2012;McConnell et al, 2012;Krug et al, 2013;Valdivia et al, 2014;Mundy et al, 2015;Hoelting et al, 2016;Nyffeler et al, 2016).…”

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confidence: 99%

OECD/EFSA workshop on developmental neurotoxicity (DNT): The use of non-animal test methods for regulatory purposes

Fritsche

Crofton

Hernández

et al. 2017

ALTEX

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“…Additionally, it is worth noting that new tools have emerged since the mid 2000's which have helped to increase the understanding of the mechanisms underlying the role of teratogens on NC and embryonic development. In particular, these approaches included the use of human NCCs differentiated from human embryonic stem cells (hESC) (Avery & Dalton, ; Zhu et al, ) to allow the identification of NC toxicants (Crofton et al, ; Ebert & Svendsen, ; Nyffeler et al, ; Pallocca et al, ; Vichier‐Guerre et al, ; Zimmer et al, ). Altogether, these studies have yielded information on the molecular pathways that regulate the toxicity of teratogens in particular developing tissues.…”

Section: Discussionmentioning

confidence: 99%

The role of teratogens in neural crest development

Cerrizuela

Vega-Lopez

Aybar

2020

Birth Defects Research

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The neural crest (NC), discovered by Wilhelm His 150 years ago, gives rise to a multipotent migratory embryonic cell population that generates a remarkably diverse and important array of cell types during the development of the vertebrate embryo. These cells originate in the neural plate border (NPB), which is the ectoderm between the neural plate and the epidermis. They give rise to the neurons and glia of the peripheral nervous system, melanocytes, chondrocytes, smooth muscle cells, odontoblasts and neuroendocrine cells, among others. Neurocristopathies are a class of congenital diseases resulting from the abnormal induction, specification, migration, differentiation or death of NC cells (NCCs) during embryonic development and have an important medical and societal impact. In general, congenital defects affect an appreciable percentage of newborns worldwide. Some of these defects are caused by teratogens, which are agents that negatively impact the formation of tissues and organs during development. In this review, we will discuss the teratogens linked to the development of many birth defects, with a strong focus on those that specifically affect the development of the NC, thereby producing neurocristopathies.Although increasing attention is being paid to the effect of teratogens on embryonic development in general, there is a strong need to critically evaluate the specific role of these agents in NC development. Therefore, increased understanding of the role of these factors in NC development will contribute to the planning of strategies aimed at the prevention and treatment of human neurocristopathies, whose etiology was previously not considered.

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Design of a high-throughput human neural crest cell migration assay to indicate potential developmental toxicants

Cited by 29 publications

References 43 publications

Combination of multiple neural crest migration assays to identify environmental toxicants from a proof-of-concept chemical library

Combination of multiple neural crest migration assays to identify environmental toxicants from a proof-of-concept chemical library

OECD/EFSA workshop on developmental neurotoxicity (DNT): The use of non-animal test methods for regulatory purposes

The role of teratogens in neural crest development

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