Neurite outgrowth in human induced pluripotent stem cell-derived neurons as a high-throughput screen for developmental neurotoxicity or neurotoxicity

Ryan, Kristen; Sirenko, Oksana; Parham, Fred; Hsieh, Jui-Hua; Cromwell, Evan F.; Tice, Raymond R.; Behl, Mamta

doi:10.1016/j.neuro.2016.02.003

Cited by 119 publications

(97 citation statements)

References 41 publications

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“…2016; Thomas et al . 2013), we quantified the degree of specificity to parameter changes using a calculated selectivity score (Ryan et al . 2016).…”

Section: Resultsmentioning

confidence: 99%

In vitro cardiotoxicity assessment of environmental chemicals using an organotypic human induced pluripotent stem cell-derived model

Sirenko¹,

Grimm

Ryan

et al. 2017

Toxicology and Applied Pharmacology

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An important target area for addressing data gaps through in vitro screening is the detection of potential cardiotoxicants. Despite the fact that current conservative estimates relate at least 23% of all cardiovascular disease cases to environmental exposures, the identities of the causative agents remain largely uncharacterized. Here, we evaluate the feasibility of a combinatorial in vitro/in silico screening approach for functional and mechanistic cardiotoxicity profiling of environmental hazards using a library of 69 representative environmental chemicals and drugs. Human induced pluripotent stem cell-derived cardiomyocytes were exposed in concentration-response for 30 min or 24 hrs and effects on cardiomyocyte beating and cellular and mitochondrial toxicity were assessed by kinetic measurements of intracellular Ca2+ flux and high-content imaging using the nuclear dye Hoechst 33342, the cell viability marker Calcein AM, and the mitochondrial depolarization probe JC-10. More than half of tested chemicals exhibited effects on cardiomyocyte rhythm after 30 min of exposure. After 24 hours, the effects on cell rhythm without cytotoxicity were observed in about one third of the compounds. Concentration-response data for in vitro bioactivity phenotypes were visualized using Toxicological Prioritization Index (ToxPi) and showed chemical class-specific clustering of environmental chemicals, including pesticides, flame retardants, and polycyclic aromatic hydrocarbons. For environmental chemicals with human exposure predictions, the activity-to-exposure ratios between modeled blood concentrations and in vitro bioactivity were between one and five orders of magnitude. These findings not only demonstrate that some ubiquitous environmental pollutants might have the potential to alter cardiomyocyte function at high exposures, but also indicate similarities in the mechanism of these effects both within and among chemicals and classes.

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“…2016; Thomas et al . 2013), we quantified the degree of specificity to parameter changes using a calculated selectivity score (Ryan et al . 2016).…”

Section: Resultsmentioning

confidence: 99%

In vitro cardiotoxicity assessment of environmental chemicals using an organotypic human induced pluripotent stem cell-derived model

Sirenko¹,

Grimm

Ryan

et al. 2017

Toxicology and Applied Pharmacology

Self Cite

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“…Previously, human iPSC-derived neurons have been evaluated to screen for neurotoxic compounds [Ryan, et al 2016]. Our laboratory has used commercially available iPSC-derived cortical neurons to evaluate their potential as a model of neurotoxicity [Wheeler, et al 2015] and to functionally validate genes identified in human clinical genome wide association studies of peripheral neuropathy following treatment with paclitaxel [Wheeler, et al 2015, Komatsu, et al 2015], vincristine [Diouf, et al 2015] and docetaxel [Hertz, et al 2016].…”

Section: Discussionmentioning

confidence: 99%

Application of stem cell derived neuronal cells to evaluate neurotoxic chemotherapy

et al. 2017

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The generation of induced pluripotent stem cells (iPSCs) and differentiation to cells composing major organs has opened up the possibility for a new model system to study adverse toxicities associated with chemotherapy. Therefore, we used human iPSC-derived neurons to study peripheral neuropathy, one of the most common adverse effects of chemotherapy and cause for dose reduction. To determine the utility of these neurons in investigating the effects of neurotoxic chemotherapy, we measured morphological differences in neurite outgrowth, cell viability as determined by ATP levels and apoptosis through measures of caspase 3/7 activation following treatment with clinically relevant concentrations of platinating agents (cisplatin, oxaliplatin and carboplatin), taxanes (paclitaxel, docetaxel and nab-paclitaxel), a targeted proteasome inhibitor (bortezomib), an antiangiogenic compound (thalidomide), and 5-fluorouracil, a chemotherapeutic that does not cause neuropathy. We demonstrate differential sensitivity of neurons to mechanistically distinct classes of chemotherapeutics. We also show a dose-dependent reduction of electrical activity as measured by mean firing rate of the neurons following treatment with paclitaxel. We compared neurite outgrowth and cell viability of iPSC-derived cortical (iCell® Neurons) and peripheral (Peri.4U) neurons to cisplatin, paclitaxel and vincristine. Goshajinkigan, a Japanese herbal neuroprotectant medicine, was protective against paclitaxel-induced neurotoxicity but not oxaliplatin as measured by morphological phenotypes. Thus, we have demonstrated the utility of human iPSC-derived neurons as a useful model to distinguish drug class differences and for studies of a potential neuroprotectant for the prevention of chemotherapy-induced peripheral neuropathy.

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“…A suitable prediction model has to take into account that the cMINC assay measures two endpoints simultaneously: migration and viability. One solution for other assays with two endpoints (e.g., neurite outgrowth) has been to calculate the ratio between effective concentrations (EC) of both endpoints (Stiegler et al, 2011;Krug et al, 2013a;Hoelting et al, 2016;Ryan et al, 2016). For example, Stiegler et al used the ratio of EC50 of viability to EC50 of neurite outgrowth; Ryan et al used the ratio of benchmark concentrations (BMC) for viability to neurite outgrowth.…”

Section: The Role Of Proliferation For Assay Outcome In the Optimizedmentioning

confidence: 99%

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

Nyffeler

Karreman

Leisner

et al. 2017

ALTEX

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Neurite outgrowth in human induced pluripotent stem cell-derived neurons as a high-throughput screen for developmental neurotoxicity or neurotoxicity

Cited by 119 publications

References 41 publications

In vitro cardiotoxicity assessment of environmental chemicals using an organotypic human induced pluripotent stem cell-derived model

In vitro cardiotoxicity assessment of environmental chemicals using an organotypic human induced pluripotent stem cell-derived model

Application of stem cell derived neuronal cells to evaluate neurotoxic chemotherapy

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

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