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Comparative Sensitivity of Human-Induced Pluripotent Stem Cell-Derived Neuronal Subtypes to Chemically Induced Neurodegeneration

Comparative Sensitivity of Human-Induced Pluripotent Stem Cell-Derived Neuronal Subtypes to... AbstractIntroduction: Development of an in vitro screening assay to predict the neurodegenerative potential of compounds in humans would benefit the safety assessment of pharmaceuticals and industrial chemicals. In this study, we compared the sensitivity of physiologically relevant human-induced pluripotent stem cell-derived GABAergic (GABA) and glutamatergic (GLUTA) neurons to chemically induced perturbation of morphological endpoints of neurite outgrowth to evaluate potential lineage-specific neurodegeneration.Materials and Methods: GABA and GLUTA neurons were treated for 24 hours with 0.1–100 μM of 10 chemicals (acetaminophen [negative control], bisindolylmaleimide-1, colchicine, dexamethasone, diazinon, doxorubicin, 1-methyl-4-phenylpyridinium, paclitaxel, rotenone, U0126) with known neurodegenerative effects in vitro, and then immunofluorescent cells were analyzed using automated high-content imaging analysis to measure neurite outgrowth endpoints.Results: No effect on any endpoint was observed with acetaminophen in either cell line. A decline in neurite count (NC) and neurite length (NL) was identified at noncytotoxic concentrations of chemicals, and they were found to be sensitive endpoints of neurodegeneration regardless of the chemicals' mechanism(s) of action. Within the chemical test set, we identified neuronal subline-specific effects, enhanced effects in one subline over the other, or similar effects between sublines relative to decreases in NC, NL, and cell density. In addition, we identified that a decrease in cell density is an acceptable comparator of cytotoxicity between sublines, but that it is a less sensitive of a measurement than adenosine triphosphate (ATP).Discussion and Conclusion(s): These findings highlight that subtle changes in neuronal morphology are a sensitive predictor of neurodegeneration, and that profiling of chemicals for lineage selective effects may be beneficial to correctly identifying degenerative potential in nervous tissues. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Applied In Vitro Toxicology Mary Ann Liebert

Comparative Sensitivity of Human-Induced Pluripotent Stem Cell-Derived Neuronal Subtypes to Chemically Induced Neurodegeneration

Comparative Sensitivity of Human-Induced Pluripotent Stem Cell-Derived Neuronal Subtypes to Chemically Induced Neurodegeneration

Applied In Vitro Toxicology , Volume 4 (4): 18 – Dec 1, 2018

Abstract

AbstractIntroduction: Development of an in vitro screening assay to predict the neurodegenerative potential of compounds in humans would benefit the safety assessment of pharmaceuticals and industrial chemicals. In this study, we compared the sensitivity of physiologically relevant human-induced pluripotent stem cell-derived GABAergic (GABA) and glutamatergic (GLUTA) neurons to chemically induced perturbation of morphological endpoints of neurite outgrowth to evaluate potential lineage-specific neurodegeneration.Materials and Methods: GABA and GLUTA neurons were treated for 24 hours with 0.1–100 μM of 10 chemicals (acetaminophen [negative control], bisindolylmaleimide-1, colchicine, dexamethasone, diazinon, doxorubicin, 1-methyl-4-phenylpyridinium, paclitaxel, rotenone, U0126) with known neurodegenerative effects in vitro, and then immunofluorescent cells were analyzed using automated high-content imaging analysis to measure neurite outgrowth endpoints.Results: No effect on any endpoint was observed with acetaminophen in either cell line. A decline in neurite count (NC) and neurite length (NL) was identified at noncytotoxic concentrations of chemicals, and they were found to be sensitive endpoints of neurodegeneration regardless of the chemicals' mechanism(s) of action. Within the chemical test set, we identified neuronal subline-specific effects, enhanced effects in one subline over the other, or similar effects between sublines relative to decreases in NC, NL, and cell density. In addition, we identified that a decrease in cell density is an acceptable comparator of cytotoxicity between sublines, but that it is a less sensitive of a measurement than adenosine triphosphate (ATP).Discussion and Conclusion(s): These findings highlight that subtle changes in neuronal morphology are a sensitive predictor of neurodegeneration, and that profiling of chemicals for lineage selective effects may be beneficial to correctly identifying degenerative potential in nervous tissues.

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Publisher
Mary Ann Liebert
Copyright
Copyright 2018, Mary Ann Liebert, Inc., publishers
ISSN
2332-1512
eISSN
2332-1539
DOI
10.1089/aivt.2017.0028
Publisher site
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Abstract

AbstractIntroduction: Development of an in vitro screening assay to predict the neurodegenerative potential of compounds in humans would benefit the safety assessment of pharmaceuticals and industrial chemicals. In this study, we compared the sensitivity of physiologically relevant human-induced pluripotent stem cell-derived GABAergic (GABA) and glutamatergic (GLUTA) neurons to chemically induced perturbation of morphological endpoints of neurite outgrowth to evaluate potential lineage-specific neurodegeneration.Materials and Methods: GABA and GLUTA neurons were treated for 24 hours with 0.1–100 μM of 10 chemicals (acetaminophen [negative control], bisindolylmaleimide-1, colchicine, dexamethasone, diazinon, doxorubicin, 1-methyl-4-phenylpyridinium, paclitaxel, rotenone, U0126) with known neurodegenerative effects in vitro, and then immunofluorescent cells were analyzed using automated high-content imaging analysis to measure neurite outgrowth endpoints.Results: No effect on any endpoint was observed with acetaminophen in either cell line. A decline in neurite count (NC) and neurite length (NL) was identified at noncytotoxic concentrations of chemicals, and they were found to be sensitive endpoints of neurodegeneration regardless of the chemicals' mechanism(s) of action. Within the chemical test set, we identified neuronal subline-specific effects, enhanced effects in one subline over the other, or similar effects between sublines relative to decreases in NC, NL, and cell density. In addition, we identified that a decrease in cell density is an acceptable comparator of cytotoxicity between sublines, but that it is a less sensitive of a measurement than adenosine triphosphate (ATP).Discussion and Conclusion(s): These findings highlight that subtle changes in neuronal morphology are a sensitive predictor of neurodegeneration, and that profiling of chemicals for lineage selective effects may be beneficial to correctly identifying degenerative potential in nervous tissues.

Journal

Applied In Vitro ToxicologyMary Ann Liebert

Published: Dec 1, 2018

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