Abstract
Human embryonic stem cells (hESCs) can proliferate indefinitely yet also differentiate in vitro, allowing normal human neurons to be generated in unlimited numbers. Here, we describe the development of an in vitro neurotoxicity assay using human dopaminergic neurons derived from hESCs. We showed that the dopaminergic neurotoxin 1-methyl-4-phenylpyridinium (MPP(+)), which produces features of Parkinson's disease in humans, was toxic for hESC-derived dopaminergic neurons. Treatment with glial cell line-derived neurotrophic factor protected tyrosine hydroxylase-positive neurons against MPP(+)-induced apoptotic cell death and loss of neuronal processes as well as against the formation of intracellular reactive oxygen species. The availability of human dopaminergic neurons, derived from hESCs, therefore allows for the possibility of directly examining the unique features of human dopaminergic neurons with respect to their responses to pharmacological agents as well as environmental and chemical toxins.
Publication types
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Research Support, N.I.H., Extramural
MeSH terms
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1-Methyl-4-phenylpyridinium / antagonists & inhibitors*
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1-Methyl-4-phenylpyridinium / toxicity*
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Animals
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Apoptosis / drug effects
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Apoptosis / physiology
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Cell Line
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Colony-Forming Units Assay / methods*
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Cytoprotection / drug effects
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Cytoprotection / physiology
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Dopamine / metabolism
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Embryonic Stem Cells / drug effects*
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Embryonic Stem Cells / metabolism
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Glial Cell Line-Derived Neurotrophic Factor / pharmacology*
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Glial Cell Line-Derived Neurotrophic Factor / therapeutic use
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Humans
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MPTP Poisoning / drug therapy
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MPTP Poisoning / metabolism
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MPTP Poisoning / physiopathology
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Mice
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Models, Biological*
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Neurons / drug effects*
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Neurons / metabolism
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Neuroprotective Agents / pharmacology
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Neuroprotective Agents / therapeutic use
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Neurotoxins / antagonists & inhibitors
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Neurotoxins / toxicity
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Oxidative Stress / drug effects
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Oxidative Stress / physiology
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Reactive Oxygen Species / metabolism
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Substantia Nigra / drug effects
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Substantia Nigra / metabolism
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Substantia Nigra / physiopathology
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Toxicology / methods
Substances
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Glial Cell Line-Derived Neurotrophic Factor
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Neuroprotective Agents
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Neurotoxins
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Reactive Oxygen Species
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1-Methyl-4-phenylpyridinium
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Dopamine