An in vitro model of human dopaminergic neurons derived from embryonic stem cells: MPP+ toxicity and GDNF neuroprotection.
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.
Zeng
Xianmin
X
Intramural Research Program (IRP), Cellular Neurobiology Research Branch, Department of Health and Human Services (DHHS), National Institute on Drug Abuse (NIDA), National Institutes of Health (NIH), Baltimore, MD, USA. xzeng@buckinstitute.org
Chen
Jia
J
Deng
Xiaolin
X
Liu
Ying
Y
Rao
Mahendra S
MS
Cadet
Jean-Lud
JL
Freed
William J
WJ
D015655:1-Methyl-4-phenylpyridinium / Q000037:antagonists & inhibitors* / Q000633:toxicity*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D002460:Cell Line; D003114:Colony-Forming Units Assay / Q000379:methods*; D019610:Cytoprotection / Q000187:drug effects / Q000502:physiology; D004298:Dopamine / Q000378:metabolism; D053595:Embryonic Stem Cells / Q000187:drug effects* / Q000378:metabolism; D051100:Glial Cell Line-Derived Neurotrophic Factor / Q000494:pharmacology* / Q000627:therapeutic use; D006801:Humans; D020267:MPTP Poisoning / Q000188:drug therapy / Q000378:metabolism / Q000503:physiopathology; D051379:Mice; D008954:Models, Biological; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D018696:Neuroprotective Agents / Q000494:pharmacology / Q000627:therapeutic use; D009498:Neurotoxins / Q000037:antagonists & inhibitors / Q000633:toxicity; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology; D017382:Reactive Oxygen Species / Q000378:metabolism; D013378:Substantia Nigra / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology; D014116:Toxicology / Q000379:methods
D051100:Glial Cell Line-Derived Neurotrophic Factor; D018696:Neuroprotective Agents; D009498:Neurotoxins; D017382:Reactive Oxygen Species; D015655:1-Methyl-4-phenylpyridinium; D004298:Dopamine