title: Cultured networks of excitatory projection neurons and inhibitory interneurons for studying human cortical neurotoxicity.
abstract: Translating neuroprotective treatments from discovery in cell and animal models to the clinic has proven challenging. To reduce the gap between basic studies of neurotoxicity and neuroprotection and clinically relevant therapies, we developed a human cortical neuron culture system from human embryonic stem cells or human inducible pluripotent stem cells that generated both excitatory and inhibitory neuronal networks resembling the composition of the human cortex. This methodology used timed administration of retinoic acid to FOXG1(+) neural precursor cells leading to differentiation of neuronal populations representative of the six cortical layers with both excitatory and inhibitory neuronal networks that were functional and homeostatically stable. In human cortical neuronal cultures, excitotoxicity or ischemia due to oxygen and glucose deprivation led to cell death that was dependent on N-methyl-D-aspartate (NMDA) receptors, nitric oxide (NO), and poly(ADP-ribose) polymerase (PARP) (a cell death pathway called parthanatos that is distinct from apoptosis, necroptosis, and other forms of cell death). Neuronal cell death was attenuated by PARP inhibitors that are currently in clinical trials for cancer treatment. This culture system provides a new platform for the study of human cortical neurotoxicity and suggests that PARP inhibitors may be useful for ameliorating excitotoxic and ischemic cell death in human neurons.
authors.affiliation: Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
authors.forename: Jin-Chong
authors.initials: JC
authors.lastname: Xu
authors.affiliation: Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
authors.forename: Jing
authors.initials: J
authors.lastname: Fan
authors.affiliation: Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
authors.forename: Xueqing
authors.initials: X
authors.lastname: Wang
authors.affiliation: Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
authors.forename: Stephen M
authors.initials: SM
authors.lastname: Eacker
authors.affiliation: Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
authors.forename: Tae-In
authors.initials: TI
authors.lastname: Kam
authors.affiliation: Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
authors.forename: Li
authors.initials: L
authors.lastname: Chen
authors.affiliation: Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
authors.forename: Xiling
authors.initials: X
authors.lastname: Yin
authors.affiliation: Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. Department of Neurology, Jinling Hospital, Nanjing University School of Medicine, 305 East Zhongshan Road, Nanjing, Jiangsu 210002, China.
authors.forename: Juehua
authors.initials: J
authors.lastname: Zhu
authors.affiliation: Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
authors.forename: Zhikai
authors.initials: Z
authors.lastname: Chi
authors.affiliation: Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
authors.forename: Haisong
authors.initials: H
authors.lastname: Jiang
authors.affiliation: Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
authors.forename: Rong
authors.initials: R
authors.lastname: Chen
authors.affiliation: Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. vdawson@jhmi.edu tdawson@jhmi.edu.
authors.forename: Ted M
authors.initials: TM
authors.lastname: Dawson
authors.affiliation: Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. Department of Physiology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. vdawson@jhmi.edu tdawson@jhmi.edu.
authors.forename: Valina L
authors.initials: VL
authors.lastname: Dawson
mesh_terms: D016923:Cell Death / Q000187:drug effects; D002454:Cell Differentiation / Q000187:drug effects; D002460:Cell Line; D002469:Cell Separation; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology*; D053595:Embryonic Stem Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D051858:Forkhead Transcription Factors / Q000378:metabolism; D005947:Glucose / Q000172:deficiency; D053823:Hedgehog Proteins / Q000378:metabolism; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D007395:Interneurons / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D008954:Models, Biological; D016202:N-Methylaspartate / Q000494:pharmacology; D009415:Nerve Net / Q000187:drug effects; D009419:Nerve Tissue Proteins / Q000378:metabolism; D009433:Neural Inhibition / Q000187:drug effects*; D058953:Neural Stem Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D009498:Neurotoxins / Q000633:toxicity*; D009569:Nitric Oxide / Q000378:metabolism; D010100:Oxygen; D015398:Signal Transduction / Q000187:drug effects; D014212:Tretinoin / Q000494:pharmacology
chemical_list: C090173:FOXG1 protein, human; D051858:Forkhead Transcription Factors; D053823:Hedgehog Proteins; D009419:Nerve Tissue Proteins; D009498:Neurotoxins; D009569:Nitric Oxide; D014212:Tretinoin; D016202:N-Methylaspartate; D005947:Glucose; D010100:Oxygen