title: Modeling Drug-Induced Neuropathy Using Human iPSCs for Predictive Toxicology.
abstract: Drugs under development can cause unpredicted toxicity in humans due to differential drug responsiveness between humans and other disease models, resulting in clinical trial failures. Human induced pluripotent stem cells (iPSCs) are expected to represent a useful tool for toxicity testing. However, among many assays, appropriate cellular assays for predicting neurotoxicity in an iPSC-based model are still uncertain. Here we generated neurons from iPSCs of Charcot-Marie-Tooth disease (CMT) patients. Some CMT patients are sensitive to anticancer drugs and present with an adverse reaction of neuropathy. We analyzed cellular phenotypes and found that mitochondria in neurites of CMT neurons were morphologically shorter and showed slower mobility compared to control. A neurosphere assay showed that treatment with drugs known to cause neuropathy caused mitochondrial aggregations in neurites with adenosine triphosphate shortage in both CMT and control neurons, although more severely in CMT. These findings suggest that the genetically susceptible model could provide a useful tool to predict drug-induced neurotoxicity.
authors.affiliation: Center for iPS Cells for Research and Application (CiRA), Kyoto University, Kyoto, Japan.|Department of Neurology, Kyoto Prefectural University of Medicine, Kyoto, Japan.
authors.forename: R
authors.initials: R
authors.lastname: Ohara
authors.affiliation: Center for iPS Cells for Research and Application (CiRA), Kyoto University, Kyoto, Japan.
authors.forename: K
authors.initials: K
authors.lastname: Imamura
authors.affiliation: Center for iPS Cells for Research and Application (CiRA), Kyoto University, Kyoto, Japan.|Department of Neurology, Kyoto Prefectural University of Medicine, Kyoto, Japan.
authors.forename: F
authors.initials: F
authors.lastname: Morii
authors.affiliation: Center for iPS Cells for Research and Application (CiRA), Kyoto University, Kyoto, Japan.
authors.forename: N
authors.initials: N
authors.lastname: Egawa
authors.affiliation: Center for iPS Cells for Research and Application (CiRA), Kyoto University, Kyoto, Japan.
authors.forename: K
authors.initials: K
authors.lastname: Tsukita
authors.affiliation: Center for iPS Cells for Research and Application (CiRA), Kyoto University, Kyoto, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Enami
authors.affiliation: Center for iPS Cells for Research and Application (CiRA), Kyoto University, Kyoto, Japan.
authors.forename: R
authors.initials: R
authors.lastname: Shibukawa
authors.affiliation: Department of Neurology, Kyoto Prefectural University of Medicine, Kyoto, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Mizuno
authors.affiliation: Department of Neurology, Kyoto Prefectural University of Medicine, Kyoto, Japan.|North Medical Center, Kyoto Prefectural University of Medicine, Kyoto, Japan.
authors.forename: M
authors.initials: M
authors.lastname: Nakagawa
authors.affiliation: Center for iPS Cells for Research and Application (CiRA), Kyoto University, Kyoto, Japan.
authors.forename: H
authors.initials: H
authors.lastname: Inoue
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000972:Antineoplastic Agents, Phytogenic / Q000633:toxicity*; D016022:Case-Control Studies; D002478:Cells, Cultured; D002607:Charcot-Marie-Tooth Disease / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D020022:Genetic Predisposition to Disease; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008954:Models, Biological; D058953:Neural Stem Cells / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D055495:Neurogenesis; D020258:Neurotoxicity Syndromes / Q000209:etiology* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D010641:Phenotype; D018570:Risk Assessment; D018874:Spheroids, Cellular; D014116:Toxicology / Q000379:methods*; D014750:Vincristine / Q000633:toxicity*
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D014750:Vincristine; D000255:Adenosine Triphosphate