title: Modeling neurological diseases with induced pluripotent cells reprogrammed from immortalized lymphoblastoid cell lines.
abstract: Patient-specific induced pluripotent stem cells (iPSCs) facilitate understanding of the etiology of diseases, discovery of new drugs and development of novel therapeutic interventions. A frequently used starting source of cells for generating iPSCs has been dermal fibroblasts (DFs) isolated from skin biopsies. However, there are also numerous repositories containing lymphoblastoid B-cell lines (LCLs) generated from a variety of patients. To date, this rich bioresource of LCLs has been underused for generating iPSCs, and its use would greatly expand the range of targeted diseases that could be studied by using patient-specific iPSCs. However, it remains unclear whether patient's LCL-derived iPSCs (LiPSCs) can function as a disease model. Therefore, we generated Parkinson's disease patient-specific LiPSCs and evaluated their utility as tools for modeling neurological diseases. We established iPSCs from two LCL clones, which were derived from a healthy donor and a patient carrying PARK2 mutations, by using existing non-integrating episomal protocols. Whole genome sequencing (WGS) and comparative genomic hybridization (CGH) analyses showed that the appearance of somatic variations in the genomes of the iPSCs did not vary substantially according to the original cell types (LCLs, T-cells and fibroblasts). Furthermore, LiPSCs could be differentiated into functional neurons by using the direct neurosphere conversion method (dNS method), and they showed several Parkinson's disease phenotypes that were similar to those of DF-iPSCs. These data indicate that the global LCL repositories can be used as a resource for generating iPSCs and disease models. Thus, LCLs are the powerful tools for generating iPSCs and modeling neurological diseases.
authors.affiliation: Department of Physiology, Keio University, School of Medicine, Shinjuku-ku, Tokyo, 160-8582, Japan.
authors.forename: Koki
authors.initials: K
authors.lastname: Fujimori
authors.affiliation: Department of Physiology, Keio University, School of Medicine, Shinjuku-ku, Tokyo, 160-8582, Japan.
authors.forename: Toshiki
authors.initials: T
authors.lastname: Tezuka
authors.affiliation: Department of Neurology, Graduate School of Medicine, The University of Tokyo, Bunkyo-ku, Tokyo, 113-8655, Japan.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Ishiura
authors.affiliation: Department of Neurology, Graduate School of Medicine, The University of Tokyo, Bunkyo-ku, Tokyo, 113-8655, Japan.
authors.forename: Jun
authors.initials: J
authors.lastname: Mitsui
authors.affiliation: Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, The University of Tokyo, Kashiwa, 277-0882, Japan.
authors.forename: Koichiro
authors.initials: K
authors.lastname: Doi
authors.affiliation: Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, The University of Tokyo, Kashiwa, 277-0882, Japan.
authors.forename: Jun
authors.initials: J
authors.lastname: Yoshimura
authors.affiliation: Department of Physiology, Yokohama City University Graduate School of Medicine, Kanazawa-ku, Kanagawa, 236-0027, Japan.|Department of Integrative Aging Neuroscience, Section of Neuroendocrinology, National Center for Geriatrics and Gerontology, Obu, Aichi, 474-8511, Japan.
authors.forename: Hirobumi
authors.initials: H
authors.lastname: Tada
authors.affiliation: Department of Physiology, Keio University, School of Medicine, Shinjuku-ku, Tokyo, 160-8582, Japan.|Institute for Innovation, Ajinomoto Co., Inc., Kawasaki-ku, Kanagawa, 210-8681, Japan.
authors.forename: Takuya
authors.initials: T
authors.lastname: Matsumoto
authors.affiliation: Department of Physiology, Keio University, School of Medicine, Shinjuku-ku, Tokyo, 160-8582, Japan.
authors.forename: Miho
authors.initials: M
authors.lastname: Isoda
authors.affiliation: Molecular Research Center for Children's Mental Development, United Graduate School of Child Development, Osaka University, Suita-shi, Osaka, 565-0871, Japan.|Department of Psychiatry, Osaka University Graduate School of Medicine, Suita-shi, Osaka, 565-0871, Japan.
authors.forename: Ryota
authors.initials: R
authors.lastname: Hashimoto
authors.affiliation: Department of Neurology, Juntendo University, School of Medicine, Bunkyo-ku, Tokyo, 113-8431, Japan.
authors.forename: Nubutaka
authors.initials: N
authors.lastname: Hattori
authors.affiliation: Department of Physiology, Yokohama City University Graduate School of Medicine, Kanazawa-ku, Kanagawa, 236-0027, Japan.
authors.forename: Takuya
authors.initials: T
authors.lastname: Takahashi
authors.affiliation: Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, The University of Tokyo, Kashiwa, 277-0882, Japan.|Medical Genome Center, The University of Tokyo Hospital, Bunkyo-ku, Tokyo, 113-8655, Japan.
authors.forename: Shinichi
authors.initials: S
authors.lastname: Morishita
authors.affiliation: Department of Neurology, Graduate School of Medicine, The University of Tokyo, Bunkyo-ku, Tokyo, 113-8655, Japan.|Medical Genome Center, The University of Tokyo Hospital, Bunkyo-ku, Tokyo, 113-8655, Japan.
authors.forename: Shoji
authors.initials: S
authors.lastname: Tsuji
authors.affiliation: Department of Physiology, Keio University, School of Medicine, Shinjuku-ku, Tokyo, 160-8582, Japan. awado@juntendo.ac.jp.|Center for Genomic and Regenerative Medicine, Juntendo University, School of Medicine, Bunkyo-ku, Tokyo, 113-8431, Japan. awado@juntendo.ac.jp.
authors.forename: Wado
authors.initials: W
authors.lastname: Akamatsu
authors.affiliation: Department of Physiology, Keio University, School of Medicine, Shinjuku-ku, Tokyo, 160-8582, Japan. hidokano@a2.keio.jp.
authors.forename: Hideyuki
authors.initials: H
authors.lastname: Okano
mesh_terms: D001483:Base Sequence; D002454:Cell Differentiation; D002461:Cell Line, Transformed; D065150:Cellular Reprogramming; D020405:Dermis / Q000166:cytology; D005347:Fibroblasts / Q000166:cytology; D004854:Herpesvirus 4, Human / Q000502:physiology; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000166:cytology*; D008214:Lymphocytes / Q000166:cytology*; D008928:Mitochondria / Q000378:metabolism; D008954:Models, Biological; D009154:Mutation / Q000235:genetics; D009422:Nervous System Diseases / Q000473:pathology*; D009474:Neurons / Q000166:cytology; D010300:Parkinson Disease / Q000473:pathology; D010641:Phenotype; D018874:Spheroids, Cellular / Q000166:cytology; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism
chemical_list: D044767:Ubiquitin-Protein Ligases; C111567:parkin protein
keywords: Disease modeling; Genomic mutation in reprogramming process; Induced pluripotent stem cells; Lymphoblastoid B-cell line; Neurological disorder