title: Cochlear Cell Modeling Using Disease-Specific iPSCs Unveils a Degenerative Phenotype and Suggests Treatments for Congenital Progressive Hearing Loss.
abstract: Hearing impairments are the most common symptom of congenital defects, and they generally remain intractable to treatment. Pendred syndrome, the most frequent syndromic form of hereditary hearing loss, is associated with mutations in the anion exchanger pendrin. Loss of pendrin function as an anion exchanger is thought to be causative, but rodent models do not exhibit progressive deafness. Here, we report a degenerative phenotype exhibiting mutant pendrin aggregates and increased susceptibility to cellular stresses in cochlear epithelial cells induced from patient-derived induced pluripotent stem cells (iPSCs). These degenerative phenotypes were rescued by site-specific gene corrections. Moreover, low-dose rapamycin and metformin reduced aggregation and cell death. Our results provide an unexpected, comprehensive understanding of deafness due to "degenerative cochlear disease" and may contribute to rational therapeutic development. This iPSC-based disease model provides an approach to the study of pathogenesis and therapeutic development for hereditary hearing loss.
authors.affiliation: Department of Otorhinolaryngology, Head and Neck Surgery, Keio University School of Medicine, 35 Shinanomachi Shinjyuku-ku, Tokyo 160-8582, Japan.
authors.forename: Makoto
authors.initials: M
authors.lastname: Hosoya
authors.affiliation: Department of Otorhinolaryngology, Head and Neck Surgery, Keio University School of Medicine, 35 Shinanomachi Shinjyuku-ku, Tokyo 160-8582, Japan.
authors.forename: Masato
authors.initials: M
authors.lastname: Fujioka
authors.affiliation: Department of Physiology, Keio University School of Medicine, 35 Shinanomachi Shinjyuku-ku, Tokyo 160-8582, Japan.
authors.forename: Takefumi
authors.initials: T
authors.lastname: Sone
authors.affiliation: Department of Physiology, Keio University School of Medicine, 35 Shinanomachi Shinjyuku-ku, Tokyo 160-8582, Japan.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Okamoto
authors.affiliation: Department of Physiology, Keio University School of Medicine, 35 Shinanomachi Shinjyuku-ku, Tokyo 160-8582, Japan; Center for Genomic and Regenerative Medicine, Juntendo University School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo 113-8421, Japan.
authors.forename: Wado
authors.initials: W
authors.lastname: Akamatsu
authors.affiliation: Laboratory for Synthetic Biology, RIKEN Quantitative Biology Center, 2-2-3 Minatojima-minamimachi, Chuo-ku, Kobe, Hyogo 650-0047, Japan.
authors.forename: Hideki
authors.initials: H
authors.lastname: Ukai
authors.affiliation: Laboratory for Synthetic Biology, RIKEN Quantitative Biology Center, 2-2-3 Minatojima-minamimachi, Chuo-ku, Kobe, Hyogo 650-0047, Japan; Department of Systems Pharmacology, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan; CREST, Japan Science and Technology Agency, 4-1-8 Honcho, Kawaguchi, Saitama 332-0012, Japan.
authors.forename: Hiroki R
authors.initials: HR
authors.lastname: Ueda
authors.affiliation: Department of Otorhinolaryngology, Head and Neck Surgery, Keio University School of Medicine, 35 Shinanomachi Shinjyuku-ku, Tokyo 160-8582, Japan.
authors.forename: Kaoru
authors.initials: K
authors.lastname: Ogawa
authors.affiliation: The Laboratory of Auditory Disorders and Division of Hearing and Balance Research, National Institute of Sensory Organs, National Tokyo Medical Center, 2-5-1 Higashigaoka, Meguro-ku, Tokyo 152-8902, Japan; Medical Genetics Center, National Tokyo Medical Center, 2-5-1 Higashigaoka, Meguro-ku, Tokyo 152-8902, Japan.
authors.forename: Tatsuo
authors.initials: T
authors.lastname: Matsunaga
authors.affiliation: Department of Physiology, Keio University School of Medicine, 35 Shinanomachi Shinjyuku-ku, Tokyo 160-8582, Japan. Electronic address: hidokano@a2.keio.jp.
authors.forename: Hideyuki
authors.initials: H
authors.lastname: Okano
mesh_terms: D000293:Adolescent; D000328:Adult; D002460:Cell Line; D002648:Child; D002675:Child, Preschool; D003051:Cochlea / Q000473:pathology*; D005260:Female; D006044:Goiter, Nodular / Q000235:genetics / Q000473:pathology / Q000628:therapy; D034381:Hearing Loss / Q000151:congenital* / Q000473:pathology / Q000628:therapy*; D006319:Hearing Loss, Sensorineural / Q000235:genetics / Q000473:pathology / Q000628:therapy; D000066449:Human Embryonic Stem Cells / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000187:drug effects / Q000378:metabolism*; D007231:Infant, Newborn; D007474:Ion Exchange; D026901:Membrane Transport Proteins / Q000737:chemistry / Q000378:metabolism; D008687:Metformin / Q000494:pharmacology; D010641:Phenotype; D066329:Protein Aggregates / Q000187:drug effects; D020123:Sirolimus / Q000494:pharmacology; D000076988:Sulfate Transporters; D014723:Vestibular Aqueduct / Q000002:abnormalities / Q000473:pathology
chemical_list: D026901:Membrane Transport Proteins; D066329:Protein Aggregates; C085609:SLC26A4 protein, human; D000076988:Sulfate Transporters; D008687:Metformin; D020123:Sirolimus
keywords: Pendred syndrome; disease-specific iPS cells; inner ear; outer sulcus cells