title: In Vitro Models of GJB2-Related Hearing Loss Recapitulate Ca2+Transients via a Gap Junction Characteristic of Developing Cochlea.
abstract: Mutation of the Gap Junction Beta 2 gene (GJB2) encoding connexin 26 (CX26) is the most frequent cause of hereditary deafness worldwide and accounts for up to 50% of non-syndromic sensorineural hearing loss cases in some populations. Therefore, cochlear CX26-gap junction plaque (GJP)-forming cells such as cochlear supporting cells are thought to be the most important therapeutic target for the treatment of hereditary deafness. The differentiation of pluripotent stem cells into cochlear CX26-GJP-forming cells has not been reported. Here, we detail the development of a novel strategy to differentiate induced pluripotent stem cells into functional CX26-GJP-forming cells that exhibit spontaneous ATP- and hemichannel-mediated Ca2+transients typical of the developing cochlea. Furthermore, these cells from CX26-deficient mice recapitulated the drastic disruption of GJPs, the primary pathology of GJB2-related hearing loss. These in vitro models should be useful for establishing inner-ear cell therapies and drug screening that target GJB2-related hearing loss.
authors.affiliation: Department of Otorhinolaryngology, Juntendo University Faculty of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo 113-8421, Japan; Research Institute for Diseases of Old Age, Juntendo University Graduate School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo 113-8421, Japan.
authors.forename: Ichiro
authors.initials: I
authors.lastname: Fukunaga
authors.affiliation: Department of Otorhinolaryngology, Juntendo University Faculty of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo 113-8421, Japan.
authors.forename: Ayumi
authors.initials: A
authors.lastname: Fujimoto
authors.affiliation: Department of Otorhinolaryngology, Juntendo University Faculty of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo 113-8421, Japan.
authors.forename: Kaori
authors.initials: K
authors.lastname: Hatakeyama
authors.affiliation: Department of Otorhinolaryngology, Juntendo University Faculty of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo 113-8421, Japan.
authors.forename: Toru
authors.initials: T
authors.lastname: Aoki
authors.affiliation: Department of Otorhinolaryngology, Juntendo University Faculty of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo 113-8421, Japan.
authors.forename: Atena
authors.initials: A
authors.lastname: Nishikawa
authors.affiliation: Department of Cell Biology, Japanese Foundation for Cancer Research, Cancer Institute, 3-8-31 Ariake, Koto-ku, Tokyo 135-8550, Japan; Team for Advanced Development and Evaluation of Human Disease Models, RIKEN BioResource Center, 3-1-1 Koyadai, Tsukuba, Ibaraki 305-0074, Japan.
authors.forename: Tetsuo
authors.initials: T
authors.lastname: Noda
authors.affiliation: Department of Cell Biology, Japanese Foundation for Cancer Research, Cancer Institute, 3-8-31 Ariake, Koto-ku, Tokyo 135-8550, Japan; Team for Advanced Development and Evaluation of Human Disease Models, RIKEN BioResource Center, 3-1-1 Koyadai, Tsukuba, Ibaraki 305-0074, Japan.
authors.forename: Osamu
authors.initials: O
authors.lastname: Minowa
authors.affiliation: Department of Cellular and Molecular Pharmacology, Juntendo University Graduate School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo 113-8421, Japan.
authors.forename: Nagomi
authors.initials: N
authors.lastname: Kurebayashi
authors.affiliation: Department of Otorhinolaryngology, Juntendo University Faculty of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo 113-8421, Japan.
authors.forename: Katsuhisa
authors.initials: K
authors.lastname: Ikeda
authors.affiliation: Department of Otorhinolaryngology, Juntendo University Faculty of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo 113-8421, Japan. Electronic address: kkamiya@juntendo.ac.jp.
authors.forename: Kazusaku
authors.initials: K
authors.lastname: Kamiya
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism*; D002478:Cells, Cultured; D003051:Cochlea / Q000196:embryology* / Q000378:metabolism*; D000072259:Connexin 26 / Q000378:metabolism*; D004475:Ectoderm / Q000378:metabolism; D005110:Extracellular Space / Q000378:metabolism; D017629:Gap Junctions / Q000378:metabolism* / Q000648:ultrastructure; D034381:Hearing Loss / Q000378:metabolism*; D057026:Induced Pluripotent Stem Cells / Q000378:metabolism; D051379:Mice; D008954:Models, Biological; D066329:Protein Aggregates; D014157:Transcription Factors / Q000378:metabolism
chemical_list: D066329:Protein Aggregates; D014157:Transcription Factors; D000072259:Connexin 26; D002118:Calcium
keywords: Ca(2+) transients; GJB2; cochlea; connexin; connexin 26; gap junction; hereditary deafness; iPSC; inner ear; supporting cells