title: Functional development of mechanosensitive hair cells in stem cell-derived organoids parallels native vestibular hair cells.
abstract: Inner ear sensory epithelia contain mechanosensitive hair cells that transmit information to the brain through innervation with bipolar neurons. Mammalian hair cells do not regenerate and are limited in number. Here we investigate the potential to generate mechanosensitive hair cells from mouse embryonic stem cells in a three-dimensional (3D) culture system. The system faithfully recapitulates mouse inner ear induction followed by self-guided development into organoids that morphologically resemble inner ear vestibular organs. We find that organoid hair cells acquire mechanosensitivity equivalent to functionally mature hair cells in postnatal mice. The organoid hair cells also progress through a similar dynamic developmental pattern of ion channel expression, reminiscent of two subtypes of native vestibular hair cells. We conclude that our 3D culture system can generate large numbers of fully functional sensory cells which could be used to investigate mechanisms of inner ear development and disease as well as regenerative mechanisms for inner ear repair.
authors.affiliation: Department of Otolaryngology, F.M. Kirby Neurobiology Center Boston Children's Hospital, and Harvard Medical School, Boston, Massachusetts 02115, USA.
authors.forename: Xiao-Ping
authors.initials: XP
authors.lastname: Liu
authors.affiliation: Department of Otolaryngology-Head and Neck Surgery and Stark Neurosciences Research Institute, Indiana University School of Medicine, Indianapolis, Indiana 46202, USA.
authors.forename: Karl R
authors.initials: KR
authors.lastname: Koehler
authors.affiliation: Department of Otolaryngology-Head and Neck Surgery and Stark Neurosciences Research Institute, Indiana University School of Medicine, Indianapolis, Indiana 46202, USA.
authors.forename: Andrew M
authors.initials: AM
authors.lastname: Mikosz
authors.affiliation: Department of Otolaryngology-Head and Neck Surgery and Stark Neurosciences Research Institute, Indiana University School of Medicine, Indianapolis, Indiana 46202, USA.
authors.forename: Eri
authors.initials: E
authors.lastname: Hashino
authors.affiliation: Department of Otolaryngology, F.M. Kirby Neurobiology Center Boston Children's Hospital, and Harvard Medical School, Boston, Massachusetts 02115, USA.
authors.forename: Jeffrey R
authors.initials: JR
authors.lastname: Holt
mesh_terms: D000818:Animals; D055415:Bone Morphogenetic Protein 4 / Q000378:metabolism; D018929:Cell Culture Techniques / Q000379:methods*; D002454:Cell Differentiation / Q000187:drug effects / Q000502:physiology*; D003470:Culture Media / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D055724:Electrophysiological Phenomena / Q000502:physiology; D018069:Hair Cells, Vestibular / Q000502:physiology*; D051379:Mice; D023421:Models, Animal; D000066450:Mouse Embryonic Stem Cells / Q000502:physiology*; D038081:Organogenesis / Q000502:physiology; D009940:Organoids / Q000166:cytology / Q000502:physiology*; D011720:Pyrazoles / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology; D011994:Recombinant Proteins / Q000378:metabolism
chemical_list: C525809:BMP4 protein, human; D055415:Bone Morphogenetic Protein 4; D003470:Culture Media; C554430:LDN 193189; D011720:Pyrazoles; D011743:Pyrimidines; D011994:Recombinant Proteins