Inner Ear Cells from Stem Cells: A Path Towards Inner Ear Cell Regeneration

Janesick, Amanda; Hashino, Eri; Heller, Stefan

doi:10.1007/978-3-031-20661-0_6

Part of the book series: Springer Handbook of Auditory Research ((SHAR,volume 75))

620 Accesses
2 Citations

Abstract

Investigating the mammalian inner ear’s sensory epithelia has been limited by the lack of accessibility, being embedded in dense bone, and further confounded by the paucity and survivability of cells after dissection. These limitations hamper the use of inner ear cells for the development of therapies aimed at regeneration and for clinically relevant, high-throughput, in vitro drug screens. In this chapter, we describe different guidance strategies to generate inner ear cells from pluripotent stem cells. We explore the challenges of producing cells with proper lineage outcomes – from first stabilizing epithelial character in otic progenitors to unresolved questions such as ensuring that differentiated cell types have a correct vestibular or cochlear identity. We then discuss somatic stem and progenitor cells that are present in non-mammalian vertebrate inner ears, but also detectable in the adult mammalian vestibular organs, as well as in the neonate rodent cochlea. Extracting knowledge from these naturally proliferative cell populations will lead us closer to the possibility of reawakening regenerative potential in the mammalian adult inner ear. Finally, we describe how technology has changed during the last two decades and how manipulation of epigenetic DNA modifications and reprogramming strategies could revolutionize the treatment of hearing loss through hair cell regeneration.

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Building inner ears: recent advances and future challenges for in vitro organoid systems

Article Open access 14 December 2020

Generating inner ear organoids containing putative cochlear hair cells from human pluripotent stem cells

Article Open access 11 September 2018

Selective ablation of cochlear hair cells promotes engraftment of human embryonic stem cell-derived progenitors in the mouse organ of Corti

Article Open access 19 June 2021

References

Abdolazimi Y, Stojanova Z, Segil N (2016) Selection of cell fate in the organ of Corti involves the integration of Hes/Hey signaling at the Atoh1 promoter. Development 143(5):841–850. https://doi.org/10.1242/dev.129320
Article CAS PubMed PubMed Central Google Scholar
Adler HJ, Raphael Y (1996) New hair cells arise from supporting cell conversion in the acoustically damaged chick inner ear. Neurosci Lett 205(1):17–20
Article CAS PubMed Google Scholar
Bermingham NA, Hassan BA, Price SD, Vollrath MA et al (1999) Math1: an essential gene for the generation of inner ear hair cells. Science 284(5421):1837–1841
Article CAS PubMed Google Scholar
Bernstein BE, Mikkelsen TS, Xie X, Kamal M et al (2006) A bivalent chromatin structure marks key developmental genes in embryonic stem cells. Cell 125(2):315–326. https://doi.org/10.1016/j.cell.2006.02.041
Article CAS PubMed Google Scholar
Bok J, Dolson DK, Hill P, Ruther U et al (2007) Development. 134(9):1713–1722. Accession Number: 17395647. https://doi.org/10.1242/dev.000760. http://www.ncbi.nlm.nih.gov/pubmed/17395647
Carey BW, Markoulaki S, Hanna JH, Faddah DA et al (2011) Reprogramming factor stoichiometry influences the epigenetic state and biological properties of induced pluripotent stem cells. Cell Stem Cell 9(6):588–598. https://doi.org/10.1016/j.stem.2011.11.003
Article CAS PubMed Google Scholar
Chai R, Xia A, Wang T, Jan TA et al (2011) Dynamic expression of Lgr5, a Wnt target gene, in the developing and mature mouse cochlea. J Assoc Res Otolaryngol 12(4):455–469. https://doi.org/10.1007/s10162-011-0267-2
Article PubMed PubMed Central Google Scholar
Chen W, Jongkamonwiwat N, Abbas L, Eshtan SJ et al (2012) Restoration of auditory evoked responses by human ES-cell-derived otic progenitors. Nature 490(7419):278–282. https://doi.org/10.1038/nature11415
Article CAS PubMed PubMed Central Google Scholar
Chessum L, Matern MS, Kelly MC, Johnson SL et al (2018) Helios is a key transcriptional regulator of outer hair cell maturation. Nature 563(7733):696–700. https://doi.org/10.1038/s41586-018-0728-4
Article CAS PubMed PubMed Central Google Scholar
Cohen DE, Melton D (2011) Turning straw into gold: directing cell fate for regenerative medicine. Nat Rev Genet 12(4):243–252. https://doi.org/10.1038/nrg2938
Article CAS PubMed Google Scholar
Corwin JT, Cotanche DA (1988) Regeneration of sensory hair cells after acoustic trauma. Science 240(4860):1772–1774. https://doi.org/10.1126/science.3381100
Article CAS PubMed Google Scholar
Corwin JT, Cotanche DA (1989) Development of location-specific hair cell stereocilia in denervated embryonic ears. J Comp Neurol 288(4):529–537. https://doi.org/10.1002/cne.902880402
Article CAS PubMed Google Scholar
Costa A, Sanchez-Guardado L, Juniat S, Gale JE et al (2015) Generation of sensory hair cells by genetic programming with a combination of transcription factors. Development 142(11):1948–1959. https://doi.org/10.1242/dev.119149
Article CAS PubMed Google Scholar
Daley GQ (2002) Prospects for stem cell therapeutics: myths and medicines. Curr Opin Genet Dev 12(5):607–613
Article CAS PubMed Google Scholar
Daley GQ, Scadden DT (2008) Prospects for stem cell-based therapy. Cell 132(4):544–548. https://doi.org/10.1016/j.cell.2008.02.009
Article CAS PubMed Google Scholar
DeJonge RE, Liu XP, Deig CR, Heller S et al (2016) Modulation of Wnt signaling enhances inner ear organoid development in 3D culture. PLoS One 11(9):e0162508. https://doi.org/10.1371/journal.pone.0162508
Article CAS PubMed PubMed Central Google Scholar
De Los AA, Ferrari F, Xi R, Fujiwara Y et al (2015) Hallmarks of pluripotency. Nature 525(7570):469–478. https://doi.org/10.1038/nature15515
Article CAS Google Scholar
Dincer Z, Piao J, Niu L, Ganat Y et al (2013) Specification of functional cranial placode derivatives from human pluripotent stem cells. Cell Rep 5(5):1387–1402. https://doi.org/10.1016/j.celrep.2013.10.048
Article CAS PubMed Google Scholar
Donnelly ML, Luke G, Mehrotra A, Li X et al (2001) Analysis of the aphthovirus 2A/2B polyprotein ‘cleavage’ mechanism indicates not a proteolytic reaction, but a novel translational effect: a putative ribosomal ‘skip’. J Gen Virol 82(Pt 5):1013–1025. https://doi.org/10.1099/0022-1317-82-5-1013
Article CAS PubMed Google Scholar
Durruthy-Durruthy R, Heller S (2015) Applications for single cell trajectory analysis in inner ear development and regeneration. Cell Tissue Res 361(1):49–57. https://doi.org/10.1007/s00441-014-2079-2
Article CAS PubMed Google Scholar
Durruthy-Durruthy R, Gottlieb A, Hartman BH, Waldhaus J et al (2014) Reconstruction of the mouse otocyst and early neuroblast lineage at single-cell resolution. Cell 157(4):964–978. https://doi.org/10.1016/j.cell.2014.03.036
Article CAS PubMed PubMed Central Google Scholar
Ealy M, Ellwanger DC, Kosaric N, Stapper AP, Heller S (2016) Single-cell analysis delineates a trajectory toward the human early otic lineage. Proc Natl Acad Sci USA 113(30):8508–8513. https://doi.org/10.1073/pnas.1605537113
Article CAS PubMed PubMed Central Google Scholar
Eiraku M, Sasai Y (2011) Mouse embryonic stem cell culture for generation of three-dimensional retinal and cortical tissues. Nat Prot 7(1):69–79. https://doi.org/10.1038/nprot.2011.429
Article CAS Google Scholar
Eiraku M, Watanabe K, Matsuo-Takasaki M, Kawada M et al (2008) Self-organized formation of polarized cortical tissues from ESCs and its active manipulation by extrinsic signals. Cell Stem Cell 3(5):519–532. https://doi.org/10.1016/j.stem.2008.09.002
Article CAS PubMed Google Scholar
Ellwanger DC, Scheibinger M, Dumont RA, Barr-Gillespie PG, Heller S (2018) Transcriptional dynamics of hair-bundle morphogenesis revealed with CellTrails. Cell Rep 23 (10):2901–2914. e2913. doi:https://doi.org/10.1016/j.celrep.2018.05.002.
Forge A, Li L, Corwin JT, Nevill G (1993) Ultrastructural evidence for hair cell regeneration in the mammalian inner ear. Science 259(5101):1616–1619
Article CAS PubMed Google Scholar
Forge A, Li L, Nevill G (1998) Hair cell recovery in the vestibular sensory epithelia of mature guinea pigs. J Comp Neurol 397(1):69–88
Article CAS PubMed Google Scholar
Fritzsch B, Straka H (2014) Evolution of vertebrate mechanosensory hair cells and inner ears: toward identifying stimuli that select mutation driven altered morphologies. J Comp Physiol A Neuroethol Sens Neural Behav Physiol 200(1):5–18. https://doi.org/10.1007/s00359-013-0865-z
Article PubMed Google Scholar
Gafni O, Weinberger L, Mansour AA, Manor YS et al (2013) Derivation of novel human ground state naive pluripotent stem cells. Nature 504(7479):282–286. https://doi.org/10.1038/nature12745
Article CAS PubMed Google Scholar
Geleoc GS, Risner JR, Holt JR (2004) Developmental acquisition of voltage-dependent conductances and sensory signaling in hair cells of the embryonic mouse inner ear. J Neurosci 24(49):11148–11159
Article CAS PubMed PubMed Central Google Scholar
Goodyear R, Richardson G (1997) Pattern formation in the basilar papilla: evidence for cell rearrangement. J Neurosci 17(16):6289–6301
Article CAS PubMed PubMed Central Google Scholar
Gritti A, Parati EA, Cova L, Frolichsthal P et al (1996) Multipotential stem cells from the adult mouse brain proliferate and self-renew in response to basic fibroblast growth factor. J Neurosci 16(3):1091–1100
Article CAS PubMed PubMed Central Google Scholar
Groves AK, Bronner-Fraser M (2000) Competence, specification and commitment in otic placode induction. Development 127(16):3489–3499
Article CAS PubMed Google Scholar
Groves AK, Fekete DM (2012) Shaping sound in space: the regulation of inner ear patterning. Development 139(2):245–257. https://doi.org/10.1242/dev.067074
Article CAS PubMed PubMed Central Google Scholar
Groves AK, LaBonne C (2014) Setting appropriate boundaries: fate, patterning and competence at the neural plate border. Dev Biol 389(1):2–12. https://doi.org/10.1016/j.ydbio.2013.11.027
Article CAS PubMed Google Scholar
Gubbels SP, Woessner DW, Mitchell JC, Ricci AJ, Brigande JV (2008) Functional auditory hair cells produced in the mammalian cochlea by in utero gene transfer. Nature 455(7212):537–541. https://doi.org/10.1038/nature07265
Article CAS PubMed PubMed Central Google Scholar
Hartman BH, Boescke R, Ellwanger DC, Keymeulen S et al (2018) Fbxo2(VHC) mouse and embryonic stem cell reporter lines delineate in vitro-generated inner ear sensory epithelia cells and enable otic lineage selection and Cre-recombination. Dev Biol 443(1):64–77. https://doi.org/10.1016/j.ydbio.2018.08.013
Article CAS PubMed PubMed Central Google Scholar
Higashi T, Nakagawa T, Kita T, Kim TS et al (2007) Effects of bone morphogenetic protein 4 on differentiation of embryonic stem cells into myosin VIIa-positive cells. Acta Otolaryngol Suppl 557:36–40. https://doi.org/10.1080/03655230601065373
Article CAS Google Scholar
Hockemeyer D, Wang H, Kiani S, Lai CS et al (2011) Genetic engineering of human pluripotent cells using TALE nucleases. Nat Biotechnol 29(8):731–734. https://doi.org/10.1038/nbt.1927
Article CAS PubMed PubMed Central Google Scholar
Holley MC, Nishida Y, Grix N (1997) Conditional immortalization of hair cells from the inner ear. Int J Dev Neurosci 15(4–5):541–552
Article CAS PubMed Google Scholar
Hou P, Li Y, Zhang X, Liu C et al (2013) Pluripotent stem cells induced from mouse somatic cells by small-molecule compounds. Science 341(6146):651–654. https://doi.org/10.1126/science.1239278
Article CAS PubMed Google Scholar
Hu Z, Corwin JT (2007) Inner ear hair cells produced in vitro by a mesenchymal-to-epithelial transition. Proc Natl Acad Sci USA 104(42):16675–16680. https://doi.org/10.1073/pnas.0704576104
Article PubMed PubMed Central Google Scholar
Hudspeth AJ (1985) The cellular basis of hearing: the biophysics of hair cells. Science 230(4727):745–752. https://doi.org/10.1126/science.2414845
Article CAS PubMed Google Scholar
Hurley KM, Gaboyard S, Zhong M, Price SD et al (2006) M-like K+ currents in type I hair cells and calyx afferent endings of the developing rat utricle. J Neurosci 26(40):10253–10269. https://doi.org/10.1523/JNEUROSCI.2596-06.2006
Article CAS PubMed PubMed Central Google Scholar
Jahan I, Pan N, Fritzsch B (2015) Opportunities and limits of the one gene approach: the ability of Atoh1 to differentiate and maintain hair cells depends on the molecular context. Front Cell Neurosci 9:26. https://doi.org/10.3389/fncel.2015.00026
Article CAS PubMed PubMed Central Google Scholar
Janesick AS, Heller S (2018) Stem Cells and the bird cochlea – where Is everybody? Cold Spring Harb Perspect Med. https://doi.org/10.1101/cshperspect.a033183
Janesick A, Scheibinger M, Benkafadar N, Kirti S et al (2021) Cell-type identity of the avian cochlea. Cell Rep 34(12):108900. https://doi.org/10.1016/j.celrep.2021.108900
Article CAS PubMed Google Scholar
Jinek M, Chylinski K, Fonfara I, Hauer M et al (2012) A programmable dual-RNA-guided DNA endonuclease in adaptive bacterial immunity. Science 337(6096):816–821. https://doi.org/10.1126/science.1225829
Article CAS PubMed PubMed Central Google Scholar
Jørgensen JM, Mathiesen C (1988) The avian inner ear. Continuous production of hair cells in vestibular sensory organs, but not in the auditory papilla. Naturwissenschaften 75(6):319–320. https://doi.org/10.1007/BF00367330
Article PubMed Google Scholar
Kalinec G, Thein P, Park C, Kalinec F (2016) HEI-OC1 cells as a model for investigating drug cytotoxicity. Hear Res 335:105–117. https://doi.org/10.1016/j.heares.2016.02.019
Article CAS PubMed Google Scholar
Kelly MC, Chang Q, Pan A, Lin X, Chen P (2012) Atoh1 directs the formation of sensory mosaics and induces cell proliferation in the postnatal mammalian cochlea in vivo. J Neurosci 32(19):6699–6710. https://doi.org/10.1523/JNEUROSCI.5420-11.2012
Article CAS PubMed PubMed Central Google Scholar
Koehler KR, Mikosz AM, Molosh AI, Patel D, Hashino E (2013) Generation of inner ear sensory epithelia from pluripotent stem cells in 3D culture. Nature 500(7461):217–221. https://doi.org/10.1038/nature12298
Article CAS PubMed PubMed Central Google Scholar
Koehler KR, Nie J, Longworth-Mills E, Liu XP et al (2017) Generation of inner ear organoids containing functional hair cells from human pluripotent stem cells. Nat Biotechnol 35(6):583–589. https://doi.org/10.1038/nbt.3840
Article CAS PubMed PubMed Central Google Scholar
Kollmar R, Nakamura SK, Kappler JA, Hudspeth AJ (2001) Expression and phylogeny of claudins in vertebrate primordia. Proc Natl Acad Sci USA 98(18):10196–10201. https://doi.org/10.1073/pnas.171325898
Article CAS PubMed PubMed Central Google Scholar
Korrapati S, Roux I, Glowatzki E, Doetzlhofer A (2013) Notch signaling limits supporting cell plasticity in the hair cell-damaged early postnatal murine cochlea. PLoS One 8(8):e73276. https://doi.org/10.1371/journal.pone.0073276
Article CAS PubMed PubMed Central Google Scholar
Kubota M, Scheibinger M, Jan TA, Heller S (2021) Greater epithelial ridge cells are the principal organoid-forming progenitors of the mouse cochlea. Cell Rep 34(3):108646. https://doi.org/10.1016/j.celrep.2020.108646
Article CAS PubMed PubMed Central Google Scholar
Ladher RK, Wright TJ, Moon AM, Mansour SL, Schoenwolf GC (2005) FGF8 initiates inner ear induction in chick and mouse. Genes and Development 19(5):603–613
Article CAS PubMed PubMed Central Google Scholar
Leung AW, Kent Morest D, Li JY (2013) Differential BMP signaling controls formation and differentiation of multipotent preplacodal ectoderm progenitors from human embryonic stem cells. Dev Biol 379(2):208–220. https://doi.org/10.1016/j.ydbio.2013.04.023
Article CAS PubMed PubMed Central Google Scholar
Li H, Liu H, Heller S (2003a) Pluripotent stem cells from the adult mouse inner ear. Nat Med 9(10):1293–1299. https://doi.org/10.1038/nm925
Article CAS PubMed Google Scholar
Li H, Roblin G, Liu H, Heller S (2003b) Generation of hair cells by stepwise differentiation of embryonic stem cells. Proc Natl Acad Sci USA 100(23):13495–13500. https://doi.org/10.1073/pnas.2334503100
Article CAS PubMed PubMed Central Google Scholar
Liu Z, Dearman JA, Cox BC, Walters BJ et al (2012) Age-dependent in vivo conversion of mouse cochlear pillar and Deiters’ cells to immature hair cells by Atoh1 ectopic expression. J Neurosci 32(19):6600–6610. https://doi.org/10.1523/JNEUROSCI.0818-12.2012
Article CAS PubMed PubMed Central Google Scholar
Liu XP, Koehler KR, Mikosz AM, Hashino E, Holt JR (2016) Functional development of mechanosensitive hair cells in stem cell-derived organoids parallels native vestibular hair cells. Nat Commun 7:11508. https://doi.org/10.1038/ncomms11508
Article CAS PubMed PubMed Central Google Scholar
Lleras-Forero L, Streit A (2012) Development of the sensory nervous system in the vertebrate head: the importance of being on time. Curr Opin Genet Dev 22(4):315–322. https://doi.org/10.1016/j.gde.2012.05.003
Article CAS PubMed Google Scholar
Loh YH, Wu Q, Chew JL, Vega VB et al (2006) The Oct4 and Nanog transcription network regulates pluripotency in mouse embryonic stem cells. Nat Genet 38(4):431–440. https://doi.org/10.1038/ng1760
Article CAS PubMed Google Scholar
Löwenheim H, Avci H, Dos Santos A, Ealy M, et al. (2019) Evidence for stem/progenitor cells in the human postmortem adult inner ear. Paper presented at the Annual Midwinter Meeting – Association for Research in Otolaryngology, Baltimore, MD, Feb 9–13, 2019.
Google Scholar
Magnus T, Liu Y, Parker GC, Rao MS (2008) Stem cell myths. Philos Trans R Soc Lond B Biol Sci 363(1489):9–22. https://doi.org/10.1098/rstb.2006.2009
Article PubMed Google Scholar
Malgrange B, Belachew S, Thiry M, Nguyen L et al (2002) Proliferative generation of mammalian auditory hair cells in culture. Mech Dev 112(1–2):79–88
Article CAS PubMed Google Scholar
Manley GA, Köppl C (1998) Phylogenetic development of the cochlea and its innervation. Curr Opin Neurobiol 8(4):468–474. https://doi.org/10.1016/s0959-4388(98)80033-0
Article CAS PubMed Google Scholar
Manor YS, Massarwa R, Hanna JH (2015) Establishing the human naive pluripotent state. Curr Opin Genet Dev 34:35–45. https://doi.org/10.1016/j.gde.2015.07.005
Article CAS PubMed Google Scholar
Marcotti W, van Netten SM, Kros CJ (2005) The aminoglycoside antibiotic dihydrostreptomycin rapidly enters mouse outer hair cells through the mechano-electrical transducer channels. J Physiol 567(Pt 2):505–521
Article CAS PubMed PubMed Central Google Scholar
Martello G, Smith A (2014) The nature of embryonic stem cells. Annu Rev Cell Dev Biol 30:647–675. https://doi.org/10.1146/annurev-cellbio-100913-013116
Article CAS PubMed Google Scholar
McGovern MM, Randle MR, Cuppini CL, Graves KA, Cox BC (2019) Multiple supporting cell subtypes are capable of spontaneous hair cell regeneration in the neonatal mouse cochlea. Development 146(4). https://doi.org/10.1242/dev.171009
McLean WJ, Yin X, Lu L, Lenz DR et al (2017) Clonal expansion of Lgr5-positive cells from mammalian cochlea and high-purity generation of sensory hair cells. Cell Rep 18(8):1917–1929. https://doi.org/10.1016/j.celrep.2017.01.066
Article CAS PubMed PubMed Central Google Scholar
Mizutari K, Fujioka M, Hosoya M, Bramhall N et al (2013) Notch inhibition induces cochlear hair cell regeneration and recovery of hearing after acoustic trauma. Neuron 77(1):58–69. https://doi.org/10.1016/j.neuron.2012.10.032
Article CAS PubMed PubMed Central Google Scholar
Muller U, Barr-Gillespie PG (2015) New treatment options for hearing loss. Nat Rev Drug Discov. https://doi.org/10.1038/nrd4533
Mulvaney J, Dabdoub A (2012) Atoh1, an essential transcription factor in neurogenesis and intestinal and inner ear development: function, regulation, and context dependency. J Assoc Res Otolaryngol 13(3):281–293. https://doi.org/10.1007/s10162-012-0317-4
Article PubMed PubMed Central Google Scholar
Niemiec AJ, Raphael Y, Moody DB (1994) Return of auditory function following structural regeneration after acoustic trauma: behavioral measures from quail. Hear Res 79(1–2):1–16
Article CAS PubMed Google Scholar
Oesterle EC (2013) Changes in the adult vertebrate auditory sensory epithelium after trauma. Hear Res 297:91–98. https://doi.org/10.1016/j.heares.2012.11.010
Article PubMed Google Scholar
Oesterle EC, Campbell S (2009) Supporting cell characteristics in long-deafened aged mouse ears. J Assoc Res Otolaryngol 10(4):525–544. https://doi.org/10.1007/s10162-009-0183-x
Article PubMed PubMed Central Google Scholar
Oesterle EC, Tsue TT, Reh TA, Rubel EW (1993) Hair-cell regeneration in organ cultures of the postnatal chicken inner ear. Hear Res 70(1):85–108
Article CAS PubMed Google Scholar
Ohnishi H, Skerleva D, Kitajiri S, Sakamoto T et al (2015) Limited hair cell induction from human induced pluripotent stem cells using a simple stepwise method. Neurosci Lett 599:49–54. https://doi.org/10.1016/j.neulet.2015.05.032
Article CAS PubMed Google Scholar
Ohyama T, Mohamed OA, Taketo MM, Dufort D, Groves AK (2006) Wnt signals mediate a fate decision between otic placode and epidermis. Development 133(5):865–875
Article CAS PubMed Google Scholar
Oshima K, Grimm CM, Corrales CE, Senn P et al (2007) Differential distribution of stem cells in the auditory and vestibular organs of the inner ear. J Assoc Res Otolaryngol 8(1):18–31. https://doi.org/10.1007/s10162-006-0058-3
Article PubMed Google Scholar
Oshima K, Shin K, Diensthuber M, Peng AW et al (2010) Mechanosensitive hair cell-like cells from embryonic and induced pluripotent stem cells. Cell 141(4):704–716. https://doi.org/10.1016/j.cell.2010.03.035
Article CAS PubMed PubMed Central Google Scholar
Pickar-Oliver A, Gersbach CA (2019) The next generation of CRISPR-Cas technologies and applications. Nat Rev Mol Cell Biol 20(8):490–507. https://doi.org/10.1038/s41580-019-0131-5
Article CAS PubMed PubMed Central Google Scholar
Rask-Andersen H, Li H, Lowenheim H, Muller M et al (2017) Supernumerary human hair cells-signs of regeneration or impaired development? A field emission scanning electron microscopy study. Ups J Med Sci 122(1):11–19. https://doi.org/10.1080/03009734.2016.1271843
Article PubMed PubMed Central Google Scholar
Retzius G (1884) Das Gehörorgan der Reptilien, der Vögel und der Säugethiere [Reprint of the Original from 1884]. eBooks on Demand (EOD) Network.
Google Scholar
Riccomagno MM, Martinu L, Mulheisen M, Wu DK, Epstein DJ (2002) Genes Dev 16(18): 2365–2378. Accession Number: 12231626. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=12231626
Roberson DW, Rubel EW (1994) Cell division in the gerbil cochlea after acoustic trauma. Am J Otol 15(1):28–34
CAS PubMed Google Scholar
Roberson DF, Weisleder P, Bohrer PS, Rubel EW (1992) Ongoing production of sensory cells in the vestibular epithelium of the chick. Hear Res 57(2):166–174
Article CAS PubMed Google Scholar
Roberson DW, Alosi JA, Cotanche DA (2004) Direct transdifferentiation gives rise to the earliest new hair cells in regenerating avian auditory epithelium. J Neurosci Res 78(4):461–471. https://doi.org/10.1002/jnr.20271
Article CAS PubMed Google Scholar
Roccio M, Perny M, Ealy M, Widmer HR et al (2018) Molecular characterization and prospective isolation of human fetal cochlear hair cell progenitors. Nat Commun 9(1):4027. https://doi.org/10.1038/s41467-018-06334-7
Article CAS PubMed PubMed Central Google Scholar
Ronaghi M, Nasr M, Ealy M, Durruthy-Durruthy R et al (2014) Inner ear hair cell-like cells from human embryonic stem cells. Stem Cells Dev 23(11):1275–1284. https://doi.org/10.1089/scd.2014.0033
Article CAS PubMed PubMed Central Google Scholar
Rosenthal N (2003) Prometheus’s vulture and the stem-cell promise. N Engl J Med 349(3):267–274. https://doi.org/10.1056/NEJMra020849
Article PubMed Google Scholar
Rowe RG, Daley GQ (2019) Induced pluripotent stem cells in disease modelling and drug discovery. Nat Rev Genet 20(7):377–388. https://doi.org/10.1038/s41576-019-0100-z
Article CAS PubMed PubMed Central Google Scholar
Rusch A, Lysakowski A, Eatock RA (1998) Postnatal development of type I and type II hair cells in the mouse utricle: acquisition of voltage-gated conductances and differentiated morphology. J Neurosci 18(18):7487–7501
Article CAS PubMed PubMed Central Google Scholar
Ryals BM, Rubel EW (1985) Differential susceptibility of avian hair cells to acoustic trauma. Hear Res 19(1):73–84. https://doi.org/10.1016/0378-5955(85)90099-1
Article CAS PubMed Google Scholar
Ryals BM, Rubel EW (1988) Hair cell regeneration after acoustic trauma in adult Coturnix quail. Science 240(4860):1774–1776. https://doi.org/10.1126/science.3381101
Article CAS PubMed Google Scholar
Sayyid ZN, Wang T, Chen L, Jones SM, Cheng AG (2019) Atoh1 directs regeneration and functional recovery of the mature mouse vestibular system. Cell Rep 28(2):312–324. e314. https://doi.org/10.1016/j.celrep.2019.06.028
Article CAS PubMed PubMed Central Google Scholar
Schaefer SA, Higashi AY, Loomis B, Schrepfer T et al (2018) From Otic Induction to Hair Cell Production: Pax2(EGFP) cell line illuminates key stages of development in mouse inner ear organoid model. Stem Cells Dev 27(4):237–251. https://doi.org/10.1089/scd.2017.0142
Article CAS PubMed PubMed Central Google Scholar
Scheibinger M, Ellwanger DC, Corrales CE, Stone JS, Heller S (2018) Aminoglycoside damage and hair cell regeneration in the chicken utricle. J Assoc Res Otolaryngol 19(1):17–29. https://doi.org/10.1007/s10162-017-0646-4
Article PubMed Google Scholar
Senn P, Oshima K, Teo D, Grimm C, Heller S (2007) Robust postmortem survival of murine vestibular and cochlear stem cells. J Assoc Res Otolaryngol 8(2):194–204. https://doi.org/10.1007/s10162-007-0079-6
Article PubMed PubMed Central Google Scholar
Shi F, Kempfle JS, Edge AS (2012) Wnt-responsive lgr5-expressing stem cells are hair cell progenitors in the cochlea. J Neurosci 32(28):9639–9648. https://doi.org/10.1523/JNEUROSCI.1064-12.2012
Article CAS PubMed PubMed Central Google Scholar
Shou J, Zheng JL, Gao WQ (2003) Robust generation of new hair cells in the mature mammalian inner ear by adenoviral expression of Hath1. Mol Cell Neurosci 23(2):169–179
Article CAS PubMed Google Scholar
Stojanova ZP, Kwan T, Segil N (2015) Epigenetic regulation of Atoh1 guides hair cell development in the mammalian cochlea. Development 142(20):3529–3536. https://doi.org/10.1242/dev.126763
Article CAS PubMed PubMed Central Google Scholar
Suga H, Kadoshima T, Minaguchi M, Ohgushi M et al (2011) Self-formation of functional adenohypophysis in three-dimensional culture. Nature 480(7375):57–62. https://doi.org/10.1038/nature10637
Article CAS PubMed Google Scholar
Swanson GJ, Howard M, Lewis J (1990) Epithelial autonomy in the development of the inner ear of a bird embryo. Dev Biol 137(2):243–257. https://doi.org/10.1016/0012-1606(90)90251-d
Article CAS PubMed Google Scholar
Takahashi K, Yamanaka S (2006) Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell 126(4):663–676. https://doi.org/10.1016/j.cell.2006.07.024
Article CAS PubMed Google Scholar
Takata N, Sakakura E, Kasukawa T, Sakuma T et al (2016) Establishment of functional genomics pipeline in mouse epiblast-like tissue by combining transcriptomic analysis and gene knockdown/knockin/knockout, using RNA interference and CRISPR/Cas9. Hum Gene Ther 27(6):436–450. https://doi.org/10.1089/hum.2015.148
Article CAS PubMed Google Scholar
Tanaka K, Smith CA (1978) Structure of the chicken’s inner ear: SEM and TEM study. Am J Anat 153(2):251–271. https://doi.org/10.1002/aja.1001530206
Article CAS PubMed Google Scholar
Teitz T, Goktug AN, Chen T, Zuo J (2016) Development of cell-based high-throughput chemical screens for protection against cisplatin-induced ototoxicity. Meth Mol Biol 1427:419–430. https://doi.org/10.1007/978-1-4939-3615-1_22
Article CAS Google Scholar
Theunissen TW, Powell BE, Wang H, Mitalipova M et al (2014) Systematic identification of culture conditions for induction and maintenance of naive human pluripotency. Cell Stem Cell 15(4):471–487. https://doi.org/10.1016/j.stem.2014.07.002
Article CAS PubMed PubMed Central Google Scholar
Warchol ME (2007) Characterization of supporting cell phenotype in the avian inner ear: implications for sensory regeneration. Hear Res 227(1–2):11–18. https://doi.org/10.1016/j.heares.2006.08.014
Article CAS PubMed Google Scholar
Warchol ME (2011) Sensory regeneration in the vertebrate inner ear: differences at the levels of cells and species. Hear Res 273(1–2):72–79. https://doi.org/10.1016/j.heares.2010.05.004
Article PubMed Google Scholar
Warchol ME, Lambert PR, Goldstein BJ, Forge A, Corwin JT (1993) Regenerative proliferation in inner ear sensory epithelia from adult guinea pigs and humans. Science 259(5101):1619–1622
Article CAS PubMed Google Scholar
White PM, Doetzlhofer A, Lee YS, Groves AK, Segil N (2006) Mammalian cochlear supporting cells can divide and trans-differentiate into hair cells. Nature 441(7096):984–987. https://doi.org/10.1038/nature04849
Article CAS PubMed Google Scholar
Wiwatpanit T, Lorenzen SM, Cantu JA, Foo CZ et al (2018) Trans-differentiation of outer hair cells into inner hair cells in the absence of INSM1. Nature 563(7733):691–695. https://doi.org/10.1038/s41586-018-0570-8
Article CAS PubMed PubMed Central Google Scholar
Woods C, Montcouquiol M, Kelley MW (2004) Math1 regulates development of the sensory epithelium in the mammalian cochlea. Nat Neurosci 7(12):1310–1318. https://doi.org/10.1038/nn1349
Article CAS PubMed Google Scholar
Wooltorton JR, Gaboyard S, Hurley KM, Price SD et al (2007) Developmental changes in two voltage-dependent sodium currents in utricular hair cells. J Neurophysiol 97(2):1684–1704. https://doi.org/10.1152/jn.00649.2006
Article CAS PubMed Google Scholar
Wright TJ, Mansour SL (2003) Fgf3 and Fgf10 are required for mouse otic placode induction. Development 130(15):3379–3390
Article CAS PubMed Google Scholar
Yamanaka S (2020) Pluripotent stem cell-based cell therapy-promise and challenges. Cell Stem Cell 27(4):523–531. https://doi.org/10.1016/j.stem.2020.09.014
Article CAS PubMed Google Scholar
Young RA (2011) Control of the embryonic stem cell state. Cell 144(6):940–954. https://doi.org/10.1016/j.cell.2011.01.032
Article CAS PubMed PubMed Central Google Scholar
Yu J, Vodyanik MA, Smuga-Otto K, Antosiewicz-Bourget J et al (2007) Induced pluripotent stem cell lines derived from human somatic cells. Science 318(5858):1917–1920. https://doi.org/10.1126/science.1151526
Article CAS PubMed Google Scholar
Zhang Y, Guo L, Lu X, Cheng C, Sun S et al (2018) Characterization of Lgr6+ cells as an enriched population of hair cell progenitors compared to Lgr5+ Cells for hair cell generation in the neonatal mouse cochlea. Front Mol Neurosci 11:147. https://doi.org/10.3389/fnmol.2018.00147
Article CAS PubMed PubMed Central Google Scholar
Zheng JL, Gao WQ (2000) Overexpression of Math1 induces robust production of extra hair cells in postnatal rat inner ears. Nat Neurosci 3(6):580–586
Article CAS PubMed Google Scholar

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Department of Otolaryngology – Head & Neck Surgery, Stanford University School of Medicine, Stanford, CA, USA
Amanda Janesick & Stefan Heller
Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA, USA
Amanda Janesick & Stefan Heller
Department of Otolaryngology–Head & Neck Surgery, Indiana University School of Medicine, Indianapolis, IN, USA
Eri Hashino

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Amanda Janesick
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Eri Hashino
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Stefan Heller
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Correspondence to Stefan Heller .

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Editors and Affiliations

Department of Otolaryngology, Washington University School of Medicine, St. Louis, MO, USA
Mark E. Warchol
Department of Otolaryngology/Head and Neck Surgery, Virginia Merrill Bloedel Hearing Research Center, University of Washington School of Medicine, Seattle, WA, USA
Jennifer S. Stone
Department of Integrative Physiology and Neuroscience, Washington State University, Vancouver, WA, USA
Allison B. Coffin
Department of Biology, University of Maryland, College Park, MD, USA
Arthur N. Popper
Department of Psychology, Loyola University Chicago, Chicago, IL, USA
Richard R. Fay

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Janesick, A., Hashino, E., Heller, S. (2023). Inner Ear Cells from Stem Cells: A Path Towards Inner Ear Cell Regeneration. In: Warchol, M.E., Stone, J.S., Coffin, A.B., Popper, A.N., Fay, R.R. (eds) Hair Cell Regeneration. Springer Handbook of Auditory Research, vol 75. Springer, Cham. https://doi.org/10.1007/978-3-031-20661-0_6

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DOI: https://doi.org/10.1007/978-3-031-20661-0_6
Published: 28 April 2023
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