Skip to main content
SpringerLink
Log in

Hair Cell Regeneration

  • Chapter
  • First Online:
Hearing Loss: Mechanisms, Prevention and Cure

Part of the book series: Advances in Experimental Medicine and Biology ((AEMB,volume 1130))

Abstract

Cochlear hair cells are mechanoreceptors of the auditory system and cannot spontaneously regenerate in adult mammals; thus hearing loss due to hair cell damage is permanent. In contrast, hair cells in nonmammalian vertebrates such as birds and in the zebrafish lateral line have the ability to regenerate after hair cell loss. Many regulatory factors, including signaling pathways, transcription factors, and epigenetic regulators, play roles in hair cell regeneration in various species. In this chapter, we review the history of hair cell regeneration research, the methods used in the study of hair cell regeneration, the properties and modulating factors of inner ear stem cells, and the re-formation of cochlear ribbon synapses and hearing function recovery.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 139.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Hardcover Book
USD 179.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  1. Johnsson LG, Hawkins JE Jr (1972) Sensory and neural degeneration with aging, as seen in microdissections of the human inner ear. Ann Otol Rhinol Laryngol 81(2):179–193

    Article  CAS  PubMed  Google Scholar 

  2. Henley CM et al (1996) Sensitive developmental periods for kanamycin ototoxic effects on distortion-product otoacoustic emissions. Hear Res 98(1–2):93–103

    Article  CAS  PubMed  Google Scholar 

  3. Murillo-Cuesta S et al (2015) Corrigendum: Transforming growth factor beta1 inhibition protects from noise-induced hearing loss. Front Aging Neurosci 7:72

    PubMed  PubMed Central  Google Scholar 

  4. Lambert PR, Gu R, Corwin JT (1997) Analysis of small hair bundles in the utricles of mature guinea pigs. Am J Otolaryngol 18(5):637–643

    CAS  Google Scholar 

  5. Bermingham-McDonogh O, Rubel EW (2003) Hair cell regeneration: winging our way towards a sound future. Curr Opin Neurobiol 13(1):119–126

    Article  CAS  PubMed  Google Scholar 

  6. Warchol ME et al (1993) Regenerative proliferation in inner ear sensory epithelia from adult guinea pigs and humans. Science 259(5101):1619–1622

    Article  CAS  PubMed  Google Scholar 

  7. White PM et al (2006) Mammalian cochlear supporting cells can divide and trans-differentiate into hair cells. Nature 441(7096):984–987

    Article  CAS  PubMed  Google Scholar 

  8. Chai RJ et al (2012) Wnt signaling induces proliferation of sensory precursors in the postnatal mouse cochlea. Proc Natl Acad Sci U S A 109(21):8167–8172

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Wang T et al (2015) Lgr5+ cells regenerate hair cells via proliferation and direct transdifferentiation in damaged neonatal mouse utricle. Nat Commun 6:6613

    Article  CAS  PubMed  Google Scholar 

  10. Li H, Liu H, Heller S (2003) Pluripotent stem cells from the adult mouse inner ear. Nat Med 9(10):1293–1299

    Article  CAS  PubMed  Google Scholar 

  11. Oshima K 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

    Article  PubMed  Google Scholar 

  12. Oshima K, Senn P, Heller S (2009) Isolation of sphere-forming stem cells from the mouse inner ear. Methods Mol Biol 493:141–162

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Chai RJ et al (2011) Dynamic expression of Lgr5, a Wnt target gene, in the developing and mature mouse cochlea. Jaro-J Assoc Res Otolaryngol 12(4):455–469

    Article  Google Scholar 

  14. Jan TA et al (2013) Tympanic border cells are Wnt-responsive and can act as progenitors for postnatal mouse cochlear cells. Development 140(6):1196–1206

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Oshima K et al (2010) Mechanosensitive hair cell-like cells from embryonic and induced pluripotent stem cells. Cell 141(4):704–716

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Savoy-Burke G et al (2014) Activated notch causes deafness by promoting a supporting cell phenotype in developing auditory hair cells. PLoS One 9(9):e108160

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  17. Lu X et al (2017) Bmi1 regulates the proliferation of cochlear supporting cells via the canonical Wnt signaling pathway. Mol Neurobiol 54(2):1326–1339

    Article  CAS  PubMed  Google Scholar 

  18. Chen Y et al (2013) Cotransfection of Pax2 and Math1 promote in situ cochlear hair cell regeneration after neomycin insult. Sci Rep 3:2996

    Article  PubMed  PubMed Central  Google Scholar 

  19. Cheng YF (2017) Atoh1 regulation in the cochlea: more than just transcription. J Zhejiang Univ Sci B

    Google Scholar 

  20. Nie X et al (2015) Transcription factor STOX1 regulates proliferation of inner ear epithelial cells via the AKT pathway. Cell Prolif 48(2):209–220

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Walters BJ et al (2014) Auditory hair cell-specific deletion of p27Kip1 in postnatal mice promotes cell-autonomous generation of new hair cells and normal hearing. J Neurosci 34(47):15751–15763

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  22. Rocha-Sanchez SM et al (2011) Mature mice lacking Rbl2/p130 gene have supernumerary inner ear hair cells and supporting cells. J Neurosci 31(24):8883–8893

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Kwan KY, Shen J, Corey DP (2015) C-MYC transcriptionally amplifies SOX2 target genes to regulate self-renewal in multipotent otic progenitor cells. Stem Cell Rep 4(1):47–60

    Article  CAS  Google Scholar 

  24. Jacques BE et al (2012) A dual function for canonical Wnt/beta-catenin signaling in the developing mammalian cochlea. Development 139(23):4395–4404

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Shi F et al (2014) beta-Catenin is required for hair-cell differentiation in the cochlea. J Neurosci 34(19):6470–6479

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Zhang YP et al (2015) Dynamic expression of Lgr6 in the developing and mature mouse cochlea. Front Cell Neurosci 9:165

    PubMed  PubMed Central  Google Scholar 

  27. Cox BC et al (2014) Spontaneous hair cell regeneration in the neonatal mouse cochlea in vivo. Development 141(4):816–829

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. 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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Romero-Carvajal A et al (2015) Regeneration of sensory hair cells requires localized interactions between the Notch and Wnt pathways. Dev Cell 34(3):267–282

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Jacques BE et al (2014) The role of Wnt/beta-catenin signaling in proliferation and regeneration of the developing basilar papilla and lateral line. Dev Neurobiol 74(4):438–456

    Article  CAS  PubMed  Google Scholar 

  31. Shi F, Hu L, Edge AS (2013) Generation of hair cells in neonatal mice by beta-catenin overexpression in Lgr5-positive cochlear progenitors. Proc Natl Acad Sci U S A 110(34):13851–13856

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Kuo BR et al (2015) In vivo cochlear hair cell generation and survival by coactivation of beta-Catenin and Atoh1. J Neurosci 35(30):10786–10798

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Ma EY, Rubel EW, Raible DW (2008) Notch signaling regulates the extent of hair cell regeneration in the zebrafish lateral line. J Neurosci 28(9):2261–2273

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Daudet N et al (2009) Notch regulation of progenitor cell behavior in quiescent and regenerating auditory epithelium of mature birds. Dev Biol 326(1):86–100

    Article  CAS  PubMed  Google Scholar 

  35. Korrapati S et al (2013) Notch signaling limits supporting cell plasticity in the hair cell-damaged early postnatal murine cochlea. PLoS One 8(8):e73276

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Mizutari K et al (2013) Notch inhibition induces cochlear hair cell regeneration and recovery of hearing after acoustic trauma. Neuron 77(1):58–69

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Li WY et al (2015) Notch inhibition induces mitotically generated hair cells in mammalian cochleae via activating the Wnt pathway. Proc Natl Acad Sci U S A 112(1):166–171

    Article  CAS  PubMed  Google Scholar 

  38. Driver EC et al (2008) Hedgehog signaling regulates sensory cell formation and auditory function in mice and humans. J Neurosci 28(29):7350–7358

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Zarei S et al (2017) Sonic hedgehog antagonists reduce size and alter patterning of the frog inner ear. Dev Neurobiol 77(12):1385–1400

    Article  PubMed  PubMed Central  Google Scholar 

  40. Riccomagno MM, Takada S, Epstein DJ (2005) Wnt-dependent regulation of inner ear morphogenesis is balanced by the opposing and supporting roles of Shh. Genes Dev 19(13):1612–1623

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Brown AS, Epstein DJ (2011) Otic ablation of smoothened reveals direct and indirect requirements for Hedgehog signaling in inner ear development. Development 138(18):3967–3976

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Lu N et al (2013) Sonic hedgehog initiates cochlear hair cell regeneration through downregulation of retinoblastoma protein. Biochem Biophys Res Commun 430(2):700–705

    Article  CAS  PubMed  Google Scholar 

  43. Chen Y et al (2017) Hedgehog signaling promotes the proliferation and subsequent hair cell formation of progenitor cells in the neonatal mouse cochlea. Front Mol Neurosci 10:426

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  44. Pickles JO (2001) The expression of fibroblast growth factors and their receptors in the embryonic and neonatal mouse inner ear. Hear Res 155(1–2):54–62

    Article  CAS  PubMed  Google Scholar 

  45. Wright TJ et al (2003) Expression of mouse fibroblast growth factor and fibroblast growth factor receptor genes during early inner ear development. Dev Dyn 228(2):267–272

    Article  CAS  PubMed  Google Scholar 

  46. Alvarez Y et al (2003) Requirements for FGF3 and FGF10 during inner ear formation. Development 130(25):6329–6338

    Article  CAS  PubMed  Google Scholar 

  47. 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 

  48. Represa J et al (1991) The int-2 proto-oncogene is responsible for induction of the inner ear. Nature 353(6344):561–563

    Article  CAS  PubMed  Google Scholar 

  49. Mansour SL, Goddard JM, Capecchi MR (1993) Mice homozygous for a targeted disruption of the proto-oncogene int-2 have developmental defects in the tail and inner ear. Development 117(1):13–28

    CAS  PubMed  Google Scholar 

  50. Mansour SL (1994) Targeted disruption of int-2 (fgf-3) causes developmental defects in the tail and inner ear. Mol Reprod Dev 39(1):62–67. discussion 67-8

    Article  CAS  PubMed  Google Scholar 

  51. McKay IJ, Lewis J, Lumsden A (1996) The role of FGF-3 in early inner ear development: an analysis in normal and kreisler mutant mice. Dev Biol 174(2):370–378

    Article  CAS  PubMed  Google Scholar 

  52. Vendrell V et al (2000) Induction of inner ear fate by FGF3. Development 127(10):2011–2019

    CAS  PubMed  Google Scholar 

  53. Leger S, Brand M (2002) Fgf8 and Fgf3 are required for zebrafish ear placode induction, maintenance and inner ear patterning. Mech Dev 119(1):91–108

    Article  CAS  PubMed  Google Scholar 

  54. Maroon H et al (2002) Fgf3 and Fgf8 are required together for formation of the otic placode and vesicle. Development 129(9):2099–2108

    CAS  PubMed  Google Scholar 

  55. Lysaght AC et al (2014) FGF23 deficiency leads to mixed hearing loss and middle ear malformation in mice. PLoS One 9(9):e107681

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  56. Ono K et al (2014) FGFR1-Frs2/3 signalling maintains sensory progenitors during inner ear hair cell formation. PLoS Genet 10(1):e1004118

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  57. Umemoto M et al (1995) Hair cell regeneration in the chick inner ear following acoustic trauma: ultrastructural and immunohistochemical studies. Cell Tissue Res 281(3):435–443

    Article  CAS  PubMed  Google Scholar 

  58. Zheng JL, Helbig C, Gao WQ (1997) Induction of cell proliferation by fibroblast and insulin-like growth factors in pure rat inner ear epithelial cell cultures. J Neurosci 17(1):216–226

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Lee SG et al (2016) Myc and Fgf are required for zebrafish neuromast hair cell regeneration. PLoS One 11(6):e0157768

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  60. Kawamoto K et al (2009) Spontaneous hair cell regeneration in the mouse utricle following gentamicin ototoxicity. Hear Res 247(1):17–26

    Article  CAS  PubMed  Google Scholar 

  61. Deyst KA, Ma J, Fallon JR (1995) Agrin: toward a molecular understanding of synapse regeneration. Neurosurgery 37(1):71–77

    Article  CAS  PubMed  Google Scholar 

  62. Deng LX et al (2013) A novel growth-promoting pathway formed by GDNF-overexpressing Schwann cells promotes propriospinal axonal regeneration, synapse formation, and partial recovery of function after spinal cord injury. J Neurosci 33(13):5655–5667

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Marler KJ et al (2008) A TrkB/EphrinA interaction controls retinal axon branching and synaptogenesis. J Neurosci 28(48):12700–12712

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Alto LT et al (2009) Chemotropic guidance facilitates axonal regeneration and synapse formation after spinal cord injury. Nat Neurosci 12(9):1106–11U8

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Tong MJ, Brugeaud A, Edge ASB (2013) Regenerated synapses between postnatal hair cells and auditory neurons. Jaro-J Assoc Res Otolaryngol 14(3):321–329

    Article  Google Scholar 

  66. Wan GQ et al (2014) Neurotrophin-3 regulates ribbon synapse density in the cochlea and induces synapse regeneration after acoustic trauma. elife 20:3

    Google Scholar 

  67. Smolders JWT (1999) Functional recovery in the avian ear after hair cell regeneration. Audiol Neuro Otol 4(6):286–302

    Article  CAS  Google Scholar 

  68. Carey JP, Fuchs AF, Rubel EW (1996) Hair cell regeneration and recovery of the vestibuloocular reflex in the avian vestibular system. J Neurophysiol 76(5):3301–3312

    Article  CAS  PubMed  Google Scholar 

  69. Atkinson PJ et al (2014) Hair cell regeneration after ATOH1 gene therapy in the cochlea of profoundly deaf adult guinea pigs. PLoS One 9(7):e102077

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  70. Baker K, Brough DE, Staecker H (2009) Repair of the vestibular system via adenovector delivery of Atoh1: a potential treatment for balance disorders. Adv Otorhinolaryngol 66:52–63

    CAS  PubMed  Google Scholar 

  71. Du X et al (2018) Regeneration of cochlear hair cells and hearing recovery through Hes1 modulation with siRNA nanoparticles in adult guinea pigs. Mol Ther 26(5):1313–1326

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Izumikawa M et al (2005) Auditory hair cell replacement and hearing improvement by Atoh1 gene therapy in deaf mammals. Nat Med 11(3):271–276

    Article  CAS  PubMed  Google Scholar 

  73. Chessum L et al (2018) Helios is a key transcriptional regulator of outer hair cell maturation. Nature 563(7733):696–700

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Zampini V et al (2011) Eps8 regulates hair bundle length and functional maturation of mammalian auditory hair cells. PLoS Biol 9(4):e1001048

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Wiwatpanit T et al (2018) Trans-differentiation of outer hair cells into inner hair cells in the absence of INSM1. Nature 563(7733):691–695

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. ENT Institute and Otorhinolaryngology Department, Affiliated Eye and ENT Hospital, Fudan University, Shanghai, China

    Yan Chen

  2. NHC Key Laboratory of Hearing Medicine (Fudan University), Shanghai Engineering Research Centre of Cochlear Implant, Shanghai, China

    Yan Chen

  3. Key Laboratory for Developmental Genes and Human Disease, Ministry of Education, Jiangsu Province High-Tech Key Laboratory for Bio-Medical Research, Institute of Life Sciences, Southeast University, Nanjing, China

    Shasha Zhang

  4. MOE Key Laboratory for Developmental Genes and Human Disease, Institute of Life Sciences, Jiangsu Province High-Tech Key Laboratory for Bio-Medical Research, Southeast University, Nanjing, China

    Renjie Chai

  5. Key Laboratory of Hearing Medicine of NHFPC, ENT Institute and Otorhinolaryngology Department, Shanghai Engineering Research Centre of Cochlear Implant, Affiliated Eye and ENT Hospital, State Key Laboratory of Medical Neurobiology, Fudan University, Shanghai, China

    Renjie Chai & Huawei Li

Authors
  1. Yan Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Shasha Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Renjie Chai
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Huawei Li
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Huawei Li .

Editor information

Editors and Affiliations

  1. Key Laboratory of Hearing Medicine of NHFPC, ENT Institute and Otorhinolaryngology Department, Shanghai Engineering Research Centre of Cochlear Implant, Affiliated Eye and ENT Hospital, State Key Laboratory of Medical Neurobiology, Fudan University, Shanghai, China

    Huawei Li

  2. MOE Key Laboratory for Developmental Genes and Human Disease, Institute of Life Sciences, Jiangsu Province High-Tech Key Laboratory for Bio-Medical Research, Southeast University, Nanjing, China

    Renjie Chai

Rights and permissions

Reprints and permissions

Copyright information

© 2019 Springer Nature Singapore Pte Ltd.

About this chapter

Check for updates. Verify currency and authenticity via CrossMark

Cite this chapter

Chen, Y., Zhang, S., Chai, R., Li, H. (2019). Hair Cell Regeneration. In: Li, H., Chai, R. (eds) Hearing Loss: Mechanisms, Prevention and Cure. Advances in Experimental Medicine and Biology, vol 1130. Springer, Singapore. https://doi.org/10.1007/978-981-13-6123-4_1

Download citation

Publish with us

Policies and ethics

Search

Navigation