Regeneration of hair cells in the mammalian vestibular system

Abstract

Hair cells regenerate throughout the lifetime of non-mammalian vertebrates, allowing these animals to recover from hearing and balance deficits. Such regeneration does not occur efficiently in humans and other mammals. Thus, balance deficits become permanent and is a common sensory disorder all over the world. Since Forge and Warchol discovered the limited spontaneous regeneration of vestibular hair cells after gentamicin-induced damage in mature mammals, significant efforts have been exerted to trace the origin of the limited vestibular regeneration in mammals after hair cell loss. Moreover, recently many strategies have been developed to promote the hair cell regeneration and subsequent functional recovery of the vestibular system, including manipulating the Wnt, Notch and Atoh1. This article provides an overview of the recent advances in hair cell regeneration in mammalian vestibular epithelia. Furthermore, this review highlights the current limitations of hair cell regeneration and provides the possible solutions to regenerate functional hair cells and to partially restore vestibular function.

Keywords

utricle / hair cell / regeneration / Atoh1 / Notch / Wnt

References

[1] Lambert PR. Inner ear hair cell regeneration in a mammal: identification of a triggering factor. Laryngoscope 1994; 104(6 Pt 1): 701–718

[2] Fan C, Zou S, Wang J, Zhang B, Song J. Neomycin damage and regeneration of hair cells in both mechanoreceptor and electroreceptor lateral line organs of the larval Siberian sturgeon (Acipenser baerii). J Comp Neurol 2016; 524(7): 1443–1456

[3] Sedó-Cabezón L, Jedynak P, Boadas-Vaello P, Llorens J. Transient alteration of the vestibular calyceal junction and synapse in response to chronic ototoxic insult in rats. Dis Model Mech 2015; 8(10): 1323–1337

[4] Slattery EL, Oshima K, Heller S, Warchol ME. Cisplatin exposure damages resident stem cells of the mammalian inner ear. Dev Dyn 2014; 243(10): 1328–1337

[5] Balak KJ, Corwin JT, Jones JE. Regenerated hair cells can originate from supporting cell progeny: evidence from phototoxicity and laser ablation experiments in the lateral line system. J Neurosci 1990; 10(8): 2502–2512

[6] Burns JC, Cox BC, Thiede BR, Zuo J, Corwin JT. In vivo proliferative regeneration of balance hair cells in newborn mice. J Neurosci 2012; 32(19): 6570–6577

[7] Roberson DF, Weisleder P, Bohrer PS, Rubel EW. Ongoing production of sensory cells in the vestibular epithelium of the chick. Hear Res 1992; 57(2): 166–174

[8] Weisleder P, Rubel EW. Hair cell regeneration in the avian vestibular epithelium. Exp Neurol 1992; 115(1): 2–6

[9] Brosel S, Laub C, Averdam A, Bender A, Elstner M. Molecular aging of the mammalian vestibular system. Ageing Res Rev 2016; 26: 72–80

[10] Rüsch A, Lysakowski A, Eatock RA. Postnatal development of type I and type II hair cells in the mouse utricle: acquisition of voltage-gated conductances and differentiated morphology. J Neurosci 1998; 18(18): 7487–7501

[11] Lopez I, Honrubia V, Lee SC, Schoeman G, Beykirch K. Quantification of the process of hair cell loss and recovery in the chinchilla crista ampullaris after gentamicin treatment. Int J Dev Neurosci 1997; 15(4-5): 447–461

[12] Forge A, Li L, Corwin JT, Nevill G. Ultrastructural evidence for hair cell regeneration in the mammalian inner ear. Science 1993; 259(5101): 1616–1619

[13] Warchol ME, Lambert PR, Goldstein BJ, Forge A, Corwin JT. Regenerative proliferation in inner ear sensory epithelia from adult guinea pigs and humans. Science 1993; 259(5101): 1619–1622

[14] Rubel EW, Dew LA, Roberson DW. Mammalian vestibular hair cell regeneration. Science 1995; 267(5198): 701–707

[15] Corwin JT, Warchol ME, Saffer LD, Finley JE, Gu R, Lamber PR. Growth factors as potential drugs for the sensory epithelia of the ear. Ciba Found Symp 1996; 196:167–182, discussion182–187

[16] Saffer LD, Gu R, Corwin JT. An RT-PCR analysis of mRNA for growth factor receptors in damaged and control sensory epithelia of rat utricles. Hear Res 1996; 94(1-2): 14–23

[17] Yamashita H, Oesterle EC. Induction of cell proliferation in mammalian inner-ear sensory epithelia by transforming growth factor α and epidermal growth factor. Proc Natl Acad Sci USA 1995; 92(8): 3152–3155

[18] Kuntz AL, Oesterle EC. Transforming growth factor-α with insulin induces proliferation in rat utricular extrasensory epithelia. Otolaryngol Head Neck Surg 1998; 118(6): 816–824

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

[20] Kuntz AL, Oesterle EC. Transforming growth factor α with insulin stimulates cell proliferation in vivo in adult rat vestibular sensory epithelium. J Comp Neurol 1998; 399(3): 413–423

[21] Zheng JL, Stewart RR, Gao WQ. Neurotrophin-4/5, brain-derived neurotrophic factor, and neurotrophin-3 promote survival of cultured vestibular ganglion neurons and protect them against neurotoxicity of ototoxins. J Neurobiol 1995; 28(3): 330–340

[22] Kopke RD, Jackson RL, Li G, Rasmussen MD, Hoffer ME, Frenz DA, Costello M, Schultheiss P, Van De Water TR. Growth factor treatment enhances vestibular hair cell renewal and results in improved vestibular function. Proc Natl Acad Sci USA 2001; 98(10): 5886–5891

[23] Marchionni MA, Goodearl AD, Chen MS, Bermingham-McDonogh O, Kirk C, Hendricks M, Danehy F, Misumi D, Sudhalter J, Kobayashi K, Wroblewski D, Lynch C, Baldassare M, Hiles Ian, Davis JB, Hsuan JJ, Totty NF, Otsu Masayuki, McBurney RN, Waterfield MD, Stroobant P, Gwynne D. Glial growth factors are alternatively spliced erbB2 ligands expressed in the nervous system. Nature 1993; 362(6418): 312–318

[24] Gu R, Montcouquiol M, Marchionni M, Corwin JT. Proliferative responses to growth factors decline rapidly during postnatal maturation of mammalian hair cell epithelia. Eur J Neurosci 2007; 25(5): 1363–1372

[25] Montcouquiol M, Corwin JT. Intracellular signals that control cell proliferation in mammalian balance epithelia: key roles for phosphatidylinositol-3 kinase, mammalian target of rapamycin, and S6 kinases in preference to calcium, protein kinase C, and mitogen-activated protein kinase. J Neurosci 2001; 21(2): 570–580

[26] Navaratnam DS, Su HS, Scott SP, Oberholtzer JC. Proliferation in the auditory receptor epithelium mediated by a cyclic AMP-dependent signaling pathway. Nat Med 1996; 2(10): 1136–1139

[27] Montcouquiol M, Corwin JT. Brief treatments with forskolin enhance s-phase entry in balance epithelia from the ears of rats. J Neurosci 2001; 21(3): 974–982

[28] Burns JC, On D, Baker W, Collado MS, Corwin JT. Over half the hair cells in the mouse utricle first appear after birth, with significant numbers originating from early postnatal mitotic production in peripheral and striolar growth zones. J Assoc Res Otolaryngol 2012; 13(5): 609–627

[29] Davies D, Magnus C, Corwin JT. Developmental changes in cell-extracellular matrix interactions limit proliferation in the mammalian inner ear. Eur J Neurosci 2007; 25(4): 985–998

[30] Meyers JR, Corwin JT. Shape change controls supporting cell proliferation in lesioned mammalian balance epithelium. J Neurosci 2007; 27(16): 4313–4325

[31] Burns JC, Christophel JJ, Collado MS, Magnus C, Carfrae M, Corwin JT. Reinforcement of cell junctions correlates with the absence of hair cell regeneration in mammals and its occurrence in birds. J Comp Neurol 2008; 511(3): 396–414

[32] Burns JC, Collado MS, Oliver ER, Corwin JT. Specializations of intercellular junctions are associated with the presence and absence of hair cell regeneration in ears from six vertebrate classes. J Comp Neurol 2013; 521(6): 1430–1448

[33] Burns JC, Corwin JT. Responses to cell loss become restricted as the supporting cells in mammalian vestibular organs grow thick junctional actin bands that develop high stability. J Neurosci 2014; 34(5): 1998–2011

[34] Whitlon DS. E-cadherin in the mature and developing organ of Corti of the mouse. J Neurocytol 1993; 22(12): 1030–1038

[35] Hackett L, Davies D, Helyer R, Kennedy H, Kros C, Lawlor P, Rivolta MN, Holley M. E-cadherin and the differentiation of mammalian vestibular hair cells. Exp Cell Res 2002; 278(1): 19–30

[36] Lu Z, Corwin JT. The influence of glycogen synthase kinase 3 in limiting cell addition in the mammalian ear. Dev Neurobiol 2008; 68(8): 1059–1075

[37] Collado MS, Thiede BR, Baker W, Askew C, Igbani LM, Corwin JT. The postnatal accumulation of junctional E-cadherin is inversely correlated with the capacity for supporting cells to convert directly into sensory hair cells in mammalian balance organs. J Neurosci 2011; 31(33): 11855–11866

[38] Kawamoto K, Izumikawa M, Beyer LA, Atkin GM, Raphael Y. Spontaneous hair cell regeneration in the mouse utricle following gentamicin ototoxicity. Hear Res 2009; 247(1): 17–26

[39] Collado MS, Burns JC, Meyers JR, Corwin JT. Variations in shape-sensitive restriction points mirror differences in the regeneration capacities of avian and mammalian ears. PLoS ONE 2011; 6(8): e23861

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

[41] Chai R, Xia A, Wang T, Jan TA, Hayashi T, Bermingham-McDonogh O, Cheng AG. Dynamic expression of Lgr5, a Wnt target gene, in the developing and mature mouse cochlea. J Assoc Res Otolaryngol 2011; 12(4): 455–469

[42] Chai R, Kuo B, Wang T, Liaw EJ, Xia A, Jan TA, Liu Z, Taketo MM, Oghalai JS, Nusse R, Zuo J, Cheng AG. Wnt signaling induces proliferation of sensory precursors in the postnatal mouse cochlea. Proc Natl Acad Sci USA 2012; 109(21): 8167–8172

[43] Shi F, Hu L, Edge ASB. Generation of hair cells in neonatal mice by b-catenin overexpression in Lgr5-positive cochlear progenitors. Proc Natl Acad Sci USA 2013; 110(34): 13851–13856

[44] Bramhall NF, Shi F, Arnold K, Hochedlinger K, Edge ASB. Lgr5-positive supporting cells generate new hair cells in the postnatal cochlea. Stem Cell Rep 2014; 2(3): 311–322

[45] Li W, Wu J, Yang J, Sun S, Chai R, Chen ZY, Li H. Notch inhibition induces mitotically generated hair cells in mammalian cochleae via activating the Wnt pathway. Proc Natl Acad Sci USA 2015; 112(1): 166–171

[46] Wang T, Chai R, Kim GS, Pham N, Jansson L, Nguyen DH, Kuo B, May LA, Zuo J, Cunningham LL, Cheng AG. Lgr5⁺ cells regenerate hair cells via proliferation and direct transdifferentiation in damaged neonatal mouse utricle. Nat Commun 2015; 6: 6613

[47] Lin J, Zhang X, Wu F, Lin W. Hair cell damage recruited Lgr5-expressing cells are hair cell progenitors in neonatal mouse utricle. Front Cell Neurosci 2015; 9: 113

[48] Forge A, Li L, Nevill G. Hair cell recovery in the vestibular sensory epithelia of mature guinea pigs. J Comp Neurol 1998; 397(1): 69–88

[49] Golub JS, Tong L, Ngyuen TB, Hume CR, Palmiter RD, Rubel EW, Stone JS. Hair cell replacement in adult mouse utricles after targeted ablation of hair cells with diphtheria toxin. J Neurosci 2012; 32(43): 15093–15105

[50] Bermingham NA, Hassan BA, Price SD, Vollrath MA, Ben-Arie N, Eatock RA, Bellen HJ, Lysakowski A, Zoghbi HY. Math1: an essential gene for the generation of inner ear hair cells. Science 1999; 284(5421): 1837–1841

[51] Zheng JL, Gao WQ. Overexpression of Math1 induces robust production of extra hair cells in postnatal rat inner ears. Nat Neurosci 2000; 3(6): 580–586

[52] Shou J, Zheng JL, Gao WQ. Robust generation of new hair cells in the mature mammalian inner ear by adenoviral expression of Hath1. Mol Cell Neurosci 2003; 23(2): 169–179

[53] Staecker H, Praetorius M, Baker K, Brough DE. Vestibular hair cell regeneration and restoration of balance function induced by math1 gene transfer. Otol Neurotol 2007; 28(2): 223–231

[54] Staecker H, Schlecker C, Kraft S, Praetorius M, Hsu C, Brough DE. Optimizing atoh1-induced vestibular hair cell regeneration. Laryngoscope 2014; 124(Suppl 5): S1–S12

[55] Schlecker C, Praetorius M, Brough DE, Presler RG Jr, Hsu C, Plinkert PK, Staecker H. Selective atonal gene delivery improves balance function in a mouse model of vestibular disease. Gene Ther 2011; 18(9): 884–890

[56] Xu JC, Huang DL, Hou ZH, Guo WW, Sun JH, Zhao LD, Yu N, Young WY, He DZ, Yang SM. Type I hair cell regeneration induced by Math1 gene transfer following neomycin ototoxicity in rat vestibular sensory epithelium. Acta Otolaryngol 2012; 132(8): 819–828

[57] Gao Z, Kelly MC, Yu D, Wu H, Lin X, Chi FL, Chen P. Spatial and age-dependent hair cell generation in the postnatal mammalian utricle. Mol Neurobiol 2016; 53(3): 1601–1612

[58] Slowik AD, Bermingham-McDonogh O. Hair cell generation by notch inhibition in the adult mammalian cristae. J Assoc Res Otolaryngol 2013; 14(6): 813–828

[59] Lanford PJ, Lan Y, Jiang R, Lindsell C, Weinmaster G, Gridley T, Kelley MW. Notch signalling pathway mediates hair cell development in mammalian cochlea. Nat Genet 1999; 21(3): 289–292

[60] Wang GP, Chatterjee I, Batts SA, Wong HT, Gong TW, Gong SS, Raphael Y. Notch signaling and Atoh1 expression during hair cell regeneration in the mouse utricle. Hear Res 2010; 267(1-2): 61–70

[61] Mizutari K, Fujioka M, Hosoya M, Bramhall N, Okano HJ, Okano H, Edge AS. Notch inhibition induces cochlear hair cell regeneration and recovery of hearing after acoustic trauma. Neuron 2013; 77(1): 58–69

[62] Lin V, Golub JS, Nguyen TB, Hume CR, Oesterle EC, Stone JS. Inhibition of Notch activity promotes nonmitotic regeneration of hair cells in the adult mouse utricles. J Neurosci 2011; 31(43): 15329–15339

[63] Jung JY, Avenarius MR, Adamsky S, Alpert E, Feinstein E, Raphael Y. siRNA targeting Hes5 augments hair cell regeneration in aminoglycoside-damaged mouse utricle. Mol Ther 2013; 21(4): 834–841

[64] Brigande JV, Heller S. Quo vadis, hair cell regeneration? Nat Neurosci 2009; 12(6): 679–685

[65] Chen P, Segil N. p27(Kip1) links cell proliferation to morphogenesis in the developing organ of Corti. Development 1999; 126(8): 1581–1590

[66] Löwenheim H, Furness DN, Kil J, Zinn C, Gültig K, Fero ML, Frost D, Gummer AW, Roberts JM, Rubel EW, Hackney CM, Zenner HP. Gene disruption of p27(Kip1) allows cell proliferation in the postnatal and adult organ of corti. Proc Natl Acad Sci USA 1999; 96(7): 4084–4088

[67] White PM, Doetzlhofer A, Lee YS, Groves AK, Segil N. Mammalian cochlear supporting cells can divide and trans-differentiate into hair cells. Nature 2006; 441(7096): 984–987

[68] Sage C, Huang M, Karimi K, Gutierrez G, Vollrath MA, Zhang DS, García-Añoveros J, Hinds PW, Corwin JT, Corey DP, Chen ZY. Proliferation of functional hair cells in vivo in the absence of the retinoblastoma protein. Science 2005; 307(5712): 1114–1118

[69] Sage C, Huang M, Vollrath MA, Brown MC, Hinds PW, Corey DP, Vetter DE, Chen ZY. Essential role of retinoblastoma protein in mammalian hair cell development and hearing. Proc Natl Acad Sci USA 2006; 103(19): 7345–7350

[70] Weber T, Corbett MK, Chow LM, Valentine MB, Baker SJ, Zuo J. Rapid cell-cycle reentry and cell death after acute inactivation of the retinoblastoma gene product in postnatal cochlear hair cells. Proc Natl Acad Sci USA 2008; 105(2): 781–785

[71] Yu Y, Weber T, Yamashita T, Liu Z, Valentine MB, Cox BC, Zuo J. In vivo proliferation of postmitotic cochlear supporting cells by acute ablation of the retinoblastoma protein in neonatal mice. J Neurosci 2010; 30(17): 5927–5936

[72] Laine H, Sulg M, Kirjavainen A, Pirvola U. Cell cycle regulation in the inner ear sensory epithelia: role of cyclin D1 and cyclin-dependent kinase inhibitors. Dev Biol 2010; 337(1): 134–146

[73] Loponen H, Ylikoski J, Albrecht JH, Pirvola U. Restrictions in cell cycle progression of adult vestibular supporting cells in response to ectopic cyclin D1 expression. PLoS ONE 2011; 6(11): e27360–e12

[74] Burns JC, Yoo JJ, Atala A, Jackson JD. MYC gene delivery to adult mouse utricles stimulates proliferation of postmitotic supporting cells in vitro. PLoS ONE 2012; 7(10): e48704

[75] Waqas M, Guo L, Zhang S, Chen Y. Zhang X, Wang L, Tang M, Shi H, Bird P I, Li H, Chai R. Characterization of Lgr5⁺ progenitor cell transcriptomes in the apical and basal turns of the mouse cochlea. Oncotorget<Date> 2016 Apr 7.</Date> [Epub ahead of print] doi: 10.18632/oncotarget.8636

Acknowledgements

This work was supported by grants from the National Basic Research Program of China (973 Program, No. 2015CB965000), National Natural Science Foundation of China (Nos. 81400463, 81570911, 81470692, 81230019, 81371094, 81500790, 81570921, 31500852, and 31501194), Jiangsu Province Natural Science Foundation (Nos. BK20150022, BK20140620, and BK20150598), Fundamental Research Funds for the Central Universities (Nos. 2242014R30022 and 021414380037), the Yingdong Huo Education Foundation, the Open Research Funds of the State Key Laboratory of Genetic Engineering, Fudan University (No. SKLGE-1407), Major Program of Shanghai Committee of Science and Technology (Nos. 14DJ1400203 and 11441901000), Doctoral Fund of Chinese Ministry of Education (No. 20120071110077), and China Postdoctoral Science Foundation Funded Project (No. 2014M551328).

Compliance with ethics guidelines

Wenyan Li, Dan You, Yan Chen, Renjie Chai, and Huawei Li declare no competing financial interests. This manuscript is a review article and does not involve a research protocol requiring approval by a relevant institutional review board or ethics committee.

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2016 Higher Education Press and Springer-Verlag Berlin Heidelberg