A Primer on Biology of Hair Cell Regeneration, Rescue, and Repair

ABSTRACT

This article is designed to provide basic introductory information for nonbiologists who want to learn more about the cellular and molecular mechanisms that may form the basis of future directions for therapies aimed at preventing or reversing hearing loss. The first section reviews basic cell biology and mechanisms of the cell cycle. Molecular factors that regulate the cell cycle, such as cyclin-dependent kinases, growth factor, and tumor suppressor proteins, are described in terms of their functions in regulating each stage of the cell cycle. These regulating factors are discussed in light of their potential roles for inducing cells to reinitiate the cell cycle and thus produce new cells. Regulatory proteins, immunologic elements, and growth factors are discussed in terms of their roles in stimulating these new cells to differentiate into hair cells. Specific examples from the auditory system are provided. The second section reviews basic mechanisms of cell death. Two types of cell death, necrosis and apoptosis, are defined. Multiple apoptotic pathways are described, including cell death triggered by ligation of cell surface "death receptors" (Fas, TNF-α-R) and cell death triggered by damage to specific cellular organelles, such as mitochondria. Finally, mechanisms of cell rescue and repair are discussed in light of the presence of cell survival signals and cell death signals. Cell survival signals, such as Bcl-2 and glutathione act to promote cell survival in the presence of a potentially death-inducing stimulus. These signals and the ways in which they might be used in the future to prevent hair cell death resulting from aging, noise, or drug exposure are briefly introduced.

KEYWORDS

Cell cycle - mitosis - cyclin-dependent kinase - apoptosis - caspase

REFERENCES

• 1 Ryals B M. Regeneration of the auditory pathway. In: Valente M, Hosford-Dunn H, Roeser RJ, eds. Audiology: Treatment New York: Thieme 2000 : 755-771
• 2 Ryals B M. Hair cell regeneration: it's not just for the birds.  Hear J . 2000;  53 10-19
• 3 Ryals B M. Page ten: hair cell regeneration: is it just for the birds?.  Hear J . 1995;  48 10:76-83
• 4 Stone J S, Oesterle E C, Rubel E W. Recent insights into regeneration of auditory and vestibular hair cells.  Curr Opin Neurol . 1998;  11 117-124
• 5 Staecker H, Van De Water R T. Factors controlling hair-cell regeneration/repair in the inner ear.  Curr Opin Neurobiol . 1998;  8 480-487
• 6 Rivolta M N. Transcription factors in the ear: molecular switches for development and differentiation.  Audiol Neurootol . 1997;  2 36-49
• 7 Nasmyth K. Viewpoint: putting the cell cycle in order.  Science . 1996;  274 1643-1645
• 8 Ruben R J. Development of the inner ear of the mouse: a radioautographic study of terminal mitoses.  Acta Otolaryngol . 1967;  220(Suppl) 1-44
• 9 Ryals B M, Rubel E W. Hair cell regeneration after acoustic trauma in adult coturnix quail.  Science . 1988;  240 1774-1776
• 10 Corwin J T, Cotanche D A. Regeneration of sensory hair cells after acoustic trauma.  Science . 1988;  240 1772-1774
• 11 Oesterle E C, Hume C R. Growth factor regulation of the cell cycle in developing and mature inner ear sensory epithelia.  J Neurocytol . 1999;  28 877-887
• 12 Stone J S, Oesterle E C, Rubel E W. Recent insights into regeneration of auditory and vestibular hair cells.  Curr Opin Neurol . 1998;  11 17-24
• 13 Staecker H, Van De Water R T. Factors controlling hair-cell regeneration/repair in the inner ear.  Curr Opin Neurobiol . 1998;  8 480-487
• 14 Warchol M E. Macrophage activity in organ cultures of the avian cochlea: demonstration of a resident population and recruitment to sites of hair cell lesions.  J Neurobiol . 1997;  33 724-734
• 15 Bhave S A, Oesterle E C, Coltrera M D. Macrophage and microglia-like cells in the avian inner ear.  J Comp Neurol . 1998;  398 241-256
• 16 Chen P, Segil N. p27(Kip1) links cell proliferation to morphogenesis in the developing organ of Corti.  Development . 1999;  126 1581-1590
• 17 Torchinsky C, Messana E P, Arsura M, Cotanche D A. Regulation of p27Kip1 during gentamicin mediated hair cell death.  J Neurocytol . 1999;  28 913-924
• 18 Baird R A, Burton M D, Fashena D S, Naeger R A. Hair cell recovery in mitotically blocked cultures of the bullfrog saccule.  Proc Natl Acad Sci U S A . 2000;  97 11722-11729
• 19 Adler H J, Komeda M, Raphael Y. Further evidence for supporting cell conversion in the damaged avian basilar papilla.  Int J Dev Neurosci . 1997;  15 375-385
• 20 Kelley M W, Xu X M, Wagner M A, Warchol M E, Corwin J T. The developing organ of Corti contains retinoic acid and forms supernumerary hair cells in response to exogenous retinoic acid in culture.  Development . 1993;  119 1041-1053
• 21 Raz Y, Kelley M W. Retinoic acid signaling is necessary for the development of the organ of Corti.  Dev Biol . 1999;  213 180-193
• 22 Steel K P, Mburu P, Gibson F. Unraveling the genetics of deafness.  Ann Otol Rhinol Laryngol Suppl . 1997;  168 59-62
• 23 Bermingham N A, Hassan B A, Price S D. MatH1: an essential gene for the generation of inner ear hair cells.  Science . 1999;  284 1837-1841
• 24 Chen P, Johnson J E, Zoghbi H Y, Segil N. The role of MatH1 in inner ear development: uncoupling the establishment of the sensory primordium from hair cell fate determination.  Development . 2002;  129 2495-2505
• 25 Zheng J L, Shou J, Guillemot F, Kageyama R, Gao W Q. Hes1 is a negative regulator of inner ear hair cell differentiation.  Development . 2000;  127 4551-4560
• 26 Stone J S, Rubel E W. Delta1 expression during avian hair cell regeneration.  Development . 1999;  126 961-973
• 27 Rubel E W. Ontogeny of structure and function in the vertebrate auditory system. In: Jacobson M, ed. Handbook of Sensory Physiology IX Berlin: Springer-Verlag 1978: 135-237
• 28 Corwin J T, Warchol M E, Kelley M W. Hair cell development.  Curr Opin Neurobiol . 1993;  3 32-37
• 29 Corwin J T, Cotanche D A. Development of location-specific hair cell stereocilia in denervated embryonic ears.  J Comp Neurol . 1989;  288 529-537
• 30 Ryals B M, Westbrook E W. TEM analysis of neural terminals on autoradiographically identified regenerated hair cells.  Hear Res . 1994;  72 81-88
• 31 Yamasoba T, Schacht J, Shoji F, Miller J M. Attenuation of cochlear damage from noise trauma by an iron chelator, a free radical scavenger and glial cell line-derived neurotrophic factor in vivo.  Brain Res . 1999;  815 317-325
• 32 Forge A, Li L. Apoptotic death of hair cells in mammalian vestibular sensory epithelia.  Hear Res . 2000;  139 97-115
• 33 Ohinata Y, Yamasoba T, Schacht J, Miller J M. Glutathione limits noise-induced hearing loss.  Hear Res . 2000;  146 28-34
• 34 Matsui J I, Ogilvie J M, Warchol M E. Inhibition of caspases prevents ototoxic and ongoing hair cell death.  J Neurosci . 2002;  22 1218-1227
• 35 Clarke P GH. Neuronal death in health and disease.  Semin Neurosci . 1994;  6 281-347
• 36 Lang H, Bever M M, Fekete D M. Cell proliferation and cell death in the developing chick inner ear: spatial and temporal patterns.  J Comp Neurol . 2000;  417 205-20
• 37 Fekete D M. Development of the vertebrate ear: insights from knockouts and mutants.  Trends Neurosci . 1999;  22 263-269
• 38 Jókay I, Soós G, Répássy G, Dezsõ B. Apoptosis in the human inner ear. Detection by in situ end-labeling of fragmented DNA and correlation with other markers.  Hear Res . 1998;  117 131-139
• 39 Waters C. Molecular mechanisms of cell death in the ear.  Ann N Y Acad Sci . 1999;  884 41-51
• 40 Watanabe K, Jinnouchi K, Hess A. Carboplatin induces less apoptosis in the cochlea of guinea pigs than cisplatin.  Chemotherapy . 2002;  48(2) 82-87
• 41 Pirvola U, Xing-Qun L, Virkkala J. Rescue of hearing, auditory hair cells and neurons by CEP-1347/Kt7515, an inhibitor of c-Jun terminal kinase activation.  J Neurosci . 2000;  20 43-50
• 42 Lang H, Liu C. Apoptosis and hair cell degeneration in the vestibular sensory epithelia of the guinea pig following a gentamicin insult.  Hear Res . 1997;  111 177-184
• 43 Usami S, Takumi Y, Fujita S, Shinkawa H, Hosokawa M. Cell death in the inner ear associated with aging is apoptosis?.  Brain Res . 1997;  747 147-150
• 44 Hu B H, Guo W, Wang P Y, Henderson D, Jiang S C. Intense noise-induced apoptosis in hair cells of guinea pig cochleae.  Acta Otolaryngol . 2000;  120 119-124
• 45 Budihardjo I, Oliver H, Lutter M, Luo X, Wang X. Biochemical pathways of caspase activation during apoptosis.  Annu Rev Cell Dev Biol . 1999;  15 269-290
• 46 Stennicke H R, Salvesen G S. Caspases-controlling intracellular signals by protease zymogen activation.  Biochim Biophys Acta . 2000;  1477 299-306
• 47 Li P, Nijhawan D, Budihardjo I. Cytochrome c and dATP-dependent formation of Apaf-1/caspase-9 complex initiates an apoptotic protease cascade.  Cell . 1997;  91 479-489
• 48 Bagger-Sjoback D, Wersall J. Gentamicin-induced mitochondrial damage in inner ear sensory cells of the lizard Calotes versicolor Acta Otolaryngol .  1978;  86 35-51
• 49 Song B B, Schacht J. Variable efficacy of radical scavengers and iron chelators to attenuate gentamicin ototoxicity in guinea pig in vivo.  Hear Res . 1996;  94 87-93
• 50 Hirose K, Westrum L E, Stone J S, Zirpel L, Rubel E W. Dynamic studies of ototoxicity in mature avian auditory epithelium.  Ann N Y Acad Sci . 1999;  884 389-409
• 51 Sha S H, Schacht J. Stimulation of free radical formation by aminoglycoside antibiotics.  Hear Res . 1999;  128 112-118
• 52 Sha S H, Taylor R, Forge A, Schacht J. Differential vulnerability of basal and apical hair cells is based on intrinsic susceptibility to free radicals.  Hear Res . 2001;  155 1-8
• 53 Muzio M, Stockwell B R, Stennicke H R, Salvesen G S, Dixit V M. An induced proximity model for caspase-8 activation.  J Biol Chem . 1998;  273 2926-2930
• 54 Warchol M E. Immune cytokines and dexamethasone influence sensory regeneration in the avian vestibular periphery.  J Neurocytol . 1999;  28 889-900
• 55 Cunningham L L, Cheng A G, Rubel E W. Caspase activation in hair cells of the mouse utricle exposed to neomycin.  J Neurosci . 2002;  22 8532-8540
• 56 Forge A, Li L. Apoptotic death of hair cells in mammalian vestibular sensory epithelia.  Hear Res . 2000;  139 97-115
• 57 Oltvai Z N, Milliman C L, Korsmeyer S J. Bcl-2 heterodimerizes in vivo with a conserved homolog, Bax, that accelerates programmed cell death.  Cell . 1993;  74 609-619
• 58 Gross A, McDonnell J M, Korsmeyer S J. BCL-2 family members and the mitochondria in apoptosis.  Genes Dev . 1999;  13 1899-1911
• 59 Hockenbery D, Nunez G, Milliman C, Schreiber R D, Korsmeyer S J. Bcl-2 is an inner mitochondrial membrane protein that blocks programmed cell death.  Nature . 1990;  348 334-336
• 60 Sedlak T W, Oltvai Z N, Yang E. Multiple Bcl-2 family members demonstrate selective dimerizations with Bax.  Proc Natl Acad Sci U S A . 1995;  92 7834-7838
• 61 Zha H, Aime-Sempe C, Sato T, Reed J C. Proapoptotic protein Bax heterodimerizes with Bcl-2 and homodimerizes with Bax via a novel domain (BH3) distinct from BH1 and BH2.  J Biol Chem . 1996;  271 7440-7444
• 62 Gross A, Jockel J, Wei M C, Korsmeyer S J. Enforced dimerization of BAX results in its translocation, mitochondrial dysfunction and apoptosis.  Embo J . 1998;  17 3878-3885
• 63 Putcha G V, Deshmukh M, Johnson Jr M E. BAX translocation is a critical event in neuronal apoptosis: regulation by neuroprotectants, BCL-2, and caspases.  J Neurosci . 1999;  19 7476-7485
• 64 Ghatan S, Larner S, Kinoshita Y. p38 MAP kinase mediates bax translocation in nitric oxide-induced apoptosis in neurons.  J Cell Biol . 2000;  150 335-347
• 65 Wang Z, Li H, Chi F, Shen Y. Transient Bax-protein immunoreactivity prior to apoptosis of spiral ganglion neurons in the postnatal rat.  Acta Otolaryngol . 2001;  121 777-778
• 66 Alam S A, Ikeda K, Oshima T. Cisplatin-induced apoptotic cell death in Mongolian gerbil cochlea.  Hear Res . 2000;  141 28-38
• 67 Bagger-Sjoback D, Wersall J. Gentamicin-induced mitochondrial damage in inner ear sensory cells of the lizard Calotes versicolor Acta Otolaryngol .  1978;  86 35-51
• 68 De Groot J M J C, Huizing E H, Veldman J E. Early ultrastructural effects of gentamicin cochleotoxicity.  Acta Otolaryngol (Stockh) . 1991;  111 273-280
• 69 Hirose K, Westrum L E, Stone J S, Zirpel L, Rubel E W. Dynamic studies of ototoxicity in mature avian auditory epithelium.  Ann N Y Acad Sci . 1999;  884 389-409
• 70 Clerici W J, Hensley K, DiMartino D L, Butterfield D A. Direct detection of ototoxicant-induced reactive oxygen species generation in cochlear explants.  Hear Res . 1996;  98 116-124
• 71 Hirose K, Hockenbery D M, Rubel E W. Reactive oxygen species in chick hair cells after gentamicin exposure in vitro.  Hear Res . 1997;  104 1-14
• 72 Hirose K, Westrum L E, Stone J S, Zirpel L, Rubel E W. Dynamic studies of ototoxicity in mature avian auditory epithelium.  Ann N Y Acad Sci . 1999;  884 389-409
• 73 Sha S H, Schacht J. Stimulation of free radical formation by aminoglycoside antibiotics.  Hear Res . 1999;  128 112-118
• 74 Atlante A, Calissano P, Bobba A. Cytochrome c is released from mitochondria in a reactive oxygen species (ROS)-dependent fashion and can operate as a ROS scavenger and as a respiratory substrate in cerebellar neurons undergoing excitotoxic death.  J Biol Chem . 2000;  275 37159-37166
• 75 Garetz S L, Altschuler R A, Schacht J. Attenuation of gentamicin ototoxicity by glutathione in the guinea pig in vivo.  Hear Res . 1994;  77 81-87
• 76 Song B B, Schacht J. Variable efficacy of radical scavengers and iron chelators to attenuate gentamicin ototoxicity in guinea pig in vivo.  Hear Res . 1996;  94 87-93
• 77 Sinswat P, Wu W J, Sha S H, Schacht J. Protection from ototoxicity of intraperitoneal gentamicin in guinea pig.  Kidney Int . 2000;  58 2525-2532
• 78 Sha S H, Taylor R, Forge A, Schacht J. Differential vulnerability of basal and apical hair cells is based on intrinsic susceptibility to free radicals.  Hear Res . 2001;  155 1-8