Abstract
In cold-blooded animals, lost sensory hair cells can be replaced via a process of regenerative cell proliferation of epithelial supporting cells. In contrast, in mammalian cochlea, receptor (hair) cells are believed to be produced only during embryogenesis; after maturity, sensory or supporting cell proliferation or regeneration are thought to occur neither under normal conditions nor after trauma. Using bromodeoxyuridine (BrdU) as a proliferation marker, we have assessed cell proliferation activity in the mature organ of Corti in the cochlea of young guinea pigs following severe damage to the outer hair cells induced by kanamycin sulfate and ethacrynic acid. Although limited, we have found BrdU-labeled nuclei in the regions of Deiters cells when BrdU is given for 3 days or longer. When BrdU is given for 10 days, at least one labeled nucleus can be observed in the organ of Corti in approximately half of the ears; proliferating cells typically appear as paired daughters, with one nucleus being displaced away from the basement membrane to the position expected of the hair cells. Double-staining with antibodies to cytokeratin, vimentin, and p27 have shown that the BrdU-labeled nuclei are located in cells phenotypically similar to Deiters cells. Most of the uptake of BrdU occurs 3–5 days following ototoxic insult, and the number of BrdU-labeled cells does not decrease until 30 days following insult. These findings indicate that Deiters cells in the mature mammalian cochlea maintain a limited competence to re-enter the cell cycle and proliferate after hair cell injury, and that they can survive at least for 1 month.
Similar content being viewed by others
References
Barres BA, Hart IK, Coles HSR, Burne JF, Voyvodic JT, Richardson WD, Raff MC (1992) Cell death and control of cell survival in the oligodendrocyte lineage. Cell 70:31–46
Baserga R (1985) The biology of cell reproduction. Harvard University Press, Cambridge
Bermingham-McDonogh O, Rubel EW (2003) Hair cell regeneration: winging our way towards a sound future. Curr Opin Neurobiol 13:119–126
Bhave SA, Stone JS, Rubel EW, Coltrera MD (1995) Cell cycle progression in gentamicin-damaged avian cochleas. J Neurosci 15:4618–4628
Bursch W, Kleine L, Tenniswood M (1990) The biochemistry of cell death by apoptosis. Biochem Cell Biol 68:1071–1074
Chardin S, Romand R (1995) Regeneration and mammalian auditory hair cells. Science 267:707–711
Chen P, Segil N (1999) p27(Kip1) links cell proliferation to morphogenes in the developing organ of Corti. Development 126:1581–1590
Chen P, Johnson JE, Zoghbi HY, Segil N (2002) The role of Math1 in inner ear development: uncoupling the establishment of the sensory primordium from hair cell fate determination. Development 129:2495–2505
Corwin T, Cotanche DA (1988) Regeneration of sensory hair cells after acoustic trauma. Science 240:1772–1774
Endo T, Nakagawa T, Lee JE, Dong Y, Kim TS, Iguchi F, Taniguchi Z, Naito Y, Ito J (2002) Alteration in expression of p27 in auditory epithelia and neurons of mice during degeneration. Neurosci Lett 334:173–176
Ferrari S, Battini R, Kaczmarek L, Rittling S, Calabretta B, Riel JK de, Philiponis V, Wei JF, Baserga R (1986) Coding sequence and growth regulation of the human vimentin gene. Mol Cell Biol 6:3614–3620
Forge A, Li L, Corwin JT, Nevill G (1993) Ultrastructural evidence for hair cell regeneration in the mammalian inner ear. Science 259:1616–1619
Izumikawa M, Minoda R, Kawamoto K, Abrashkin KA, Swiderski DL, Dolan DF, Brough DE, Raphael Y (2005) Auditory hair cell replacement and hearing improvement by Atoh1 gene therapy in deaf mammals. Nat Med 11:271–276
Kawamoto K, Ishimoto S, Minoda R, Brough DE, Raphael Y (2003) Math1 gene transfer generates new cochlear hair cells in mature guinea pigs in vivo. J Neurosci 23:4395–4400
Kil J, Gu R, Zhao YD, Hasson T, Lowenheim H, Fero M (2000) Inhibition of p27Kip1 induces hair cell regeneration in the organ of Corti. Assoc Res Otolaryngol Abstr 23:5510
Kuntz AL, Oesterle EC (1998) Transforming growth factor alpha with insulin stimulates cell proliferation in vivo in adult rat vestibular sensory epithelium. J Comp Neurol 399:413–423
Lang H, Fekete DM (2001) Lineage analysis in the chicken inner ear shows differences in clonal dispersion for epithelial, neuronal, and mesenchymal cells. Dev Biol 234:120–137
Lefebvre PP, Malgrange B, Staecker H, Moonen G, Van de Water TR (1993) Retinoic acid stimulates regeneration of mammalian auditory hair cells. Science 260:692–695
Li L, Forge A (1997) Morphological evidence for supporting cell to hair cell conversion in the mammalian utricular macula. Int J Dev Neurosci 15:433–446
Malek NP, Sundberg H, McGrew S, Nakayama K, Kyriakides TR, Roberts JM (2001) A mouse knock-in model exposes sequential proteolytic pathways that regulate p27Kip1 in G1 and S phase. Nature 413:323–327
Mantela J, Jiang Z, Ylikoski J, Fritzsch B, Zacksenhaus E, Pirvola U (2005) The retinoblastoma gene pathway regulates the postmitotic state of hair cells of the mouse inner ear. Development 132:2377–2388
Matei V, Pauley S, Kaing S, Rowitch D, Beisel KW, Morris K, Feng F, Jones K, Lee J, Fritzsch B (2005) Smaller inner ear sensory epithelia in Neurog1 null mice are related to earlier hair cell cycle exit. Dev Dyn 234:633–650
Oesterle EC, Sarthy PV, Rubel EW (1990) Intermediate filaments in the inner ear of normal and experimentally damaged guinea pigs. Hear Res 47:1–16
Raphael Y (2002) Cochlear pathology, sensory cell death and regeneration. Br Med Bull 63:25–38
Raphael Y, Altschuler RA (1991) Scar formation after drug-induced cochlear insult. Hear Res 51:173–183
Roberson DW, Rubel EW (1994) Cell division in the gerbil cochlea after acoustic trauma. Am J Otol 15:28–34
Rubel EW, Dew LA, Roberson W (1995) Mammalian vestibular hair cell regeneration. Science 267:701–707
Ruben RJ (1967) Development of the inner ear of the mouse: a radioautographic study of terminal mitoses. Acta Otolaryngol Suppl 220:1–44
Ryals BM, Rubel EW (1988) Hair cell regeneration after acoustic trauma in adult Coturnix quail. Science 240:1774–1776
Slepecky NB (1996) Structure of the mammalian cochlea. In: Dallos P, Popper AN, Fay RR (eds) The cochlea. Springer, Berlin Heiderberg New York, pp 46–129
Stone JS, Cotanche DA (1994) Identification of the timing of S phase and the patterns of cell proliferation during hair cell regeneration in the chick cochlea. J Comp Neurol 341:50–67
Stone JS, Rubel EW (2000) Temporal, spatial, and morphologic features of hair cell regeneration in the avian basilar papilla. J Comp Neurol 417:1–16
Stone JS, Choi YS, Woolley SM, Yamashita H, Rubel EW (1999) Progenitor cell cycling during hair cell regeneration in the vestibular and auditory epithelia of the chick. J Neurocytol 28:863–876
Thomaidou D, Mione MC, Cavanagh JFR, Parnavelas JG (1997) Apoptosis and its relation to the cell cycle in the developing cerebral cortex. J Neurosci 17:1075–1085
Voyvodic JT, Burne JF, Raff MC (1995) Identification of normal cell death in the rat retina: applications for normal composition in cell lineage analysis. Eur J Neurosci 7:2469–2478
West RA, Brummett RE, Himes DL (1973) Interaction of kanamycin and ethacrynic acid. Severe cochlear damage in guinea pigs. Arch Otolaryngol 98:32–37
Yaginuma H, Tomita M, Takashita N, McKay SE, Cardwell C, Yin Q-W, Oppenheim RW (1996) A novel type of programmed neuronal death in the cervical spinal cord of the chick embryo. J Neurosci 16:3685–3703
Yamasoba T, Schacht J, Shoji F, Miller JM (1999) 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 815:317–325
Yamasoba T, Kondo K, Miyajima C, Suzuki M (2003) Changes in cell proliferation in rat and guinea pig cochlea after aminoglycoside-induced damage. Neurosci Lett 347:171–174
Acknowledgements
We are grateful to Drs. Josef M. Miller, Joseph E. Hawkins, Yasuya Nomura, and Masato Nakafuku for helpful comments and discussion and to Mr. Yoshiro Mori, Mr. Ko-ichi Miyazawa, Ms. Atsuko Tsuyuzaki, Ms. Yukari Kurasawa, and Dr. Shinichi Ishimoto for technical support.
Author information
Authors and Affiliations
Corresponding author
Additional information
This work was supported by the Ministry of Health, Labour, and Welfare, Japan (grants 12120101, 15110201) and by the Ministry of Education, Culture, Sports, Science, and Technology, Japan (grant 13470357) to T.Y.
Rights and permissions
About this article
Cite this article
Yamasoba, T., Kondo, K. Supporting cell proliferation after hair cell injury in mature guinea pig cochlea in vivo. Cell Tissue Res 325, 23–31 (2006). https://doi.org/10.1007/s00441-006-0157-9
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00441-006-0157-9