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Open in a separate window. Figure 1.

Laboratory-based results Nonmammalian vertebrate hair cell regeneration reveals existence of inner ear stem cells In , Corwin and Cotanche 5 and, independently, Ryals and Rubel 6 reported that cochlear hair cells regenerate after acoustic trauma in birds. Figure 2. Generating replacement hair cells by reexpressing Atonal homolog 1 Atoh1 The basic helix-loop-helix transcription factor Atoh1 also known as Math1 has emerged as a candidate for gene-based treatment of auditory and vestibular disorders 19 , Generating replacement hair cells by disrupting Notch signaling In the normally quiescent bird auditory epithelium, hair cell regeneration seems to reactivate developmental programs, and the Notch signaling pathway is probably the one we know most about.

Generating replacement hair cells by inhibiting cell cycle inhibitors In birds and many nonmammalian vertebrates, supporting cells are able to produce new hair cells through two mechanisms: transdifferentiation and mitotic regeneration. Therapeutic approaches State-of-the-art treatment for hearing loss consists of devices such as hearing aids for mild to profound hearing loss, and cochlear implants for profound hearing loss and deafness. Stem cells and cell delivery Several laboratories have begun to explore the implantation of stem cell—derived precursor cells into the damaged cochlea.

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Small molecule modulators of gene expression and pharmacotherapeutics Many of the difficulties specifically associated with progenitor cell transplantation and gene delivery can be overcome with small molecule activators or inhibitors of gene expression. Conclusions and outlook Substantial progress has been made in recent years to accumulate tools that potentially can be used, alone or in combination, to develop strategies for hair cell regeneration.

References 1. Cochlear inner and outer hair cells: functional differences. Otol Neurotol. Histopathology and molecular genetics of hearing loss in the human. Int J Pediatr Otorhinolaryngol. Ann Otol Rhinol Laryngol. Regeneration of sensory hair cells after acoustic trauma. Hair cell regeneration after acoustic trauma in adult Coturnix quail. Hearing loss and cochlear pathology in monkeys after noise exposure. Acta Otolaryngol Stockh ; 81 — Raphael Y, Altschuler RA. Reorganization of cytoskeletal and junctional proteins during cochlear hair cell degeneration. Cell Motil Cytoskeleton.

Regenerative proliferation in inner ear sensory epithelia from adult guinea pigs and humans. Ultrastructural evidence for hair cell regeneration in the mammalian inner ear.


Contribution of olfactory neural stem cells to tissue maintenance and regeneration. Pluripotent stem cells from the adult mouse inner ear. Nat Med. Neural stem cells and neurospheres—re-evaluating the relationship.

Tinnitus Springer Handbook of Auditory Research PDF

Nat Methods. Hu Z, Corwin JT.

Hearing loss

Inner ear hair cells produced in vitro by a mesenchymal-to-epithelial transition. Oshima K, et al. Differential distribution of stem cells in the auditory and vestibular organs of the inner ear. J Assoc Res Otolaryngol. Savary E, et al.

Distinct population of hair cell progenitors can be isolated from the postnatal mouse cochlea using side population analysis. Stem Cells. Zhai S, et al. Isolation and culture of hair cell progenitors from postnatal rat cochleae. J Neurobiol. Mammalian cochlear supporting cells can divide and trans-differentiate into hair cells. Math1 gene transfer generates new cochlear hair cells in mature guinea pigs in vivo. J Neurosci. Izumikawa M, et al. Auditory hair cell replacement and hearing improvement by Atoh1 gene therapy in deaf mammals.

Lumpkin EA, et al. Math1-driven GFP expression in the developing nervous system of transgenic mice. Gene Expr Patterns. Bermingham NA, et al.

Math1: an essential gene for the generation of inner ear hair cells. Math1 regulates development of the sensory epithelium in the mammalian cochlea.

Noise-induced cochlear synaptopathy: Past findings and future studies - ScienceDirect

Overexpression of Math1 induces robust production of extra hair cells in postnatal rat inner ears. Functional auditory hair cells produced in the mammalian cochlea by in utero gene transfer. Loss of Fgfr3 leads to excess hair cell development in the mouse organ of Corti. Dev Dyn. Mansour SL, et al. Hearing loss in a mouse model of Muenke syndrome.


Hum Mol Genet. Notch ligands with contrasting functions: Jagged1 and Delta1 in the mouse inner ear. Daudet N, et al. Notch regulation of progenitor cell behavior in quiescent and regenerating auditory epithelium of mature birds. Dev Biol. Notch signaling regulates the extent of hair cell regeneration in the zebrafish lateral line. Yamamoto N, et al. J Mol Med. Takebayashi S, et al. Multiple roles of Notch signaling in cochlear development. Notch signaling regulates the pattern of auditory hair cell differentiation in mammals. Hori R, et al. Pharmacological inhibition of Notch signaling in the mature guinea pig cochlea.

Chen P, Segil N. Lowenheim H, et al. Gene disruption of p27 Kip1 allows cell proliferation in the postnatal and adult organ of Corti. Mantela J, et al. The retinoblastoma gene pathway regulates the postmitotic state of hair cells of the mouse inner ear. Sage C, et al. Proliferation of functional hair cells in vivo in the absence of the retinoblastoma protein.