title: Notch inhibition induces cochlear hair cell regeneration and recovery of hearing after acoustic trauma.
abstract: Hearing loss due to damage to auditory hair cells is normally irreversible because mammalian hair cells do not regenerate. Here, we show that new hair cells can be induced and can cause partial recovery of hearing in ears damaged by noise trauma, when Notch signaling is inhibited by a γ-secretase inhibitor selected for potency in stimulating hair cell differentiation from inner ear stem cells in vitro. Hair cell generation resulted from an increase in the level of bHLH transcription factor Atoh1 in response to inhibition of Notch signaling. In vivo prospective labeling of Sox2-expressing cells with a Cre-lox system unambiguously demonstrated that hair cell generation resulted from transdifferentiation of supporting cells. Manipulating cell fate of cochlear sensory cells in vivo by pharmacological inhibition of Notch signaling is thus a potential therapeutic approach to the treatment of deafness.
authors: Department of Otology and Laryngology, Harvard Medical School, Boston, MA 02115, USA.
authors: Kunio
authors: K
authors: Mizutari
authors: Masato
authors: M
authors: Fujioka
authors: Makoto
authors: M
authors: Hosoya
authors: Naomi
authors: N
authors: Bramhall
authors: Hirotaka James
authors: HJ
authors: Okano
authors: Hideyuki
authors: H
authors: Okano
authors: Albert S B
authors: AS
authors: Edge
mesh_terms: D000161:Acoustic Stimulation / Q000009:adverse effects; D000409:Alanine / Q000031:analogs & derivatives / Q000494:pharmacology / Q000627:therapeutic use; D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors / Q000378:metabolism; D000818:Animals; D000831:Animals, Newborn; D001381:Azepines / Q000494:pharmacology / Q000627:therapeutic use; D003051:Cochlea / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D005260:Female; D006198:Hair Cells, Auditory / Q000166:cytology / Q000378:metabolism*; D006309:Hearing / Q000187:drug effects / Q000502:physiology*; D006317:Hearing Loss, Noise-Induced / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009416:Nerve Regeneration / Q000187:drug effects / Q000502:physiology*; D009924:Organ Culture Techniques; D051880:Receptors, Notch / Q000037:antagonists & inhibitors* / Q000502:physiology*; D020127:Recovery of Function / Q000187:drug effects / Q000502:physiology*
chemical_list: D001381:Azepines; C484278:N2-((2S)-2-(3,5-difluorophenyl)-2-hydroxyethanoyl)-N1-((7S)-5-methyl-6-oxo-6,7-dihydro-5H-dibenzo(b,d)azepin-7-yl)-L-alaninamide; D051880:Receptors, Notch; D053829:Amyloid Precursor Protein Secretases; D000409:Alanine