TY - JOUR
T1 - Notch Inhibition Induces Cochlear Hair Cell Regeneration and Recovery of Hearing after Acoustic Trauma
AU - Mizutari, Kunio
AU - Fujioka, Masato
AU - Hosoya, Makoto
AU - Bramhall, Naomi
AU - Okano, Hirotaka James
AU - Okano, Hideyuki
AU - Edge, Albert S.B.
N1 - Funding Information:
We thank M.C. Liberman for critical comments on the manuscript. We thank Yukiko Watada and Yumi Matsuzaki for assistance. This work was supported by grants RO1 DC007174, R21 DC010440, and P30 DC05209 from the National Institute on Deafness and other Communicative Disorders (NIDCD); by the Tillotson Corporation, the Shulsky Foundation, and Robert Boucai; by the Mochida Memorial Foundation for Medical and Pharmaceutical Research; and by grants for International Activities in Life Sciences and Medicine, Keio University Medical Science Fund.
PY - 2013/1/9
Y1 - 2013/1/9
N2 - 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.
AB - 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.
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U2 - 10.1016/j.neuron.2012.10.032
DO - 10.1016/j.neuron.2012.10.032
M3 - Article
C2 - 23312516
AN - SCOPUS:84872173335
SN - 0896-6273
VL - 77
SP - 58
EP - 69
JO - Neuron
JF - Neuron
IS - 1
ER -