TY - JOUR
T1 - Renewed proliferation in adult mouse cochlea and regeneration of hair cells
AU - Shu, Yilai
AU - Li, Wenyan
AU - Huang, Mingqian
AU - Quan, Yi Zhou
AU - Scheffer, Deborah
AU - Tian, Chunjie
AU - Tao, Yong
AU - Liu, Xuezhong
AU - Hochedlinger, Konrad
AU - Indzhykulian, Artur A.
AU - Wang, Zhengmin
AU - Li, Huawei
AU - Chen, Zheng Yi
N1 - Funding Information:
We are grateful to David Corey for critical reading of the manuscript. We would like to thank Shan Sun, Sofia Chen for help with the figures, Haobing Wang for help with the movies and Corena Loeb for editing the manuscript. The authors acknowledge funding from NIH R01DC006908, R56DC006908 (Z-Y.C.), DOD W81XWH1810331 (Z-Y.C.), Fredrick and Ines Yeatts hair cell regeneration fellowship (Z-Y.C.) and David-Shulsky Foundation (Z-Y.C.), the Major State Basic Research Development Program of China (2011CB504506)(Z.W.), (2011CB504500)(H.L.), Key Laboratory of Hearing Medicine, National Health and Family Planning Commission, Shanghai, China (Z.W.; H.L.), the National Natural Science Foundation of China (No. 81230019)(H.L.) (No. 81822011, 81771013) (Y.S.), Science and Technology Commission of Shanghai Municipality (17ZR1448600, 18410712400) (Y.S.), NIH R01DC005575, R01DC012115 (X.L.) and NIH R01DC017166 (A.A.I.).
Publisher Copyright:
© 2019, The Author(s).
PY - 2019/12/1
Y1 - 2019/12/1
N2 - The adult mammalian inner ear lacks the capacity to divide or regenerate. Damage to inner ear generally leads to permanent hearing loss in humans. Here, we present that reprogramming of the adult inner ear induces renewed proliferation and regeneration of inner ear cell types. Co-activation of cell cycle activator Myc and inner ear progenitor gene Notch1 induces robust proliferation of diverse adult cochlear sensory epithelial cell types. Transient MYC and NOTCH activities enable adult supporting cells to respond to transcription factor Atoh1 and efficiently transdifferentiate into hair cell-like cells. Furthermore, we uncover that mTOR pathway participates in MYC/NOTCH-mediated proliferation and regeneration. These regenerated hair cell-like cells take up the styryl dye FM1-43 and are likely to form connections with adult spiral ganglion neurons, supporting that Myc and Notch1 co-activation is sufficient to reprogram fully mature supporting cells to proliferate and regenerate hair cell-like cells in adult mammalian auditory organs.
AB - The adult mammalian inner ear lacks the capacity to divide or regenerate. Damage to inner ear generally leads to permanent hearing loss in humans. Here, we present that reprogramming of the adult inner ear induces renewed proliferation and regeneration of inner ear cell types. Co-activation of cell cycle activator Myc and inner ear progenitor gene Notch1 induces robust proliferation of diverse adult cochlear sensory epithelial cell types. Transient MYC and NOTCH activities enable adult supporting cells to respond to transcription factor Atoh1 and efficiently transdifferentiate into hair cell-like cells. Furthermore, we uncover that mTOR pathway participates in MYC/NOTCH-mediated proliferation and regeneration. These regenerated hair cell-like cells take up the styryl dye FM1-43 and are likely to form connections with adult spiral ganglion neurons, supporting that Myc and Notch1 co-activation is sufficient to reprogram fully mature supporting cells to proliferate and regenerate hair cell-like cells in adult mammalian auditory organs.
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U2 - 10.1038/s41467-019-13157-7
DO - 10.1038/s41467-019-13157-7
M3 - Article
C2 - 31797926
AN - SCOPUS:85076008430
VL - 10
JO - Nature Communications
JF - Nature Communications
SN - 2041-1723
IS - 1
M1 - 5530
ER -