Abstract

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.

Details

Title
Renewed proliferation in adult mouse cochlea and regeneration of hair cells
Author
Yilai Shu 1 ; Li, Wenyan 1 ; Huang, Mingqian 2 ; Yi-Zhou, Quan 2 ; Scheffer, Deborah 3 ; Tian, Chunjie 2 ; Tao, Yong 2 ; Liu, Xuezhong 4 ; Hochedlinger, Konrad 5   VIAFID ORCID Logo  ; Indzhykulian, Artur A 2 ; Wang, Zhengmin 6 ; Li, Huawei 6 ; Zheng-Yi, Chen 2   VIAFID ORCID Logo 

1  Department of Otolaryngology-Head and Neck Surgery, Graduate Program in Speech and Hearing Bioscience and Techology and Program in Neuroscience, Harvard Medical School, Boston, MA, USA; Eaton-Peabody Laboratory, Massachusetts Eye and Ear Infirmary, Boston, MA, USA; ENT Institute and Otorhinolaryngology Department of the Affiliated Eye and ENT Hospital, State Key Laboratory of Medical Neurobiology, Institutes of Biomedcial Sciences, Fudan University, Shanghai, China; NHC Key Laboratory of Hearing Medicine, Fudan University, Shanghai, China 
2  Department of Otolaryngology-Head and Neck Surgery, Graduate Program in Speech and Hearing Bioscience and Techology and Program in Neuroscience, Harvard Medical School, Boston, MA, USA; Eaton-Peabody Laboratory, Massachusetts Eye and Ear Infirmary, Boston, MA, USA 
3  Department of Otolaryngology-Head and Neck Surgery, Graduate Program in Speech and Hearing Bioscience and Techology and Program in Neuroscience, Harvard Medical School, Boston, MA, USA; Eaton-Peabody Laboratory, Massachusetts Eye and Ear Infirmary, Boston, MA, USA; Department of Neurobiology and Howard Hughes Medical Institute, Harvard Medical School, Boston, MA, USA 
4  Department of Otolaryngology, University of Miami School of Medicine, Miami, FL, USA 
5  Department of Molecular Biology, Cancer Center and Center for Regenerative Medicine, Massachusetts General Hospital, Boston, MA, USA; Department of Stem Cell and Regenerative Biology and Harvard Stem Cell Institute, Cambridge, MA, USA; Howard Hughes Medical Institute, Chevy Chase, MD, USA 
6  ENT Institute and Otorhinolaryngology Department of the Affiliated Eye and ENT Hospital, State Key Laboratory of Medical Neurobiology, Institutes of Biomedcial Sciences, Fudan University, Shanghai, China; NHC Key Laboratory of Hearing Medicine, Fudan University, Shanghai, China 
Pages
1-15
Publication year
2019
Publication date
Dec 2019
Publisher
Nature Publishing Group
e-ISSN
20411723
Source type
Scholarly Journal
Language of publication
English
DOI
https://doi.org/10.1038/s41467-019-13157-7
ProQuest document ID
2321689260
Copyright
© 2019. This work is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.