Dual expression of Atoh1 and Ikzf2 promotes transformation of adult cochlear supporting cells into outer hair cells

Abstract

Mammalian cochlear outer hair cells (OHCs) are essential for hearing. Severe hearing impairment follows OHC degeneration. Previous attempts at regenerating new OHCs from cochlear supporting cells (SCs) have been unsuccessful, notably lacking expression of the key OHC motor protein, Prestin. Thus, regeneration of Prestin+ OHCs represents a barrier to restore auditory function in vivo. Here, we reported the successful in vivo conversion of adult mouse cochlear SCs into Prestin+ OHC-like cells through the concurrent induction of two key transcriptional factors known to be necessary for OHC development: Atoh1 and Ikzf2. Single cell RNA sequencing revealed the upregulation of 729 OHC genes and downregulation of 331 SC genes in OHC-like cells. The resulting differentiation status of these OHC-like cells was much more advanced than previously achieved. This study thus established an efficient approach to induce the regeneration of Prestin+ OHCs, paving the way for in vivo cochlear repair via SC transdifferentiation.

Data availability

Sequencing data have been deposited in GEO under accession codes: GSE161156.

The following previously published data sets were used

Article and author information

Author details

  1. Suhong Sun

    Institute of Neuroscience, Chinese Academy of Sciences, Shanghai, China
    Competing interests
    Suhong Sun, We filed an auditory hair cell regeneration patent based on the key findings of this manuscript..
  2. Shuting Li

    Institute of Neuroscience, Chinese Academy of Sciences, Shanghai, China
    Competing interests
    Shuting Li, We filed an auditory hair cell regeneration patent based on the key findings of this manuscript..
  3. Zhengnan Luo

    Institute of Neuroscience, Chinese Academy of Sciences, Shanghai, China
    Competing interests
    Zhengnan Luo, We filed an auditory hair cell regeneration patent based on the key findings of this manuscript..
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-8204-6277
  4. Minhui Ren

    Institute of Neuroscience, Chinese Academy of Sciences, Shanghai, China
    Competing interests
    Minhui Ren, We filed an auditory hair cell regeneration patent based on the key findings of this manuscript..
  5. Shunji He

    Institute of Neuroscience, Chinese Academy of Sciences, Shanghai, China
    Competing interests
    Shunji He, We filed an auditory hair cell regeneration patent based on the key findings of this manuscript..
  6. Guangqin Wang

    Institute of Neuroscience, State Key Laboratory of Neuroscience,CAS Center for Excellence in Brain Science and Intelligence Technology, Chinese Academy of Sciences, Shanghai, China
    Competing interests
    Guangqin Wang, We filed an auditory hair cell regeneration patent based on the key findings of this manuscript..
  7. Zhiyong Liu

    Institute of Neuroscience, Chinese Academy of Sciences, Shanghai, China
    For correspondence
    Zhiyongliu@ion.ac.cn
    Competing interests
    Zhiyong Liu, We filed an auditory hair cell regeneration patent based on the key findings of this manuscript..
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-9675-1233

Funding

National Natural Science Foundation of China (81771012)

  • Zhiyong Liu

Ministry of Science and Technology of the People's Republic of China (2017YFA0103901)

  • Zhiyong Liu

Chinese Academy of Sciences (XDB32060100)

  • Zhiyong Liu

Shanghai Municipal Bureau of Quality and Technical Supervision (2018SHZDZX05)

  • Zhiyong Liu

Shanghai Jiao Tong University (SSMU-ZLCX20180601)

  • Zhiyong Liu

Boehringer Ingelheim (DE811138149)

  • Zhiyong Liu

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Reviewing Editor

  1. Doris K Wu, NIDCD, NIH, United States

Ethics

Animal experimentation: All mice were bred and raised in SPF level animal rooms and animal procedures were performed according to guidelines (NA-032-2019) of the IACUC of Institute of Neuroscience (ION), Chinese Academy of Sciences.

Version history

  1. Received: January 14, 2021
  2. Preprint posted: January 21, 2021 (view preprint)
  3. Accepted: September 2, 2021
  4. Accepted Manuscript published: September 3, 2021 (version 1)
  5. Version of Record published: September 14, 2021 (version 2)

Copyright

© 2021, Sun et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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  1. Suhong Sun
  2. Shuting Li
  3. Zhengnan Luo
  4. Minhui Ren
  5. Shunji He
  6. Guangqin Wang
  7. Zhiyong Liu
(2021)
Dual expression of Atoh1 and Ikzf2 promotes transformation of adult cochlear supporting cells into outer hair cells
eLife 10:e66547.
https://doi.org/10.7554/eLife.66547

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https://doi.org/10.7554/eLife.66547

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