Oncotarget

Research Papers:

Wnt activation followed by Notch inhibition promotes mitotic hair cell regeneration in the postnatal mouse cochlea

Wenli Ni, Shan Zeng, Wenyan Li, Yan Chen, Shasha Zhang, Mingliang Tang, Shan Sun, Renjie Chai and Huawei Li _

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Oncotarget. 2016; 7:66754-66768. https://doi.org/10.18632/oncotarget.11479

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Abstract

Wenli Ni1,2,*, Shan Zeng1,2,*, Wenyan Li1,2, Yan Chen1,3,4, Shasha Zhang5,6, Mingliang Tang5,6, Shan Sun1,3,4, Renjie Chai5,6, Huawei Li1,2,3

1Otorhinolaryngology Department of The Affiliated Eye and ENT Hospital, State Key Laboratory of Medical Neurobiology, Fudan University, Shanghai, PR China

2Institutes of Biomedical Sciences, Fudan University, Shanghai, PR China

3Central Laboratory, Affiliated Eye and ENT Hospital of Fudan University, Shanghai, PR China

4Key Laboratory of Hearing Medicine of The National Health and Family Planning Commission, Shanghai, PR China

5Key Laboratory for Developmental Genes and Human Disease, Ministry of Education, Institute of Life Sciences, Southeast University, Nanjing, PR China

6Co-Innovation Center of Neuroregeneration, Nantong University, Nantong, PR China

*These authors contributed equally to this work

Correspondence to:

Huawei Li, email: hwli@shmu.edu.cn

Renjie Chai, email: renjiec@seu.edu.cn

Keywords: Wnt, Notch, proliferation, regeneration, lineage tracing

Received: January 25, 2016     Accepted: June 29, 2016     Published: August 22, 2016

ABSTRACT

Hair cell (HC) loss is the main cause of permanent hearing loss in mammals. Previous studies have reported that in neonatal mice cochleae, Wnt activation promotes supporting cell (SC) proliferation and Notch inhibition promotes the trans-differentiation of SCs into HCs. However, Wnt activation alone fails to regenerate significant amounts of new HCs, Notch inhibition alone regenerates the HCs at the cost of exhausting the SC population, which leads to the death of the newly regenerated HCs. Mitotic HC regeneration might preserve the SC number while regenerating the HCs, which could be a better approach for long-term HC regeneration. We present a two-step gene manipulation, Wnt activation followed by Notch inhibition, to accomplish mitotic regeneration of HCs while partially preserving the SC number. We show that Wnt activation followed by Notch inhibition strongly promotes the mitotic regeneration of new HCs in both normal and neomycin-damaged cochleae while partially preserving the SC number. Lineage tracing shows that the majority of the mitotically regenerated HCs are derived specifically from the Lgr5+ progenitors with or without HC damage. Our findings suggest that the co-regulation of Wnt and Notch signaling might provide a better approach to mitotically regenerate HCs from Lgr5+ progenitor cells.


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