title: Wnt activation followed by Notch inhibition promotes mitotic hair cell regeneration in the postnatal mouse cochlea.
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.
authors: Otorhinolaryngology Department of The Affiliated Eye and ENT Hospital, State Key Laboratory of Medical Neurobiology, Fudan University, Shanghai, PR China.|Institutes of Biomedical Sciences, Fudan University, Shanghai, PR China.
authors: Wenli
authors: W
authors: Ni
authors: Otorhinolaryngology Department of The Affiliated Eye and ENT Hospital, State Key Laboratory of Medical Neurobiology, Fudan University, Shanghai, PR China.|Institutes of Biomedical Sciences, Fudan University, Shanghai, PR China.
authors: Shan
authors: S
authors: Zeng
authors: Otorhinolaryngology Department of The Affiliated Eye and ENT Hospital, State Key Laboratory of Medical Neurobiology, Fudan University, Shanghai, PR China.|Institutes of Biomedical Sciences, Fudan University, Shanghai, PR China.
authors: Wenyan
authors: W
authors: Li
authors: Otorhinolaryngology Department of The Affiliated Eye and ENT Hospital, State Key Laboratory of Medical Neurobiology, Fudan University, Shanghai, PR China.|Central Laboratory, Affiliated Eye and ENT Hospital of Fudan University, Shanghai, PR China.|Key Laboratory of Hearing Medicine of The National Health and Family Planning Commission, Shanghai, PR China.
authors: Yan
authors: Y
authors: Chen
authors: Key Laboratory for Developmental Genes and Human Disease, Ministry of Education, Institute of Life Sciences, Southeast University, Nanjing, PR China.|Co-innovation Center of Neuroregeneration, Nantong University, Nantong, China.
authors: Shasha
authors: S
authors: Zhang
authors: Key Laboratory for Developmental Genes and Human Disease, Ministry of Education, Institute of Life Sciences, Southeast University, Nanjing, PR China.|Co-innovation Center of Neuroregeneration, Nantong University, Nantong, China.
authors: Mingliang
authors: M
authors: Tang
authors: Otorhinolaryngology Department of The Affiliated Eye and ENT Hospital, State Key Laboratory of Medical Neurobiology, Fudan University, Shanghai, PR China.|Central Laboratory, Affiliated Eye and ENT Hospital of Fudan University, Shanghai, PR China.|Key Laboratory of Hearing Medicine of The National Health and Family Planning Commission, Shanghai, PR China.
authors: Shan
authors: S
authors: Sun
authors: Key Laboratory for Developmental Genes and Human Disease, Ministry of Education, Institute of Life Sciences, Southeast University, Nanjing, PR China.|Co-innovation Center of Neuroregeneration, Nantong University, Nantong, China.
authors: Renjie
authors: R
authors: Chai
authors: Otorhinolaryngology Department of The Affiliated Eye and ENT Hospital, State Key Laboratory of Medical Neurobiology, Fudan University, Shanghai, PR China.|Institutes of Biomedical Sciences, Fudan University, Shanghai, PR China.|Central Laboratory, Affiliated Eye and ENT Hospital of Fudan University, Shanghai, PR China.
authors: Huawei
authors: H
authors: Li
mesh_terms: D000818:Animals; D049109:Cell Proliferation; D003051:Cochlea / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D006198:Hair Cells, Auditory / Q000166:cytology / Q000378:metabolism*; D008164:Luminescent Proteins / Q000235:genetics / Q000378:metabolism; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008938:Mitosis; D043562:Receptors, G-Protein-Coupled / Q000235:genetics / Q000378:metabolism; D051880:Receptors, Notch / Q000235:genetics / Q000378:metabolism*; D012038:Regeneration; D013234:Stem Cells / Q000166:cytology / Q000378:metabolism; D046509:Tissue Culture Techniques; D060449:Wnt Signaling Pathway; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism*
chemical_list: C493597:Lgr5 protein, mouse; D008164:Luminescent Proteins; D043562:Receptors, G-Protein-Coupled; D051880:Receptors, Notch; D051176:beta Catenin
keywords: Notch; Wnt; lineage tracing; proliferation; regeneration