title: Notch inhibition induces mitotically generated hair cells in mammalian cochleae via activating the Wnt pathway.
abstract: The activation of cochlear progenitor cells is a promising approach for hair cell (HC) regeneration and hearing recovery. The mechanisms underlying the initiation of proliferation of postnatal cochlear progenitor cells and their transdifferentiation to HCs remain to be determined. We show that Notch inhibition initiates proliferation of supporting cells (SCs) and mitotic regeneration of HCs in neonatal mouse cochlea in vivo and in vitro. Through lineage tracing, we identify that a majority of the proliferating SCs and mitotic-generated HCs induced by Notch inhibition are derived from the Wnt-responsive leucine-rich repeat-containing G protein-coupled receptor 5 (Lgr5(+)) progenitor cells. We demonstrate that Notch inhibition removes the brakes on the canonical Wnt signaling and promotes Lgr5(+) progenitor cells to mitotically generate new HCs. Our study reveals a new function of Notch signaling in limiting proliferation and regeneration potential of postnatal cochlear progenitor cells, and provides a new route to regenerate HCs from progenitor cells by interrupting the interaction between the Notch and Wnt pathways.
authors.affiliation: Department of Otorhinolaryngology, Department of Otology and Laryngology, Harvard Medical School, Boston MA 02115; Eaton Peabody Laboratory, Massachusetts Eye & Ear Infirmary, Boston MA 02114;
authors.forename: Wenyan
authors.initials: W
authors.lastname: Li
authors.affiliation: Department of Otorhinolaryngology.
authors.forename: Jingfang
authors.initials: J
authors.lastname: Wu
authors.affiliation: Department of Otorhinolaryngology, Affiliated No. 2 Hospital of Anhui Medical University, Hefei, Anhui 230601, China; and.
authors.forename: Jianming
authors.initials: J
authors.lastname: Yang
authors.affiliation: Department of Otorhinolaryngology, Key Laboratory of Hearing Science, Ministry of Health, Affiliated Eye and Ear, Nose, Throat Hospital.
authors.forename: Shan
authors.initials: S
authors.lastname: Sun
authors.affiliation: Jiangsu Province Co-innovation Center of Neuroregeneration, Key Laboratory for Developmental Genes and Human Disease, Ministry of Education, Institute of Life Sciences, Southeast University, Nanjing 210096, China.
authors.forename: Renjie
authors.initials: R
authors.lastname: Chai
authors.affiliation: Department of Otology and Laryngology, Harvard Medical School, Boston MA 02115; Eaton Peabody Laboratory, Massachusetts Eye & Ear Infirmary, Boston MA 02114; hwli@shmu.edu.cn zheng-yi_chen@meei.harvard.edu.
authors.forename: Zheng-Yi
authors.initials: ZY
authors.lastname: Chen
authors.affiliation: Department of Otorhinolaryngology, Key Laboratory of Hearing Science, Ministry of Health, Affiliated Eye and Ear, Nose, Throat Hospital, Institute of Stem Cell and Regeneration Medicine, Institutes of Biomedical Science, and State Key Laboratory of Medical Neurobiology, Fudan University, Shanghai 200032, China; hwli@shmu.edu.cn zheng-yi_chen@meei.harvard.edu.
authors.forename: Huawei
authors.initials: H
authors.lastname: Li
mesh_terms: D000818:Animals; D019070:Cell Lineage; D049109:Cell Proliferation; D006198:Hair Cells, Auditory / Q000166:cytology* / Q000378:metabolism*; D007760:Labyrinth Supporting Cells / Q000378:metabolism; D051379:Mice; D008938:Mitosis; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism; D051880:Receptors, Notch / Q000037:antagonists & inhibitors / Q000378:metabolism*; D055748:SOXB1 Transcription Factors / Q000378:metabolism; D060449:Wnt Signaling Pathway
chemical_list: C493597:Lgr5 protein, mouse; D043562:Receptors, G-Protein-Coupled; D051880:Receptors, Notch; D055748:SOXB1 Transcription Factors
keywords: Notch1; hair cells; inner ear; proliferation; β-catenin