title: Bmi1 Regulates the Proliferation of Cochlear Supporting Cells Via the Canonical Wnt Signaling Pathway.
abstract: Cochlear supporting cells (SCs), which include the cochlear progenitor cells, have been shown to be a promising resource for hair cell (HC) regeneration, but the mechanisms underlying the initiation and regulation of postnatal cochlear SC proliferation are not yet fully understood. Bmi1 is a member of the Polycomb protein family and has been reported to regulate the proliferation of stem cells and progenitor cells in multiple organs. In this study, we investigated the role of Bmi1 in regulating SC and progenitor cell proliferation in neonatal mice cochleae. We first showed that knockout of Bmi1 significantly inhibited the proliferation of SCs and Lgr5-positive progenitor cells after neomycin injury in neonatal mice in vitro, and we then showed that Bmi1 deficiency significantly reduced the sphere-forming ability of the organ of Corti and Lgr5-positive progenitor cells in neonatal mice. These results suggested that Bmi1 is required for the initiation of SC and progenitor cell proliferation in neonatal mice. Next, we found that DKK1 expression was significantly upregulated, while beta-catenin and Lgr5 expression were significantly downregulated in neonatal Bmi1-/-mice compared to wild-type controls. The observation that Bmi1 knockout downregulates Wnt signaling provides compelling evidence that Bmi1 is required for the Wnt signaling pathway. Furthermore, the exogenous Wnt agonist BIO overcame the downregulation of SC proliferation in Bmi1-/-mice, suggesting that Bmi1 knockout might inhibit the proliferation of SCs via downregulation of the canonical Wnt signaling pathway. Our findings demonstrate that Bmi1 plays an important role in regulating the proliferation of cochlear SCs and Lgr5-positive progenitor cells in neonatal mice through the Wnt signaling pathway, and this suggests that Bmi1 might be a new therapeutic target for HC regeneration.
authors: Department of Otorhinolaryngology and Hearing Research Institute of Affiliated Eye and ENT Hospital, State Key Laboratory of Medicine Neurobiology, Fudan University, Room 611, Building 9, No. 83, Fenyang Road, Xuhui District, Shanghai, 200031, China.
authors: Xiaoling
authors: X
authors: Lu
authors: Department of Otorhinolaryngology and Hearing Research Institute of Affiliated Eye and ENT Hospital, State Key Laboratory of Medicine Neurobiology, Fudan University, Room 611, Building 9, No. 83, Fenyang Road, Xuhui District, Shanghai, 200031, 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, 210096, China.|Co-innovation Center of Neuroregeneration, Nantong University, Nantong, 226001, China.
authors: Jieyu
authors: J
authors: Qi
authors: Department of Otorhinolaryngology and Hearing Research Institute of Affiliated Eye and ENT Hospital, State Key Laboratory of Medicine Neurobiology, Fudan University, Room 611, Building 9, No. 83, Fenyang Road, Xuhui District, Shanghai, 200031, China.
authors: Wenyan
authors: W
authors: Li
authors: Department of Otorhinolaryngology and Hearing Research Institute of Affiliated Eye and ENT Hospital, State Key Laboratory of Medicine Neurobiology, Fudan University, Room 611, Building 9, No. 83, Fenyang Road, Xuhui District, Shanghai, 200031, China.
authors: Liman
authors: L
authors: Liu
authors: Department of Otorhinolaryngology and Hearing Research Institute of Affiliated Eye and ENT Hospital, State Key Laboratory of Medicine Neurobiology, Fudan University, Room 611, Building 9, No. 83, Fenyang Road, Xuhui District, Shanghai, 200031, China.
authors: Yanping
authors: Y
authors: Zhang
authors: Department of Otorhinolaryngology and Hearing Research Institute of Affiliated Eye and ENT Hospital, State Key Laboratory of Medicine Neurobiology, Fudan University, Room 611, Building 9, No. 83, Fenyang Road, Xuhui District, Shanghai, 200031, 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, 210096, China.|Co-innovation Center of Neuroregeneration, Nantong University, Nantong, 226001, China.
authors: Shasha
authors: S
authors: Zhang
authors: Institutes of Biomedical Sciences, Fudan University, Shanghai, 200032, China.
authors: Lei
authors: L
authors: Wang
authors: State Key Laboratory of Reproductive Medicine, Research Center for Bone and Stem Cells, Department of Human Anatomy, Nanjing Medical University, Nanjing, 210096, China.
authors: Dengshun
authors: D
authors: Miao
authors: Key Laboratory for Developmental Genes and Human Disease, Ministry of Education, Institute of Life Sciences, Southeast University, Nanjing, 210096, China. renjiec@seu.edu.cn.|Co-innovation Center of Neuroregeneration, Nantong University, Nantong, 226001, China. renjiec@seu.edu.cn.
authors: Renjie
authors: R
authors: Chai
authors: Department of Otorhinolaryngology and Hearing Research Institute of Affiliated Eye and ENT Hospital, State Key Laboratory of Medicine Neurobiology, Fudan University, Room 611, Building 9, No. 83, Fenyang Road, Xuhui District, Shanghai, 200031, China. hwli@shmu.edu.cn.|Institutes of Biomedical Sciences, Fudan University, Shanghai, 200032, China. hwli@shmu.edu.cn.
authors: Huawei
authors: H
authors: Li
mesh_terms: D000818:Animals; D049109:Cell Proliferation / Q000502:physiology*; D003051:Cochlea / Q000166:cytology* / Q000378:metabolism*; D051379:Mice; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D063150:Polycomb Repressive Complex 1 / Q000502:physiology*; D011518:Proto-Oncogene Proteins / Q000502:physiology*; D060449:Wnt Signaling Pathway / Q000502:physiology*
chemical_list: C489421:Bmi1 protein, mouse; D011518:Proto-Oncogene Proteins; D063150:Polycomb Repressive Complex 1
keywords: Beta-catenin; Hair cells; Lgr5; Proliferation; Supporting cells; Wnt