title: Lgr5+ cells regenerate hair cells via proliferation and direct transdifferentiation in damaged neonatal mouse utricle.
abstract: Recruitment of endogenous progenitors is critical during tissue repair. The inner ear utricle requires mechanosensory hair cells (HCs) to detect linear acceleration. After damage, non-mammalian utricles regenerate HCs via both proliferation and direct transdifferentiation. In adult mammals, limited transdifferentiation from unidentified progenitors occurs to regenerate extrastriolar Type II HCs. Here we show that HC damage in neonatal mouse utricle activates the Wnt target gene Lgr5 in striolar supporting cells. Lineage tracing and time-lapse microscopy reveal that Lgr5+ cells transdifferentiate into HC-like cells in vitro. In contrast to adults, HC ablation in neonatal utricles in vivo recruits Lgr5+ cells to regenerate striolar HCs through mitotic and transdifferentiation pathways. Both Type I and II HCs are regenerated, and regenerated HCs display stereocilia and synapses. Lastly, stabilized ß-catenin in Lgr5+ cells enhances mitotic activity and HC regeneration. Thus Lgr5 marks Wnt-regulated, damage-activated HC progenitors and may help uncover factors driving mammalian HC regeneration.
authors: Department of Otolaryngology-Head and Neck Surgery, Stanford University School of Medicine, Stanford, California 94305, USA.
authors: Tian
authors: T
authors: Wang
authors: 1] Department of Otolaryngology-Head and Neck Surgery, Stanford University School of Medicine, Stanford, California 94305, USA [2] Key Laboratory for Developmental Genes and Human Disease, Ministry of Education, Institute of Life Sciences, Southeast University, Nanjing 210096, China [3] Co-innovation Center of Neuroregeneration, Nantong University, Nantong 226001, China.
authors: Renjie
authors: R
authors: Chai
authors: Department of Otolaryngology-Head and Neck Surgery, Stanford University School of Medicine, Stanford, California 94305, USA.
authors: Grace S
authors: GS
authors: Kim
authors: Department of Otolaryngology-Head and Neck Surgery, Stanford University School of Medicine, Stanford, California 94305, USA.
authors: Nicole
authors: N
authors: Pham
authors: Department of Otolaryngology-Head and Neck Surgery, Stanford University School of Medicine, Stanford, California 94305, USA.
authors: Lina
authors: L
authors: Jansson
authors: Department of Otolaryngology-Head and Neck Surgery, Stanford University School of Medicine, Stanford, California 94305, USA.
authors: Duc-Huy
authors: DH
authors: Nguyen
authors: Department of Developmental Neurobiology, St. Jude Children's Research Hospital, Memphis, Tennessee 38103, USA.
authors: Bryan
authors: B
authors: Kuo
authors: National Institute on Deafness and Other Communication Disorders, National Institutes of Health, Bethesda, Maryland 20892, USA.
authors: Lindsey A
authors: LA
authors: May
authors: Department of Developmental Neurobiology, St. Jude Children's Research Hospital, Memphis, Tennessee 38103, USA.
authors: Jian
authors: J
authors: Zuo
authors: National Institute on Deafness and Other Communication Disorders, National Institutes of Health, Bethesda, Maryland 20892, USA.
authors: Lisa L
authors: LL
authors: Cunningham
authors: Department of Otolaryngology-Head and Neck Surgery, Stanford University School of Medicine, Stanford, California 94305, USA.
authors: Alan G
authors: AG
authors: Cheng
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D049109:Cell Proliferation / Q000502:physiology*; D054338:Cell Transdifferentiation / Q000502:physiology*; D018069:Hair Cells, Vestibular / Q000166:cytology / Q000502:physiology*; D066298:In Vitro Techniques; D051379:Mice; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism*; D012038:Regeneration / Q000502:physiology*; D012444:Saccule and Utricle / Q000166:cytology / Q000293:injuries / Q000502:physiology*; D051176:beta Catenin / Q000378:metabolism
chemical_list: C493597:Lgr5 protein, mouse; D043562:Receptors, G-Protein-Coupled; D051176:beta Catenin