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Lgr5+ cells regenerate hair cells via proliferation and direct transdifferentiation in damaged neonatal mouse utricle

Author

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  • Tian Wang

    (Stanford University School of Medicine)

  • Renjie Chai

    (Stanford University School of Medicine
    Key Laboratory for Developmental Genes and Human Disease, Ministry of Education, Institute of Life Sciences, Southeast University
    Co-innovation Center of Neuroregeneration, Nantong University)

  • Grace S. Kim

    (Stanford University School of Medicine)

  • Nicole Pham

    (Stanford University School of Medicine)

  • Lina Jansson

    (Stanford University School of Medicine)

  • Duc-Huy Nguyen

    (Stanford University School of Medicine)

  • Bryan Kuo

    (St. Jude Children’s Research Hospital)

  • Lindsey A. May

    (National Institute on Deafness and Other Communication Disorders, National Institutes of Health)

  • Jian Zuo

    (St. Jude Children’s Research Hospital)

  • Lisa L. Cunningham

    (National Institute on Deafness and Other Communication Disorders, National Institutes of Health)

  • Alan G. Cheng

    (Stanford University School of Medicine)

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.

Suggested Citation

  • Tian Wang & Renjie Chai & Grace S. Kim & Nicole Pham & Lina Jansson & Duc-Huy Nguyen & Bryan Kuo & Lindsey A. May & Jian Zuo & Lisa L. Cunningham & Alan G. Cheng, 2015. "Lgr5+ cells regenerate hair cells via proliferation and direct transdifferentiation in damaged neonatal mouse utricle," Nature Communications, Nature, vol. 6(1), pages 1-15, May.
    • Handle: RePEc:nat:natcom:v:6:y:2015:i:1:d:10.1038_ncomms7613
    DOI: 10.1038/ncomms7613
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    Cited by:

    1. Yadong Qi & Jiamin He & Yawen Zhang & Qiwei Ge & Qiwen Wang & Luyi Chen & Jilei Xu & Lan Wang & Xueqin Chen & Dingjiacheng Jia & Yifeng Lin & Chaochao Xu & Ying Zhang & Tongyao Hou & Jianmin Si & Shuj, 2023. "Heat-inactivated Bifidobacterium adolescentis ameliorates colon senescence through Paneth-like-cell-mediated stem cell activation," Nature Communications, Nature, vol. 14(1), pages 1-19, December.
    2. Tian Wang & Angela H. Ling & Sara E. Billings & Davood K. Hosseini & Yona Vaisbuch & Grace S. Kim & Patrick J. Atkinson & Zahra N. Sayyid & Ksenia A. Aaron & Dhananjay Wagh & Nicole Pham & Mirko Schei, 2024. "Single-cell transcriptomic atlas reveals increased regeneration in diseased human inner ear balance organs," Nature Communications, Nature, vol. 15(1), pages 1-19, December.

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