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

Tian Wang, Renjie Chai, Grace S. Kim, Nicole Pham, Lina Jansson, Duc-Huy Nguyen, Bryan Kuo, Lindsey A. May, Jian Zuo, Lisa L. Cunningham and Alan G. Cheng ()
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Tian Wang: Stanford University School of Medicine
Renjie Chai: Stanford University School of Medicine
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

Nature Communications, 2015, vol. 6, issue 1, 1-15

Abstract: 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.

Date: 2015
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DOI: 10.1038/ncomms7613

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