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 β-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.

Sensory hair cell development and regeneration: similarities and differences

“…In this context, Wnt activators have been shown to increase the degree of regeneration after damage (Head et al, 2013;Jacques et al, 2014). Similarly, recent studies of the damaged neonatal mouse utricle revealed that Wnt/β-catenin activation increases both supporting cell proliferation and, subsequently, hair cell regeneration in vivo (Wang et al, 2015). It remains to be tested whether supporting cells in the damaged, adult mammalian cochlea can proliferate and regenerate in response to Wnt/β-catenin activation.…”

Insights into sensory hair cell regeneration from the zebrafish lateral line

“…While the adult mammalian cochlea cannot mount a native regenerative response to HC damage, encouragingly, damaged postmitotic neonatal cochleae and utricles spontaneously regenerate a limited number of HCs by both mitotic regeneration and transdifferentiation [18][19][20]. Likewise, some spontaneous mitotic regeneration and HC production occurs in the adult mouse utricle [21,22].…”

Severe streptomycin ototoxicity in the mouse utricle leads to a flat epithelium but the peripheral neural degeneration is delayed

“…Both in vivo and in cultured explants, the extent of regeneration in the vestibular epithelium is limited and depends to a large extent on trans-differentiation of SCs (Forge et al, 1998; Forge et al, 1993; Golub et al, 2012; Kawamoto et al, 2009; Slowik et al, 2013; Tanyeri et al, 1995; Wang et al, 2010; Wang et al, 2015; Warchol et al, 1993). In the current study, a small number of Myosin VIIa-positive cells are sparsely detected in the vestibular FE.…”

“…The mammalian vestibular sensory epithelium undergoes a limited amount of spontaneous hair cell (HC) regeneration after damage (Burns et al, 2012; Forge et al, 1998; Forge et al, 1993; Golub et al, 2012; Kawamoto et al, 2009; Slowik et al, 2013; Tanyeri et al, 1995; Wang et al, 2015; Warchol et al, 1993). The regenerated HCs are largely derived by transdifferentiation of surviving supporting cells (SCs) (Lin et al, 2011; Slowik et al, 2013; Wang et al, 2015).…”

“…The regenerated HCs are largely derived by transdifferentiation of surviving supporting cells (SCs) (Lin et al, 2011; Slowik et al, 2013; Wang et al, 2015). Therefore, the surviving SCs are potential targets for treatments to enhance the spontaneous HC regeneration, which is otherwise incomplete.…”