Abstract
The utricle is one of the five sensory organs in the mammalian vestibular system, and while the utricle has a limited ability to repair itself, this is not sufficient for the recovery of vestibular function after hair cell (HC) loss induced by ototoxic drugs. In order to further explore the possible self-recovery mechanism of the adult mouse vestibular system, we established a reliable utricle epithelium injury model for studying the regeneration of HCs and examined the toxic effects of 3,3′-iminodiproprionitrile (IDPN) on the utricle in vivo in C57BL/6J mice, which is one of the most commonly used strains in inner ear research. This work focused on the epithelial cell loss, vestibular dysfunction, and spontaneous cell regeneration after IDPN administration. HC loss and supporting cell (SC) loss after IDPN treatment was dose-dependent and resulted in dysfunction of the vestibular system, as indicated by the swim test and the rotating vestibular ocular reflex (VOR) test. EdU-positive SCs were observed only in severely injured utricles wherein above 47% SCs were dead. No EdU-positive HCs were observed in either control or injured utricles. RT-qPCR showed transient upregulation of Hes5 and Hey1 and fluctuating upregulation of Axin2 and β-catenin after IDPN administration. We conclude that a single intraperitoneal injection of IDPN is a practical way to establish an injured utricle model in adult C57BL/6J mice in vivo. We observed activation of Notch and Wnt signaling during the limited spontaneous HC regeneration after vestibular sensory epithelium damage, and such signaling might act as the promoting factors for tissue self-repair in the inner ear.
Highlights
The sensory organs of the mammalian inner ear include the organ of Corti in the cochlea, which senses sound, and the macula sacculi, macula utriculi, and crista ampullaris from the vestibular system that sense acceleration and postural signals
Seoane et al showed that extrusion is a major mechanism of hair cell (HC) death in mammals; that necrosis, apoptosis, and extrusion form a continuum of modes of HC loss; and that the intensity of the damaging stimulus determines the prevalence of each mode [17]
The association of HC degeneration with behavioral syndrome was found in dose-response studies in acute, repeated, and chronic dosing in rats [6, 18, 19]
Summary
The sensory organs of the mammalian inner ear include the organ of Corti in the cochlea, which senses sound, and the macula sacculi, macula utriculi, and crista ampullaris from the vestibular system that sense acceleration and postural signals. HCs are the mechanoreceptors in all inner ear sensory organs and are responsible for normal auditory and balance functions. The sensory organs of the mammalian inner ear have only very limited self-renewal capacity in the vestibular system and no self-renewal in the cochlea, and this means that dysfunction of vestibular sensation and hearing is permanent [1,2,3]. It is a very important task to promote HC regeneration and rebuild the function of the inner ear. Unlike a cochlear injury model, there are few practical vestibular injury models reported with data of objective tests for evaluating the function of the vestibular
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