Abstract

Sensory hair cells are mechanoreceptors required for hearing and balance functions. From embryonic development, hair cells acquire apical stereociliary bundles for mechanosensation, basolateral ion channels that shape receptor potential, and synaptic contacts for conveying information centrally. These key maturation steps are sequential and presumed coupled; however, whether hair cells emerging postnatally mature similarly is unknown. Here, we show that in vivo postnatally generated and regenerated hair cells in the utricle, a vestibular organ detecting linear acceleration, acquired some mature somatic features but hair bundles appeared nonfunctional and short. The utricle consists of two hair cell subtypes with distinct morphological, electrophysiological and synaptic features. In both the undamaged and damaged utricle, fate-mapping and electrophysiology experiments showed that Plp1+ supporting cells took on type II hair cell properties based on molecular markers, basolateral conductances and synaptic properties yet stereociliary bundles were absent, or small and nonfunctional. By contrast, Lgr5+ supporting cells regenerated hair cells with type I and II properties, representing a distinct hair cell precursor subtype. Lastly, direct physiological measurements showed that utricular function abolished by damage was partially regained during regeneration. Together, our data reveal a previously unrecognized aberrant maturation program for hair cells generated and regenerated postnatally and may have broad implications for inner ear regenerative therapies.

Highlights

  • Inner ear hair cells are mechanoreceptors critical for auditory and vestibular functions, and their degeneration are primary causes of hearing and balance dysfunction

  • Control experiments using corn oil on P3 Plp1-tdTomato mice revealed no labeled hair cells (n = 665 and 608 hair cells in the extrastriola and striola from 3 mice) and only rare labeled supporting cells at P30 (0.5% of 954 extrastriolar and 0.1% of 946 striolar supporting cells from 3 mice, S1F Fig). This suggests that P3 Plp1+ supporting cells contribute to postnatally generated hair cells, which we term HCPG3 hereon

  • We found that Osteopontin was expressed at the apical neck of type I hair cells with Tuj1+ calyces, while Annexin A4 and Mapt were expressed in the cell membrane of type II hair cells throughout the P30 utricle (Fig 2A–2D and 2K–2N, S2J and S2K Fig)

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Summary

Introduction

Inner ear hair cells are mechanoreceptors critical for auditory and vestibular functions, and their degeneration are primary causes of hearing and balance dysfunction. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript

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