Sensory hair cells are mechanoreceptors of the auditory and vestibular systems and are crucial for hearing and balance. In adult mammals, auditory hair cells are unable to regenerate, and damage to these cells results in permanent hearing loss. By contrast, hair cells in the chick cochlea and the zebrafish lateral line are able to regenerate, prompting studies into the signaling pathways, morphogen gradients and transcription factors that regulate hair cell development and regeneration in various species. Here, we review these findings and discuss how various signaling pathways and factors function to modulate sensory hair cell development and regeneration. By comparing and contrasting development and regeneration, we also highlight the utility and limitations of using defined developmental cues to drive mammalian hair cell regeneration.

SUMMARY Utricular hair cells (HCs) are mechanoreceptors required for vestibular function. After damage, regeneration of mammalian utricular HCs is limited and regenerated HCs appear immature. Thus, loss of vestibular function is presumed irreversible. Here, we found partial HC replacement and functional recovery in the mature mouse utricle, both enhanced by overexpressing the transcription factor Atoh1. Following damage, long-term fate mapping revealed that support cells non-mitotically and modestly regenerated HCs displaying no or immature bundles. By contrast, Atoh1 overexpression stimulated proliferation and widespread regeneration of HCs exhibiting elongated bundles, patent mechanotransduction channels, and synaptic connections. Finally, although damage without Atoh1 overexpression failed to initiate or sustain a spontaneous functional recovery, Atoh1 overexpression significantly enhanced both the degree and percentage of animals exhibiting sustained functional recovery. Therefore, the mature, damaged utricle has an Atoh1-responsive regenerative program leading to functional recovery, underscoring the potential of a reprogramming approach to sensory regeneration.

SUMMARYPermanent hearing loss is caused by the irreversible damage of cochlear sensory hair cells and nonsensory supporting cells. In the postnatal cochlea, the sensory epithelium is terminally differentiated, whereas tympanic border cells (TBCs) beneath the sensory epithelium are proliferative. The functions of TBCs are poorly characterized. Using an Axin2 lacZ Wnt reporter mouse, we found transient but robust Wnt signaling and proliferation in TBCs during the first 3 postnatal weeks, when the number of TBCs decreases. In vivo lineage tracing shows that a subset of hair cells and supporting cells is derived postnatally from Axin2-expressing TBCs. In cochlear explants, Wnt agonists stimulated the proliferation of TBCs, whereas Wnt inhibitors suppressed it. In addition, purified Axin2 lacZ cells were clonogenic and self-renewing in culture in a Wnt-dependent manner, and were able to differentiate into hair celllike and supporting cell-like cells. Taken together, our data indicate that Axin2-positive TBCs are Wnt responsive and can act as precursors to sensory epithelial cells in the postnatal cochlea.

ObjectivesTo investigate the possible effects of anxiety and/or depression symptoms on the treatment outcomes and recurrence of benign paroxysmal positional vertigo (BPPV).MethodsThis is a retrospective study conducted at a single institution. 142 consecutive patients diagnosed with idiopathic BPPV at the Department of Otology in Shengjing Hospital of China Medical University between October 2016 and July 2017 were retrospectively reviewed. 127 patients were finally included in this study. Zung self-rating anxiety scale (SAS) and Zung self-rating depression scale (SDS) were used to evaluate the presence of anxiety and/or depression, respectively, in our BPPV patients. A significant score (at or above 50 for SAS and 53 for SDS) represents the presence of clinically significant symptoms. Two-tailed Student’s t-test, χ2 test, and logistic regression analysis were used as appropriate. A p value less than 0.05 was considered statistically significant.ResultsThe prevalence of anxiety and/or depression symptoms in BPPV patients in the present study was 49.61%. The effectiveness of the first time canalith repositioning maneuver (CRM) was 70.08%. With weekly follow-up treatments of CRM, the success rate increased to 97.64% by 1 month. The total recurrence rate at 6-month follow-up post-cure was 14.17%. Holding all other variables constant, patients with psychiatric symptoms (Relative-risk ratio: 3.160; p = 0.027) and patients with non-posterior semicircular canal (PSC) involvement (Relative-risk ratio: 7.828, p = 0.013) were more likely to experience residual dizziness (RD) even after effective CRM treatment. Psychiatric symptoms (Relative-risk ratio: 6.543; p = 0.001) and female gender (Relative-risk ratio: 4.563; p = 0.010) are risk factors for the failure of first time CRM. In addition, BPPV patients with psychiatric symptoms (Odds ratio: 9.184, p = 0.008) were significantly more likely to experience recurrences within the first 6 months after a successful maneuver.ConclusionAnxiety-depression status significantly reduced the efficacy of the first time CRM and increased the risk for recurrence. Other factors, such as female gender and non-PSC involvement are also susceptible risk factors for BPPV patients to require multiple treatments and experience delayed recovery. A screening for psychiatric symptoms in BPPV patients and active treatment of these symptoms would benefit both physicians and patients in understanding and improving the prognosis of the disease and treatment options.

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.