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Hearing Loss: Molecular Mechanisms, Treatment and Prevention
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Hearing Loss: Molecular Mechanisms, Treatment and Prevention

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: closed (15 April 2023) | Viewed by 22719

Special Issue Editor

Dr. Huib Versnel

E-Mail Website
Guest Editor
Department of Otorhinolaryngology and Head & Neck Surgery, University Medical Center Utrecht, Utrecht University, Room G.02.531, P.O. Box 85500, 3508 GA Utrecht, The Netherlands
Interests: auditory system; cochlear implantation; hearing loss; neuroprotection; plasticity
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

The World Health Organization has indicated that about half a billion people worldwide suffer disabling hearing loss and another billion are at risk. Consequences for individuals include social isolation and cognitive decline, and hearing loss has enormous costs for society (estimates in USA alone: USD 1 trillion). Therefore, research dedicated to the prevention and treatment of hearing loss is crucial for the global population. This Special Issue reports fundamental research on molecular mechanisms involved in sensorineural hearing loss (i.e., damage to the cochlea), and subsequent changes along the auditory pathway. Cochlear damage occurs due to ototoxic drugs, loud sounds, aging and/or genetic and multiple other factors, and harms various structures including hair cells, synapses, spiral ganglion cells and strial cells. Furthermore, this Special Issue aims to indicate directions towards innovative treatment and prevention based on insights into molecular mechanisms. 

Dr. Natalia F. Smith-Cortinez is the guest editor assistant of the special issue. She will help Dr. Huib Versnel manage the special issue together

Dr. Huib Versnel
Guest Editor

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Keywords

  • cochlea
  • inner ear
  • organ of Corti
  • hair cell
  • stria vascularis
  • spiral ganglion neuron
  • deafness
  • auditory system
  • ototoxicity
  • noise trauma

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Published Papers (6 papers)

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Research

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33 pages, 3558 KiB  
Article
Conditional Ablation of Glucocorticoid and Mineralocorticoid Receptors from Cochlear Supporting Cells Reveals Their Differential Roles for Hearing Sensitivity and Dynamics of Recovery from Noise-Induced Hearing Loss
by Charles C. Barnes, Kathleen T. Yee and Douglas E. Vetter
Int. J. Mol. Sci. 2023, 24(4), 3320; https://doi.org/10.3390/ijms24043320 - 7 Feb 2023
Cited by 1 | Viewed by 2717
Abstract
Endogenous glucocorticoids (GC) are known to modulate basic elements of cochlear physiology. These include both noise-induced injury and circadian rhythms. While GC signaling in the cochlea can directly influence auditory transduction via actions on hair cells and spiral ganglion neurons, evidence also indicates [...] Read more.
Endogenous glucocorticoids (GC) are known to modulate basic elements of cochlear physiology. These include both noise-induced injury and circadian rhythms. While GC signaling in the cochlea can directly influence auditory transduction via actions on hair cells and spiral ganglion neurons, evidence also indicates that GC signaling exerts effects via tissue homeostatic processes that can include effects on cochlear immunomodulation. GCs act at both the glucocorticoid receptor (GR) and the mineralocorticoid receptor (MR). Most cell types in the cochlea express both receptors sensitive to GCs. The GR is associated with acquired sensorineural hearing loss (SNHL) through its effects on both gene expression and immunomodulatory programs. The MR has been associated with age-related hearing loss through dysfunction of ionic homeostatic balance. Cochlear supporting cells maintain local homeostatic requirements, are sensitive to perturbation, and participate in inflammatory signaling. Here, we have used conditional gene manipulation techniques to target Nr3c1 (GR) or Nr3c2 (MR) for tamoxifen-induced gene ablation in Sox9-expressing cochlear supporting cells of adult mice to investigate whether either of the receptors sensitive to GCs plays a role in protecting against (or exacerbating) noise-induced cochlear damage. We have selected mild intensity noise exposure to examine the role of these receptors related to more commonly experienced noise levels. Our results reveal distinct roles of these GC receptors for both basal auditory thresholds prior to noise exposure and during recovery from mild noise exposure. Prior to noise exposure, auditory brainstem responses (ABRs) were measured in mice carrying the floxed allele of interest and the Cre recombinase transgene, but not receiving tamoxifen injections (defined as control (no tamoxifen treatment), versus conditional knockout (cKO) mice, defined as mice having received tamoxifen injections. Results revealed hypersensitive thresholds to mid- to low-frequencies after tamoxifen-induced GR ablation from Sox9-expressing cochlear supporting cells compared to control (no tamoxifen) mice. GR ablation from Sox9-expressing cochlear supporting cells resulted in a permanent threshold shift in mid-basal cochlear frequency regions after mild noise exposure that produced only a temporary threshold shift in both control (no tamoxifen) f/fGR:Sox9iCre+ and heterozygous f/+GR:Sox9iCre+ tamoxifen-treated mice. A similar comparison of basal ABRs measured in control (no tamoxifen) and tamoxifen-treated, floxed MR mice prior to noise exposure indicated no difference in baseline thresholds. After mild noise exposure, MR ablation was initially associated with a complete threshold recovery at 22.6 kHz by 3 days post-noise. Threshold continued to shift to higher sensitivity over time such that by 30 days post-noise exposure the 22.6 kHz ABR threshold was 10 dB more sensitive than baseline. Further, MR ablation produced a temporary reduction in peak 1 neural amplitude one day post-noise. While supporting cell GR ablation trended towards reducing numbers of ribbon synapses, MR ablation reduced ribbon synapse counts but did not exacerbate noise-induced damage including synapse loss at the experimental endpoint. GR ablation from the targeted supporting cells increased the basal resting number of Iba1-positive (innate) immune cells (no noise exposure) and decreased the number of Iba1-positive cells seven days following noise exposure. MR ablation did not alter innate immune cell numbers at seven days post-noise exposure. Taken together, these findings support differential roles of cochlear supporting cell MR and GR expression at basal, resting conditions and especially during recovery from noise exposure. Full article
(This article belongs to the Special Issue Hearing Loss: Molecular Mechanisms, Treatment and Prevention)
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15 pages, 2740 KiB  
Article
Protective Effect of Avenanthramide-C on Auditory Hair Cells against Oxidative Stress, Inflammatory Cytokines, and DNA Damage in Cisplatin-Induced Ototoxicity
by Alphonse Umugire, Yoon Seok Nam, Ye Eun Nam, Young Mi Choi, Se Myeong Choi, Sungsu Lee, Jong Hyun Cho and Hyong-Ho Cho
Int. J. Mol. Sci. 2023, 24(3), 2947; https://doi.org/10.3390/ijms24032947 - 2 Feb 2023
Cited by 8 | Viewed by 2517
Abstract
Cisplatin-induced ototoxicity leads to hearing impairment, possibly through reactive oxygen species (ROS) production and DNA damage in cochlear hair cells (HC), although the exact mechanism is unknown. Avenanthramide-C (AVN-C), a natural, potent antioxidant, was evaluated in three study groups of normal adult C57Bl/6 [...] Read more.
Cisplatin-induced ototoxicity leads to hearing impairment, possibly through reactive oxygen species (ROS) production and DNA damage in cochlear hair cells (HC), although the exact mechanism is unknown. Avenanthramide-C (AVN-C), a natural, potent antioxidant, was evaluated in three study groups of normal adult C57Bl/6 mice (control, cisplatin, and AVN-C+cisplatin) for the prevention of cisplatin-induced hearing loss. Auditory brainstem responses and immunohistochemistry of outer hair cells (OHCs) were ascertained. Cell survival, ROS production, Phospho-H2AX-enabled tracking of DNA damage-repair kinetics, and expression levels of inflammatory cytokines (TNF-α, IL-1β, IL6, iNOS, and COX2) were assessed using House Ear Institute-Organ of Corti 1 (HEI-OC1 Cells). In the in vivo mouse model, following cisplatin-induced damage, AVN-C decreased the hearing thresholds and sheltered all cochlear turns’ OHCs. In HEI-OC1 cells, AVN-C preserved cell viability and decreased ROS production, whereas cisplatin enhanced both ROS levels and cell viability. In HEI-OC1 cells, AVN-C downregulated IL6, IL-1β, TNF-α, iNOS, and COX2 production that was upregulated by cisplatin treatment. AVN-C attenuated the cisplatin-enhanced nuclear H2AX activation. AVN-C had a strong protective effect against cisplatin-induced ototoxicity through inhibition of ROS and inflammatory cytokine production and DNA damage and is thus a promising candidate for preventing cisplatin-induced sensorineural hearing loss. Full article
(This article belongs to the Special Issue Hearing Loss: Molecular Mechanisms, Treatment and Prevention)
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16 pages, 1836 KiB  
Article
Pericytes of Stria Vascularis Are Targets of Cisplatin-Induced Ototoxicity: New Insights into the Molecular Mechanisms Involved in Blood-Labyrinth Barrier Breakdown
by Carmelina Daniela Anfuso, Alessia Cosentino, Aleksandra Agafonova, Agata Zappalà, Giovanni Giurdanella, Angela Trovato Salinaro, Vittorio Calabrese and Gabriella Lupo
Int. J. Mol. Sci. 2022, 23(24), 15790; https://doi.org/10.3390/ijms232415790 - 13 Dec 2022
Cited by 6 | Viewed by 2193
Abstract
The stria vascularis (SV) contributes to cochlear homeostasis and consists of three layers, one of which contains the blood-labyrinthic barrier (BLB), with a large number of bovine cochlear pericytes (BCPs). Cisplatin is a chemotherapeutic drug that can damage the SV and cause hearing [...] Read more.
The stria vascularis (SV) contributes to cochlear homeostasis and consists of three layers, one of which contains the blood-labyrinthic barrier (BLB), with a large number of bovine cochlear pericytes (BCPs). Cisplatin is a chemotherapeutic drug that can damage the SV and cause hearing loss. In this study, cell viability, proliferation rate, cytotoxicity and reactive oxygen species production were evaluated. The protein content of phospho-extracellular signal-regulated kinases (ERK) 1/2, total ERK 1/2, phospho-cytosolic phospholipase A2 (cPLA2), total cPLA2 and cyclooxygenase 2 (COX-2) and the release of prostaglandin E2 (PGE2) and vascular endothelial growth factor (VEGF) from BCPs were analyzed. Finally, the protective effect of platelet-derived growth factor (PDGF-BB) on BCPs treated with cisplatin was investigated. Cisplatin reduced viability and proliferation, activated ERK 1/2, cPLA2 and COX-2 expression and increased PGE2 and VEGF release; these effects were reversed by Dexamethasone. The presence of PDGF-BB during the treatment with cisplatin significantly increased the proliferation rate. No studies on cell regeneration in ear tissue evaluated the effect of the PDGF/Dex combination. The aim of this study was to investigate the effects of cisplatin on cochlear pericytes and propose new otoprotective agents aimed at preventing the reduction of their vitality and thus maintaining the BLB structure. Full article
(This article belongs to the Special Issue Hearing Loss: Molecular Mechanisms, Treatment and Prevention)
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Review

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23 pages, 790 KiB  
Review
Regeneration of Hair Cells from Endogenous Otic Progenitors in the Adult Mammalian Cochlea: Understanding Its Origins and Future Directions
by Natalia Smith-Cortinez, A. Katherine Tan, Robert J. Stokroos, Huib Versnel and Louise V. Straatman
Int. J. Mol. Sci. 2023, 24(9), 7840; https://doi.org/10.3390/ijms24097840 - 25 Apr 2023
Cited by 4 | Viewed by 5187
Abstract
Sensorineural hearing loss is caused by damage to sensory hair cells and/or spiral ganglion neurons. In non-mammalian species, hair cell regeneration after damage is observed, even in adulthood. Although the neonatal mammalian cochlea carries regenerative potential, the adult cochlea cannot regenerate lost hair [...] Read more.
Sensorineural hearing loss is caused by damage to sensory hair cells and/or spiral ganglion neurons. In non-mammalian species, hair cell regeneration after damage is observed, even in adulthood. Although the neonatal mammalian cochlea carries regenerative potential, the adult cochlea cannot regenerate lost hair cells. The survival of supporting cells with regenerative potential after cochlear trauma in adults is promising for promoting hair cell regeneration through therapeutic approaches. Targeting these cells by manipulating key signaling pathways that control mammalian cochlear development and non-mammalian hair cell regeneration could lead to regeneration of hair cells in the mammalian cochlea. This review discusses the pathways involved in the development of the cochlea and the impact that trauma has on the regenerative capacity of the endogenous progenitor cells. Furthermore, it discusses the effects of manipulating key signaling pathways targeting supporting cells with progenitor potential to promote hair cell regeneration and translates these findings to the human situation. To improve hearing recovery after hearing loss in adults, we propose a combined approach targeting (1) the endogenous progenitor cells by manipulating signaling pathways (Wnt, Notch, Shh, FGF and BMP/TGFβ signaling pathways), (2) by manipulating epigenetic control, and (3) by applying neurotrophic treatments to promote reinnervation. Full article
(This article belongs to the Special Issue Hearing Loss: Molecular Mechanisms, Treatment and Prevention)
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18 pages, 580 KiB  
Review
Functional and Molecular Markers for Hearing Loss and Vertigo Attacks in Meniere’s Disease
by Chao-Hui Yang, Ming-Yu Yang, Chung-Feng Hwang and Kuang-Hsu Lien
Int. J. Mol. Sci. 2023, 24(3), 2504; https://doi.org/10.3390/ijms24032504 - 28 Jan 2023
Cited by 10 | Viewed by 3511
Abstract
Meniere’s disease (MD) is one of the most complicated diseases in the otologic clinic. The complexity of MD is partially due to the multifactorial etiological mechanisms and the heterogenous symptoms, including episodic vertigo, hearing loss, aural fullness and tinnitus. As a result, the [...] Read more.
Meniere’s disease (MD) is one of the most complicated diseases in the otologic clinic. The complexity of MD is partially due to the multifactorial etiological mechanisms and the heterogenous symptoms, including episodic vertigo, hearing loss, aural fullness and tinnitus. As a result, the diagnosis of MD and differentiating MD from other diseases with similar symptoms, such as vestibular migraine (VM), is challenging. In addition, it is difficult to predict the progression of hearing loss and the frequency of vertigo attacks. Detailed studies have revealed that functional markers, such as pure tone audiometry (PTA), electrocochleography (ECochG), vestibular evoked myogenic potential (VEMP), caloric test, video head impulse test (vHIT) and magnetic resonance imaging (MRI) could help to evaluate MD with different hearing levels and frequency of vertigo attacks. Investigations of molecular markers such as autoimmunity, inflammation, protein signatures, vasopressin and circadian clock genes in MD are still underway. This review will summarize these functional and molecular markers, address how these markers are associated with hearing loss and vertigo attacks in MD, and analyze the results of the markers between MD and VM. Full article
(This article belongs to the Special Issue Hearing Loss: Molecular Mechanisms, Treatment and Prevention)
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14 pages, 3947 KiB  
Review
Emerging Roles of RNA-Binding Proteins in Inner Ear Hair Cell Development and Regeneration
by De-Li Shi, Xiao-Ning Cheng, Audrey Saquet and Raphaëlle Grifone
Int. J. Mol. Sci. 2022, 23(20), 12393; https://doi.org/10.3390/ijms232012393 - 16 Oct 2022
Cited by 8 | Viewed by 5728
Abstract
RNA-binding proteins (RBPs) regulate gene expression at the post-transcriptional level. They play major roles in the tissue- and stage-specific expression of protein isoforms as well as in the maintenance of protein homeostasis. The inner ear is a bi-functional organ, with the cochlea and [...] Read more.
RNA-binding proteins (RBPs) regulate gene expression at the post-transcriptional level. They play major roles in the tissue- and stage-specific expression of protein isoforms as well as in the maintenance of protein homeostasis. The inner ear is a bi-functional organ, with the cochlea and the vestibular system required for hearing and for maintaining balance, respectively. It is relatively well documented that transcription factors and signaling pathways are critically involved in the formation of inner ear structures and in the development of hair cells. Accumulating evidence highlights emerging functions of RBPs in the post-transcriptional regulation of inner ear development and hair cell function. Importantly, mutations of splicing factors of the RBP family and defective alternative splicing, which result in inappropriate expression of protein isoforms, lead to deafness in both animal models and humans. Because RBPs are critical regulators of cell proliferation and differentiation, they present the potential to promote hair cell regeneration following noise- or ototoxin-induced damage through mitotic and non-mitotic mechanisms. Therefore, deciphering RBP-regulated events during inner ear development and hair cell regeneration can help define therapeutic strategies for treatment of hearing loss. In this review, we outline our evolving understanding of the implications of RBPs in hair cell formation and hearing disease with the aim of promoting future research in this field. Full article
(This article belongs to the Special Issue Hearing Loss: Molecular Mechanisms, Treatment and Prevention)
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