Bryony Ariya Nayagam

Cochlear homeostasis is critical for the preservation of hearing sensitivity by maintaining optimal cochlear fluid composition, sustaining electrochemical gradients, and supporting the function of sensory and supporting cells in the cochlea. Sensorineural hearing loss, resulting from the damage or loss of sensory hair cells, auditory neurons and other cochlear cells and structures, is intimately linked to disruptions in the homeostatic environment. In this narrative review, we explore the cellular and molecular pathways underpinning cochlear homeostasis in health and disease and examine the mechanisms by which failed homeostasis leads to sensorineural hearing loss. We further discuss current research avenues and emerging therapeutic strategies to restore or compensate for the loss of homeostatic balance. These interventions suggest a future where regenerative healing is possible, ultimately leading to permanent repair and functional recovery.

Recent single-cell transcriptomic approaches are uncovering the breadth and depth of cell diversity within the mammalian inner ear. Macrophages, detected from fetal week 5 in the human inner ear, persist into adulthood and yet remain poorly understood in terms of their origin and function. Using self-generated and public scRNA-seq data, we identified seven distinct macrophage subtypes spanning fetal weeks 7.5 to 16.4 and adulthood. Each macrophage subtype is linked to specific developmental stages and displays a unique gene expression profile. These findings corroborate earlier histological evidence of resident and non-resident macrophages in both the developing and adult human cochlea. We also showed that the human inner ear is seeded by macrophages from both embryonic and more definitive sources, corroborating studies in mice. By analyzing ligand–receptor interactions, we highlight potential macrophage contributions to inner ear organogenesis. This research provides new insights into the diverse roles of human inner ear macrophages.

Cochlear homeostasis is critical for the preservation of hearing sensitivity by maintaining optimal cochlear fluid composition, sustaining electrochemical gradients, and supporting the function of sensory and supporting cells in the cochlea. Sensorineural hearing loss, resulting from the damage or loss of sensory hair cells, auditory neurons and other cochlear cells and structures, is intimately linked to disruptions in the homeostatic environment. In this narrative review, we explore the cellular and molecular pathways underpinning cochlear homeostasis in health and disease and examine the mechanisms by which failed homeostasis leads to sensorineural hearing loss. We further discuss current research avenues and emerging therapeutic strategies to restore or compensate for the loss of homeostatic balance. These interventions suggest a future where regenerative healing is possible, ultimately leading to permanent repair and functional recovery.

Recent single-cell transcriptomic approaches are uncovering the breadth and depth of cell diversity within the mammalian inner ear. Macrophages, detected from gestational week 7 in the human inner ear, persist into adulthood, and yet remain poorly understood in terms of their origin and function. Using self-generated and public scRNA-seq data, we identify seven distinct macrophage subtypes spanning fetal weeks 7.5 to 16.4 and adulthood. Each macrophage subtype is linked to specific developmental stages and displays a unique gene expression profile. These findings corroborate earlier histological evidence of resident and non-resident macrophages in both the developing and adult human cochlea. We also show that the human inner ear is seeded by macrophages from both embryonic and more definitive sources, corroborating studies in mouse. By analyzing ligand-receptor interactions, we highlight potential macrophage contributions to inner ear organogenesis. This research provides new insights into the diverse roles of human inner ear macrophages.

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Aim: Over the last two decades, numerous experimental studies have examined the feasibility of delivering stem cells into the cochlea to restore hearing. While these studies have spawned new cell therapy companies, there is little information on what patients understand or expect from these emerging therapies. Methods: This study sought to understand the awareness and perspectives of Australian audiologists and their adult patients toward stem cell therapies for treating hearing loss. Results: An anonymous survey indicated 91% of patients and 39% of audiologists were unaware of these therapies being developed. Thirty percent of audiologists reported being asked about stem cell therapies for hearing loss, but 70% were not confident answering patient queries about this and were unsure where to gather information. Primary concerns reported by patients were cost (45%) and safety of treatment (42%). Interestingly, 58% of patients were unsure of how this therapy would improve their hearing, yet 25% of these patients expected that their hearing would return to normal. Conclusion: There was strong support for development of educational materials for both patient and clinician. The increasingly important role of audiologists in providing patient counselling was reflected in overwhelming support (from both patient and clinician) for audiologists providing such information. In recent years, scientific studies have investigated the possibility of using stem cells to improve or restore hearing. Although some companies claim to be able use stem cell therapies to treat hearing loss now, there is currently not enough evidence to show these treatments are safe or effective. This study aimed to understand the awareness and perspectives of Australian audiologists and their adult patients toward stem cell therapies for hearing restoration. The study was conducted as a survey at an audiology clinic in Melbourne, Australia. The study found 91% of patients and 39% of audiologists were not aware of stem cell therapies for hearing loss. Although 30% of audiologists said they had been asked by a patient about stem cell therapies, 70% said they would not feel confident responding to a question from a patient. Primary patient concerns about stem cell therapies for hearing loss were cost (45%) and safety (42%). Most patients (57%) were unsure what stem cell therapies would do, but 25% expected that this treatment would return their hearing to normal. This study demonstrates the increasingly important role of audiologists in providing support to patients about future potential therapies for hearing loss, as reflected in overwhelming support (from both patient and clinician) for audiologists providing such information.

Aminoglycoside antibiotics are lifesaving medicines, crucial for the treatment of chronic or drug resistant infections. However, aminoglycosides are toxic to the sensory hair cells in the inner ear. As a result, aminoglycoside-treated individuals can develop permanent hearing loss and vestibular impairment. There is considerable evidence that reactive oxygen species (ROS) production and the subsequent phosphorylation of c-Jun N-terminal kinase (JNK) and P38 mitogen-activated protein kinase (P38) drives apoptosis in aminoglycoside-treated hair cells. However, treatment strategies that directly inhibit ROS, JNK, or P38 are limited by the importance of these molecules for normal cellular function. Alternatively, the upstream regulator apoptosis signal-regulating kinase 1 (ASK1/MAP3K5) is a key mediator of ROS-induced JNK and P38 activation under pathologic but not homeostatic conditions. We investigated ASK1 as a mediator of drug-induced hair cell death using cochlear explants from Ask1 knockout mice, demonstrating that Ask1 deficiency attenuates neomycin-induced hair cell death. We then evaluated pharmacological inhibition of ASK1 with GS-444217 as a potential otoprotective therapy. GS-444217 significantly attenuated hair cell death in neomycin-treated explants but did not impact aminoglycoside efficacy against P. aeruginosa in the broth dilution test. Overall, we provide significant pre-clinical evidence that ASK1 inhibition represents a novel strategy for preventing aminoglycoside ototoxicity. Key messages: ASK1 is an upstream, redox-sensitive regulator of P38 and JNK, which are known mediators of hair cell death. Ask1 knockout does not affect hair cell development in vivo, but significantly reduces aminoglycoside-induced hair cell death in vitro. A small-molecule inhibitor of ASK1 attenuates neomycin-induced hair cell death, and does not impact antibiotic efficacy in vitro. ASK1 may be a novel molecular target for preventing aminoglycoside-induced hearing loss.

Objective. Infrared light can be used to modulate the activity of neuronal cells through thermally-evoked capacitive currents and thermosensitive ion channel modulation. The infrared power threshold for action potentials has previously been found to be far lower in the in vivo cochlea when compared with other neuronal targets, implicating spiral ganglion neurons (SGNs) as a potential target for infrared auditory prostheses. However, conflicting experimental evidence suggests that this low threshold may arise from an intermediary mechanism other than direct SGN stimulation, potentially involving residual hair cell activity. Approach. Patch-clamp recordings from cultured SGNs were used to explicitly quantify the capacitive and ion channel currents in an environment devoid of hair cells. Neurons were irradiated by a 1870 nm laser with pulse durations of 0.2–5.0 ms and powers up to 1.5 W. A Hodgkin-Huxley-type model was established by first characterising the voltage dependent currents, and then incorporating laser-evoked currents separated into temperature-dependent and temperature-gradient-dependent components. This model was found to accurately simulate neuronal responses and allowed the results to be extrapolated to stimulation parameter spaces not accessible during this study. Main results. The previously-reported low in vivo SGN stimulation threshold was not observed, and only subthreshold depolarisation was achieved, even at high light exposures. Extrapolating these results with our Hodgkin-Huxley-type model predicts an action potential threshold which does not deviate significantly from other neuronal types. Significance. This suggests that the low-threshold response that is commonly reported in vivo may arise from an alternative mechanism, and calls into question the potential usefulness of the effect for auditory prostheses. The step-wise approach to modelling optically-evoked currents described here may prove useful for analysing a wider range of cell types where capacitive currents and conductance modulation are dominant.

Objective. To evaluate the electrochemical properties, biological response, and surface characterization of an electrodeposited Platinum-Iridium (Pt-Ir) electrode coating on cochlear implants subjected to chronic stimulation in vivo. Approach . Electrochemical impedance spectroscopy (EIS), charge storage capacity (CSC), charge injection limit (CIL), and voltage transient (VT) impedance were measured bench-top before and after implant and in vivo . Coated Pt-Ir and uncoated Pt electrode arrays were implanted into cochlea of normal hearing rats and stimulated for ∼4 h d, 5 d week ⁻¹ for 5 weeks at levels within the normal clinical range. Neural function was monitored using electrically-evoked auditory brainstem responses. After explant, the electrode surfaces were assessed, and cochleae examined histologically. Main results . When measured on bench-top before and after stimulation, Pt-Ir coated electrodes had significantly lower VT impedance (p < 0.001) and significantly higher CSC (p < 0.001) and CIL (p < 0.001) compared to uncoated Pt electrodes. In vivo , the CSC and CIL of Pt-Ir were significantly higher than Pt throughout the implantation period ( p = 0.047 and p < 0.001, respectively); however, the VT impedance ( p = 0.3) was not. There was no difference in foreign body response between material cohorts, although cochleae implanted with coated electrodes contained small deposits of Pt-Ir. There was no evidence of increased neural loss or loss of neural function in either group. Surface examination revealed no Pt corrosion on any electrodes. Significance . Electrodeposited Pt-Ir electrodes demonstrated significant improvements in electrochemical performance on the bench-top and in vivo compared to uncoated Pt. Neural function and tissue response to Pt-Ir electrodes were not different from uncoated Pt, despite small deposits of Pt-Ir in the tissue capsule. Electrodeposited Pt-Ir coatings offer promise as an improved electrode coating for active neural prostheses.