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Mammalian hearing requires the development of the organ of Corti, a sensory epithelium comprising unique cell types. The limited number of each of these cell types, combined with their close proximity, has prevented characterization of individual cell types and/or their developmental progression. To examine cochlear development more closely, we transcriptionally profile approximately 30,000 isolated mouse cochlear cells collected at four developmental time points. Here we report on the analysis of those cells including the identification of both known and unknown cell types. Trajectory analysis for OHCs indicates four phases of gene expression while fate mapping of progenitor cells suggests that OHCs and their surrounding supporting cells arise from a distinct (lateral) progenitor pool. Tgfβr1 is identified as being expressed in lateral progenitor cells and a Tgfβr1 antagonist inhibits OHC development. These results provide insights regarding cochlear development and demonstrate the potential value and application of this data set. How the development of the cochlear epithelium is regulated is unclear. Here, the authors use single cell RNAseq analysis to provide insight into the transcriptional changes arising during development of the murine cochlear inner and outer hair cells.

The cover image is based on the article  Pcolce2 overexpression promotes supporting cell reprogramming in the neonatal mouse cochlea  by Changling Xu et al.,  https://doi.org/10.1111/cpr.13633 . image

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.

An alternative to bilateral cochlear implantation is offered by the Neurelec Digisonic registered SP Binaural cochlear implant, which allows stimulation of both cochleae within a single device. The purpose of this prospective study was to compare a group of Neurelec Digisonic registered SP Binaural implant users (denoted BINAURAL group, n = 7) with a group of bilateral adult cochlear implant users (denoted BILATERAL group, n = 6) in terms of speech perception, sound localization, and self-assessment of health status and hearing disability. Speech perception was assessed using word recognition at 60 dB SPL in quiet and in a 'cocktail party' noise delivered through five loudspeakers in the hemi-sound field facing the patient (signal-to-noise ratio = +10 dB). The sound localization task was to determine the source of a sound stimulus among five speakers positioned between -90 and +90 from midline. Change in health status was assessed using the Glasgow Benefit Inventory and hearing disability was evaluated with the Abbreviated Profile of Hearing Aid Benefit. Speech perception was not statistically different between the two groups, even though there was a trend in favor of the BINAURAL group (mean percent word recognition in the BINAURAL and BILATERAL groups: 70 vs. 56.7% in quiet, 55.7 vs. 43.3% in noise). There was also no significant difference with regard to performance in sound localization and self-assessment of health status and hearing disability. On the basis of the BINAURAL group's performance in hearing tasks involving the detection of interaural differences, implantation with the Neurelec Digisonic registered SP Binaural implant may be considered to restore effective binaural hearing. Based on these first comparative results, this device seems to provide benefits similar to those of traditional bilateral cochlear implantation, with a new approach to stimulate both auditory nerves. Copyright [copy 2013 S. Karger AG, Basel

The adult mammalian inner ear lacks the capacity to divide or regenerate. Damage to inner ear generally leads to permanent hearing loss in humans. Here, we present that reprogramming of the adult inner ear induces renewed proliferation and regeneration of inner ear cell types. Co-activation of cell cycle activator Myc and inner ear progenitor gene Notch1 induces robust proliferation of diverse adult cochlear sensory epithelial cell types. Transient MYC and NOTCH activities enable adult supporting cells to respond to transcription factor Atoh1 and efficiently transdifferentiate into hair cell-like cells. Furthermore, we uncover that mTOR pathway participates in MYC/NOTCH-mediated proliferation and regeneration. These regenerated hair cell-like cells take up the styryl dye FM1-43 and are likely to form connections with adult spiral ganglion neurons, supporting that Myc and Notch1 co-activation is sufficient to reprogram fully mature supporting cells to proliferate and regenerate hair cell-like cells in adult mammalian auditory organs. The adult mammalian inner ear cells cannot regenerate nor proliferate. Here, the authors show that co-activation of Myc and NOTCH pathways can stimulate proliferation of inner ear sensory epithelial cells, which can be induced to become hair cell-like cells in vitro and in vivo.

Hair-cell triggers Cochlear hair cells form the sound-sensing apparatus of vertebrates and their loss or damage results in hearing impairment. Mammals cannot regenerate these cells, but previous work has shown that ectopic expression of the transcription factor Atonal homologue 1 (Atoh1) can induce cells that would not normally differentiate as cochlear hair cells to become hair cell-like. Now Gubbels et al . show that i n utero gene transfer of Atoh1 into mouse cochleas generates ectopic hair cells in the cochlea. Importantly, these supernumerary hair cells are functionally competent and display neuronal connectivity. This is a major step towards experiments to test for the ability of gene therapies to ameliorate hearing loss in mouse models of human deafness. Sensory hair cells in the mammalian cochlea convert mechanical stimuli into electrical impulses that subserve audition 1 , 2 . Loss of hair cells and their innervating neurons is the most frequent cause of hearing impairment 3 . Atonal homologue 1 (encoded by Atoh1 , also known as Math1 ) is a basic helix–loop–helix transcription factor required for hair-cell development 4 , 5 , 6 , and its misexpression in vitro 7 , 8 and in vivo 9 , 10 generates hair-cell-like cells. Atoh1 -based gene therapy to ameliorate auditory 10 and vestibular 11 dysfunction has been proposed. However, the biophysical properties of putative hair cells induced by Atoh1 misexpression have not been characterized. Here we show that in utero gene transfer of Atoh1 produces functional supernumerary hair cells in the mouse cochlea. The induced hair cells display stereociliary bundles, attract neuronal processes and express the ribbon synapse marker carboxy-terminal binding protein 2 (refs 12 , 13 ). Moreover, the hair cells are capable of mechanoelectrical transduction 1 , 2 and show basolateral conductances with age-appropriate specializations. Our results demonstrate that manipulation of cell fate by transcription factor misexpression produces functional sensory cells in the postnatal mammalian cochlea. We expect that our in utero gene transfer paradigm will enable the design and validation of gene therapies to ameliorate hearing loss in mouse models of human deafness 14 , 15 .

The human inner ear, which is segregated by a blood/labyrinth barrier, contains resident macrophages [CD163, ionized calcium-binding adaptor molecule 1 (IBA1)-, and CD68-positive cells] within the connective tissue, neurons, and supporting cells. In the lateral wall of the cochlea, these cells frequently lie close to blood vessels as perivascular macrophages. Macrophages are also shown to be recruited from blood-borne monocytes to damaged and dying hair cells induced by noise, ototoxic drugs, aging, and diphtheria toxin-induced hair cell degeneration. Precise monitoring may be crucial to avoid self-targeting. Macrophage biology has recently shown that populations of resident tissue macrophages may be fundamentally different from circulating macrophages. We removed uniquely preserved human cochleae during surgery for treating petroclival meningioma compressing the brain stem, after ethical consent. Molecular and cellular characterization using immunofluorescence with antibodies against IBA1, TUJ1, CX3CL1, and type IV collagen, and super-resolution structured illumination microscopy (SR-SIM) were made together with transmission electron microscopy. The super-resolution microscopy disclosed remarkable phenotypic variants of IBA1 cells closely associated with the spiral ganglion cells. Monitoring cells adhered to neurons with \"synapse-like\" specializations and protrusions. Active macrophages migrated occasionally nearby damaged hair cells. Results suggest that the human auditory nerve is under the surveillance and possible neurotrophic stimulation of a well-developed resident macrophage system. It may be alleviated by the non-myelinated nerve soma partly explaining why, in contrary to most mammals, the human's auditory nerve is conserved following deafferentiation. It makes cochlear implantation possible, for the advantage of the profoundly deaf. The IBA1 cells may serve additional purposes such as immune modulation, waste disposal, and nerve regeneration. Their role in future stem cell-based therapy needs further exploration.

In 2008, Hahn et al. presented a method for cultivating a 3D organ culture of the cochlea. Although this method is well established, it is currently only applied to early postnatal animals. Given the known differences in regeneration and repair abilities between early postnatal and adult mammalian cochleae, our goal was to further develop and optimize this method to extend it beyond early postnatal animals to include adult mammalian cochleae. After rapidly dissecting the cochlea, it is opened and placed in a neurotrophin-containing culture medium. The culture is then maintained at 32 °C in a rotating bioreactor for 24 h. The combination of mild hypothermia (32 °C), quick cochlea dissection, and the addition of 10 ng/mL of Brain-derived neurotrophic factor (Bdnf) and 5 ng/mL of Neurotrophin 3 (Ntf3) to the culture medium ensures the complete cell survival of all cochlear cell types in 10-day-old mice. The modifications to the established method include the incorporation of neurotrophins (Bdnf and Ntf3) into the culture medium and cultivation under mild hypothermic conditions (32 °C). By introducing neurotrophins and cultivating at 32 °C, a 3D organ culture of the cochlea can also be established with 10-day-old mice. This in vitro model preserves all cochlear cell types under conditions similar to those found in vivo.

CRISPR–Cas9 genome editing is used to correct a dominant-negative mutation in a mouse model of inherited deafness, resulting in improvements in cochlear function and hearing. Hindering heritable hearing loss Nearly half of all deafness cases arise from genetic factors, yet there are limited treatment options available for inherited hearing loss. David Liu and colleagues develop a genome-editing approach to target a dominantly inherited form of deafness. In a mouse model of human deafness, CRISPR–Cas9 editing can disrupt the mutant allele and reduce hearing loss. The results support the potential utility of protein–RNA complex delivery in post-mitotic cells as a gene-editing strategy for some autosomal-dominant diseases. Although genetic factors contribute to almost half of all cases of deafness, treatment options for genetic deafness are limited 1 , 2 , 3 , 4 , 5 . We developed a genome-editing approach to target a dominantly inherited form of genetic deafness. Here we show that cationic lipid-mediated in vivo delivery of Cas9–guide RNA complexes can ameliorate hearing loss in a mouse model of human genetic deafness. We designed and validated, both in vitro and in primary fibroblasts, genome editing agents that preferentially disrupt the dominant deafness-associated allele in the Tmc1 (transmembrane channel-like gene family 1) Beethoven ( Bth ) mouse model, even though the mutant Tmc1 Bth allele differs from the wild-type allele at only a single base pair. Injection of Cas9–guide RNA–lipid complexes targeting the Tmc1 Bth allele into the cochlea of neonatal Tmc1 Bth /+ mice substantially reduced progressive hearing loss. We observed higher hair cell survival rates and lower auditory brainstem response thresholds in injected ears than in uninjected ears or ears injected with control complexes that targeted an unrelated gene. Enhanced acoustic startle responses were observed among injected compared to uninjected Tmc1 Bth /+ mice. These findings suggest that protein–RNA complex delivery of target gene-disrupting agents in vivo is a potential strategy for the treatment of some types of autosomal-dominant hearing loss.