GJB2 c.35del variant up-regulates GJA1 gene expression and affects differentiation of human stem cells.

Pathogenic DNA alterations in GJB2 are present in nearly half of non-syndromic hearing loss cases with autosomal recessive inheritance. The most frequent variant in GJB2 causing non-syndromic hearing loss is the frameshifting c.35del. GJB2 encodes Cx26, a protein of the connexin family that assembles hemichannels and gap junctions. The expression of paralogous proteins is believed to compensate for the loss of function of specific connexins. As Cx26 has been involved in cell differentiation in distinct tissues, we employed stem cells derived from human exfoliated deciduous teeth (SHEDs), homozygous for the c.35del variant, to assess GJB2 roles in stem cell differentiation and the relationship between its loss of function and the expression of paralogous genes. Primary SHED cultures from patients and control individuals were compared. SHEDs from patients had significantly less GJB2 mRNA and increased amount of GJA1 (Cx43), but not GJB6 (Cx30) or GJB3 (Cx31) mRNA. In addition, they presented higher induced differentiation to adipocytes and osteocytes but lower chondrocyte differentiation. Our results suggest that GJA1 increased expression may be involved in functional compensation for GJB2 loss of function in human stem cells, and it may explain changes in differentiation properties observed in SHEDs with and without the c.35del variant.

NCOA3 identified as a new candidate to explain autosomal dominant progressive hearing loss.

Hearing loss is a frequent sensory impairment in humans and genetic factors account for an elevated fraction of the cases. We have investigated a large family of five generations, with 15 reported individuals presenting non-syndromic, sensorineural, bilateral and progressive hearing loss, segregating as an autosomal dominant condition. Linkage analysis, using SNP-array and selected microsatellites, identified a region of near 13 cM in chromosome 20 as the best candidate to harbour the causative mutation. After exome sequencing and filtering of variants, only one predicted deleterious variant in the NCOA3 gene (NM_181659, c.2810C > G; p.Ser937Cys) fit in with our linkage data. RT-PCR, immunostaining and in situ hybridization showed expression of ncoa3 in the inner ear of mice and zebrafish. We generated a stable homozygous zebrafish mutant line using the CRISPR/Cas9 system. ncoa3-/- did not display any major morphological abnormalities in the ear, however, anterior macular hair cells showed altered orientation. Surprisingly, chondrocytes forming the ear cartilage showed abnormal behaviour in ncoa3-/-, detaching from their location, invading the ear canal and blocking the cristae. Adult mutants displayed accumulation of denser material wrapping the otoliths of ncoa3-/- and increased bone mineral density. Altered zebrafish swimming behaviour corroborates a potential role of ncoa3 in hearing loss. In conclusion, we identified a potential candidate gene to explain hereditary hearing loss, and our functional analyses suggest subtle and abnormal skeletal behaviour as mechanisms involved in the pathogenesis of progressive sensory function impairment.

A rare genomic duplication in 2p14 underlies autosomal dominant hearing loss DFNA58.

Here we define a ~200 Kb genomic duplication in 2p14 as the genetic signature that segregates with postlingual progressive sensorineural autosomal dominant hearing loss (HL) in 20 affected individuals from the DFNA58 family, first reported in 2009. The duplication includes two entire genes, PLEK and CNRIP1, and the first exon of PPP3R1 (protein coding), in addition to four uncharacterized long non-coding (lnc) RNA genes and part of a novel protein-coding gene. Quantitative analysis of mRNA expression in blood samples revealed selective overexpression of CNRIP1 and of two lncRNA genes (LOC107985892 and LOC102724389) in all affected members tested, but not in unaffected ones. Qualitative analysis of mRNA expression identified also fusion transcripts involving parts of PPP3R1, CNRIP1 and an intergenic region between PLEK and CNRIP1, in the blood of all carriers of the duplication, but were heterogeneous in nature. By in situ hybridization and immunofluorescence, we showed that Cnrip1, Plek and Ppp3r1 genes are all expressed in the adult mouse cochlea including the spiral ganglion neurons, suggesting changes in expression levels of these genes in the hearing organ could underlie the DFNA58 form of deafness. Our study highlights the value of studying rare genomic events leading to HL, such as copy number variations. Further studies will be required to determine which of these genes, either coding proteins or non-coding RNAs, is or are responsible for DFNA58 HL.

Molecular and genetic characterization of a large Brazilian cohort presenting hearing loss.

Hearing loss is one of the most common sensory defects, affecting 5.5% of the worldwide population and significantly impacting health and social life. It is mainly attributed to genetic causes, but their relative contribution reflects the geographical region's socio-economic development. Extreme genetic heterogeneity with hundreds of deafness genes involved poses challenges for molecular diagnosis. Here we report the investigation of 542 hearing-impaired subjects from all Brazilian regions to search for genetic causes. Biallelic GJB2/GJB6 causative variants were identified in 12.9% (the lowest frequency was found in the Northern region, 7.7%), 0.4% carried GJB2 dominant variants, and 0.6% had the m.1555A > G variant (one aminoglycoside-related). In addition, other genetic screenings, employed in selected probands according to clinical presentation and presumptive inheritance patterns, identified causative variants in 2.4%. Ear malformations and auditory neuropathy were diagnosed in 10.8% and 3.5% of probands, respectively. In 3.8% of prelingual/perilingual cases, Waardenburg syndrome was clinically diagnosed, and in 71.4%, these diagnoses were confirmed with pathogenic variants revealed; seven out of them were novel, including one CNV. All these genetic screening strategies revealed causative variants in 16.2% of the cases. Based on causative variants in the molecular diagnosis and genealogy analyses, a probable genetic etiology was found in ~ 50% of the cases. The present study highlights the relevance of GJB2/GJB6 as a cause of hearing loss in all Brazilian regions and the importance of screening unselected samples for estimating frequencies. Moreover, when a comprehensive screening is not available, molecular diagnosis can be enhanced by selecting probands for specific screenings.

Exome Sequencing Identifies a Novel Nonsense Mutation of MYO6 as the Cause of Deafness in a Brazilian Family.

We investigated 313 unrelated subjects who presented with hearing loss to identify the novel genetic causes of this condition in Brazil. Causative GJB2/GJB6 mutations were found in 12.7% of the patients. Among the familial cases (100/313), four were selected for exome sequencing. In one case, two novel heterozygous variants were found and were predicted to be pathogenic based on bioinformatics tools, that is, p.Ser906* (MYO6) and p.Arg42Cys (GJB3). We confirmed that this nonsense MYO6 mutation segregated with deafness in this family. Only the proband and her unaffected mother exhibited the GJB3 mutation, which is in the same amino acid of a known Erythrokeratodermia variabilis mutation. None of the patients exhibited this skin disease, but the proband exhibited a more severe hearing loss. Hence, the GJB3 mutation was considered to be a variant of uncertain significance. In conclusion, we described a novel nonsense MYO6 mutation that was responsible for the hearing loss in a Brazilian family. This mutation resides in the neck domain of myosin-VI after the motor domain. Thus, our data give further support for genotype-phenotype correlations, which state that when the motor domain of the protein is functioning, the hearing loss is milder and has a later onset. The three remaining families without mutations in the known genes suggest that there are still deafness genes to be revealed.

A Cell Junctional Protein Network Associated with Connexin-26.

GJB2 mutations are the leading cause of non-syndromic inherited hearing loss. GJB2 encodes connexin-26 (CX26), which is a connexin (CX) family protein expressed in cochlea, skin, liver, and brain, displaying short cytoplasmic N-termini and C-termini. We searched for CX26 C-terminus binding partners by affinity capture and identified 12 unique proteins associated with cell junctions or cytoskeleton (CGN, DAAM1, FLNB, GAPDH, HOMER2, MAP7, MAPRE2 (EB2), JUP, PTK2B, RAI14, TJP1, and VCL) by using mass spectrometry. We show that, similar to other CX family members, CX26 co-fractionates with TJP1, VCL, and EB2 (EB1 paralogue) as well as the membrane-associated protein ASS1. The adaptor protein CGN (cingulin) co-immuno-precipitates with CX26, ASS1, and TJP1. In addition, CGN co-immunoprecipitation with CX30, CX31, and CX43 indicates that CX association is independent on the CX C-terminus length or sequence. CX26, CGN, FLNB, and DAMM1 were shown to distribute to the organ of Corti and hepatocyte plasma membrane. In the mouse liver, CX26 and TJP1 co-localized at the plasma membrane. In conclusion, CX26 associates with components of other membrane junctions that integrate with the cytoskeleton.

Novel partial duplication of EYA1 causes branchiootic syndrome in a large Brazilian family.

OBJECTIVE: To identify novel genetic causes of syndromic hearing loss in Brazil. DESIGN: To map a candidate chromosomal region through linkage studies in an extensive Brazilian family and identify novel pathogenic variants using sequencing and array-CGH. STUDY SAMPLE: Brazilian pedigree with individuals affected by BO syndrome characterized by deafness and malformations of outer, middle and inner ear, auricular and cervical fistulae, but no renal abnormalities. RESULTS: Whole genome microarray-SNP scanning on samples of 11 affected individuals detected a multipoint Lod score of 2.6 in the EYA1 gene region (chromosome 8). Sequencing of EYA1 in affected patients did not reveal pathogenic mutations. However, oligonucleotide-array-CGH detected a duplication of 71.8Kb involving exons 4 to 10 of EYA1 (heterozygous state). Real-time-PCR confirmed the duplication in fourteen of fifteen affected individuals and absence in 13 unaffected individuals. The exception involved a consanguineous parentage and was assumed to involve a different genetic mechanism. CONCLUSIONS: Our findings implicate this EYA1 partial duplication segregating with BO phenotype in a Brazilian pedigree and is the first description of a large duplication leading to the BOR/BO syndrome.

White noise effect on listening effort among patients with chronic tinnitus and normal hearing thresholds.

OBJECTIVE: This study investigated the effects of WN on LE in subjects with chronic tinnitus and normal hearing thresholds. The study was a prospective, non-randomized, before-and-after, intra-participant intervention. METHODS: Twenty-five subjects performed the following tests: conventional and high-frequency audiometry, acuphenometry, screening questionnaires for depression and anxiety symptoms, Tinnitus Handicap Inventory (THI), Montreal Cognitive Assessment, and high WM test from the Working Memory Assessment Battery, Federal University of Minas Gerais (WMAB) as the LE measure in two conditions: No Added Noise (NAN) and with Added Noise (AN). RESULTS: Seventeen participants (68%) performed better on AN condition. Data analysis revealed a 45% improvement in the WMAB total span count on AN setting, with a significant p value (p=0.001). CONCLUSION: The subgroup of participants without traces of anxiety symptoms, up to mild traces of depressive symptoms, having unilateral tinnitus, and a THI level up to grade 2, had improved WM performance in the presence of WN, which suggests a release of cognitive resources and less auditory effort under these combined conditions. EVIDENCE LEVEL: 4.

Generation of four induced pluripotent stem cells lines from PBMC of the DFNA58 family members: Two hearing-impaired duplication carriers (USPi006-A e USPi007-A) and two normal-hearing noncarriers (USPi004-A and USPi005-A).

The DFNA58 locus contains a genomic duplication involving three protein-coding genes (CNRIP1, PLEK, and PPP3R1's exon 1) and other uncharacterized lncRNA genes (LOC101927723, LOC107985892 and LOC102724389). To clarify the role of these genes in hearing and precisely determine their role in hearing loss, four iPSC lines were generated from two carriers and two noncarriers of the duplication.

Translation and validation of the Tinnitus Primary Function Questionnaire into Brazilian Portuguese.

OBJECTIVE: In this study, the Tinnitus Primary Function Questionnaire was translated, culturally adapted and validated for Brazilian Portuguese. METHODS: This study was carried out in two stages. First, a prospective study of translation and cultural adaptation was carried out with a group of 20 patients. The questionnaire was translated, revised and back-translated from Portuguese into English. Subsequently, a retrospective study was carried out with 1,095 patients, 18 months after the first stage. The validation and reliability of the Tinnitus Primary Function Questionnaire was verified by comparing its results with the results of the Tinnitus Handicap Inventory. RESULTS: The interclass correlation coefficient of the behavioral aspects ranged from 0.82 to 0.90 and the total score was 0.93, while Cronbach's alpha was >0.94 for the total score during the test-retest application. To validate the questionnaire, a database was used, which consisted of 1,095 patients submitted to tinnitus assessment using the Tinnitus Primary Function Questionnaire and Tinnitus Handicap Inventory simultaneously. Patients were enrolled from 14 Brazilian states (46% female), with a mean age of 58 years. The reliability of the Tinnitus Primary Function Questionnaire was tested during validation for the four different evaluated behavioral aspects, and the results were significantly high for all aspects and the total score. To validate the Tinnitus Primary Function Questionnaire, the results of the total Tinnitus Primary Function Questionnaire and Tinnitus Handicap Inventory scores were compared using Pearson's product-moment correlation test. The results indicate a high correlation between the two questionnaires (r=0.84; p<0.001; 95% CI 0.82-0.85). CONCLUSION: The data from the Tinnitus Primary Function Questionnaire showed a high correlation with those of the Tinnitus Handicap Inventory. This indicates that the Portuguese version of the Tinnitus Primary Function Questionnaire can be adopted as a valuable tool in the clinical evaluation of patients with tinnitus. LEVEL OF EVIDENCE: 2C.

Effectiveness of Dry Needling in Bothersome Chronic Tinnitus in Patients with Myofascial Trigger Points.

Introduction Therapeutic dry needling (DN) is effective in reducing the discomfort of chronic somatosensory tinnitus in patients with myofascial trigger points (MTP)s. Objective To evaluate the efficacy of DN in chronic somatosensory tinnitus discomfort in patients with MTP. Methods Placebo-controlled paired trial that included 16 patients with a diagnosis of somatosensory chronic tinnitus and with the presence of at least one active or latent MTP. Treatment was performed in two phases: (1) four sessions (one session per week for four consecutive weeks) of placebo DN and (2) four sessions of therapeutic DN with a gap (washout) of 15 days between these phases. Results The Tinnitus Handicap Inventory (THI) variable and its emotional domain had a statistically significant reduction in therapeutic DN when compared with placebo DN ( p = 0.024 and p = 0.011, respectively). The tinnitus visual analogic scale (VAS) signaled a reduction in tinnitus discomfort when compared with moments before and after therapeutic DN ( p < 0.05). Conclusion The therapeutic DN technique for MTP in patients with chronic tinnitus of somatosensory origin proved effective in reducing symptom discomfort, as measured by the THI (total score) and its emotional domain when compared with placebo DN.

Translation, Cultural Adaptation and Validation to Brazilian Portuguese of the Tinnitus Functional Index Questionnaire.

Introduction Tinnitus affects a large portion of the world's population. There are several questionnaires being used for the evaluation of the severity of tinnitus and its impact in quality of life; however, they do not measure treatment-related changes. So, a new self-reported questionnaire was developed, the Tinnitus Functional Index (TFI), which has been translated into several languages. Objective To perform the translation, cultural adaptation and validation of the TFI questionnaire for Brazilian Portuguese. Method This is a multicenter project divided into two stages: translation and cultural adaptation; and validation and reliability. For the validation, the Brazilian Portuguese version of the TFI was correlated with the Tinnitus Handicap Inventory (THI) domains for tinnitus and quality of life and was evaluated by the Spearman ρ test. The reliability and internal consistency were evaluated by the Cronbach α test. Result The Brazilian version of the TFI was obtained through an initial translation process, synthesis of translations, backtranslation and evaluation by a committee of experts. This version was then applied in 88 patients complaining of tinnitus from speech therapy and otorhinolaryngology outpatient clinics of the three school clinics. The Brazilian version presented high reliability, as evidenced by the Cronbach α value (α = 0.870), and strong correlation (rho = 0.760 and p = 0.000). Conclusion The high reliability found in the results demonstrates that the Brazilian Portuguese version of the TFI is a valid and reliable instrument to evaluate the severity and impact of tinnitus on quality of life and changes related to its treatment.

Hearing aid effectiveness on patients with chronic tinnitus and associated hearing loss.

OBJECTIVE: Our study aimed to measure the effectiveness of using HA in reducing the disturbance caused by tinnitus. METHODS: Study was designed as a within-subjects clinical trial. Nineteen patients with chronic tinnitus and untreated sensorineural hearing loss were under counseling, HA fitting and 6 months follow-up. Tinnitus assessment was performed with Tinnitus Handicap Inventory (THI), Visual Analog Scale (VAS), pitch and loudness matching, and Minimum Masking Level measurements (MML). RESULTS: following 6 months of HA use, a reduction in reported tinnitus and hearing handicap scales scores was observed both statistically and clinically. The pitch and loudness matching, as well as MML at the baseline and final evaluation were compared. MML's thresholds reduced significantly after 6 months of HA use. CONCLUSION: Our study has provided evidence that HA fitting is a valuable treatment strategy for chronic tinnitus relief and associated hearing loss subtype of patient.

Evaluating the efficacy of hearing aids for tinnitus therapy - A Positron emission tomography study.

Brain imaging studies have revealed neural changes in chronic tinnitus patients that are not restricted to auditory brain areas; rather, the engagement of limbic system structures, attention and memory networks are has been noted. Hearing aids (HA) provide compensation for comorbid hearing loss and may decrease tinnitus-related perception and annoyance. Using resting state positron emission tomography our goal was to analyze metabolic and functional brain changes after six months of effective HA use by patients with chronic tinnitus and associated sensorineural hearing loss. 33 age and hearing loss matched participants with mild/moderate hearing loss were enrolled in this study: 19 with tinnitus, and 14 without tinnitus. Participants with tinnitus of more than 6 months with moderate/severe Tinnitus Handicap Inventory (THI) and Visual Analogue Scale (VAS) scores composed the tinnitus group. A full factorial 2X2 ANOVA was conducted for imaging analysis, with group (tinnitus and controls) and time point (pre-intervention and post-intervention) as factors. Six months after HA fitting, tinnitus scores reduced statistically and clinically. Analysis revealed increased glycolytic metabolism in the left orbitofrontal cortex, right temporal lobe and right hippocampus, and reduced glycolytic metabolism in the left cerebellum and inferior parietal lobe within the tinnitus group. The hearing loss control group showed no significant metabolic changes in the analysis. Parsing out the contribution of tinnitus independent of hearing loss, allowed us to identify areas implicated in declines in tinnitus handicap as a result of the intervention. Brain regions implicated in the present study may be part of chronic tinnitus-specific network.

Retention of progenitor cell phenotype in otospheres from guinea pig and mouse cochlea.

BACKGROUND: Culturing otospheres from dissociated organ of Corti is an appropriate starting point aiming at the development of cell therapy for hair cell loss. Although guinea pigs have been widely used as an excellent experimental model for studying the biology of the inner ear, the mouse cochlea has been more suitable for yielding otospheres in vitro. The aim of this study was to compare conditions and outcomes of otosphere suspension cultures from dissociated organ of Corti of either mouse or guinea pig at postnatal day three (P3), and to evaluate the guinea pig as a potential cochlea donor for preclinical cell therapy. METHODS: Organs of Corti were surgically isolated from P3 guinea pig or mouse cochlea, dissociated and cultivated under non-adherent conditions. Cultures were maintained in serum-free DMEM:F12 medium, supplemented with epidermal growth factor (EGF) plus either basic fibroblast growth factor (bFGF) or transforming growth factor alpha (TGFα). Immunofluorescence assays were conducted for phenotype characterization. RESULTS: The TGFα group presented a number of spheres significantly higher than the bFGF group. Although mouse cultures yielded more cells per sphere than guinea pig cultures, sox2 and nestin distributed similarly in otosphere cells from both organisms. We present evidence that otospheres retain properties of inner ear progenitor cells such as self-renewal, proliferation, and differentiation into hair cells or supporting cells. CONCLUSIONS: Dissociated guinea pig cochlea produced otospheres in vitro, expressing sox2 and nestin similarly to mouse otospheres. Our data is supporting evidence for the presence of inner ear progenitor cells in the postnatal guinea pig. However, there is limited viability for these cells in neonatal guinea pig cochlea when compared to the differentiation potential observed for the mouse organ of Corti at the same developmental stage.

Neurotology: definitions and evidence-based therapies - Results of the I Brazilian Forum of Neurotology.

INTRODUCTION: Neurotology is a rapidly expanding field of knowledge. The study of the vestibular system has advanced so much that even basic definitions, such as the meaning of vestibular symptoms, have only recently been standardized. OBJECTIVE: To present a review of the main subjects of neurotology, including concepts, diagnosis and treatment of Neurotology, defining current scientific evidence to facilitate decision-making and to point out the most evidence-lacking areas to stimulate further new research. METHODS: This text is the result of the I Brazilian Forum of Neurotology, which brought together the foremost Brazilian researchers in this area for a literature review. In all, there will be three review papers to be published. This first review will address definitions and therapies, the second one will address diagnostic tools, and the third will define the main diseases diagnoses. Each author performed a bibliographic search in the LILACS, SciELO, PubMed and MEDLINE databases on a given subject. The text was then submitted to the other Forum participants for a period of 30 days for analysis. A special chapter, on the definition of vestibular symptoms, was translated by an official translation service, and equally submitted to the other stages of the process. There was then a in-person meeting in which all the texts were orally presented, and there was a discussion among the participants to define a consensual text for each chapter. The consensual texts were then submitted to a final review by four professors of neurotology disciplines from three Brazilian universities and finally concluded. Based on the full text, available on the website of the Brazilian Association of Otorhinolaryngology and Cervical-Facial Surgery, this summary version was written as a review article. RESULT: The text presents the official translation into Portuguese of the definition of vestibular symptoms proposed by the Bárány Society and brings together the main scientific evidence for each of the main existing therapies for neurotological diseases. CONCLUSION: This text rationally grouped the main topics of knowledge regarding the definitions and therapies of Neurotology, allowing the reader a broad view of the approach of neurotological patients based on scientific evidence and national experience, which should assist them in clinical decision-making, and show the most evidence-lacking topics to stimulate further study.

Sudden hearing loss: a ten-year outpatient experience.

The aim of this study was to determine the effects of various treatment modalities employed for patients with sudden sensorineural hearing loss (SHL). We retrospectively evaluated the records of patients treated in the sudden hearing loss section of the Otolaryngology Department at Clinic Hospital, School of Medicine, University of São Paulo, Brazil, between 1996 and 2006. Our study included patients with SHL of sudden onset (occurring over a 72-hour period) at equal to or greater than 30 dB at three consecutive frequencies. We divided patients into five groups by profile and treated them with dextran, dexamethasone, acyclovir, nicotinic acid, and papaverine hydrochloride (with or without vitamin A). We performed audiometry at baseline and on days 30, 90, 120, and 180 of treatment. We determined outcome as the difference between day-0 and day-180 pure-tone averages (PTAs). Among the 139 patients evaluated, baseline PTA was similar in all groups. We observed significant improvements in PTAs after 180 days of treatment and noted a significant linear correlation between time from SHL onset to initial visit and recovery. However, no significant difference was evident among the treatment groups. In the treatment of SHL, dextran provided no more benefit than did dexamethasone or acyclovir. Earlier initiation of treatment improves the prognosis for patients with SHL.

White noise effect on listening effort among patients with chronic tinnitus and normal hearing thresholds

Abstract Objective This study investigated the effects of WN on LE in subjects with chronic tinnitus and normal hearing thresholds. The study was a prospective, non-randomized, before-and-after, intra-participant intervention. Methods Twenty-five subjects performed the following tests: conventional and high-frequency audiometry, acuphenometry, screening questionnaires for depression and anxiety symptoms, Tinnitus Handicap Inventory (THI), Montreal Cognitive Assessment, and high WM test from the Working Memory Assessment Battery, Federal University of Minas Gerais (WMAB) as the LE measure in two conditions: No Added Noise (NAN) and with Added Noise (AN). Results Seventeen participants (68%) performed better on AN condition. Data analysis revealed a 45% improvement in the WMAB total span count on AN setting, with a significant p value (p = 0.001). Conclusion The subgroup of participants without traces of anxiety symptoms, up to mild traces of depressive symptoms, having unilateral tinnitus, and a THI level up to grade 2, had improved WM performance in the presence of WN, which suggests a release of cognitive resources and less auditory effort under these combined conditions. Evidence level 4.

Stem-cell therapy for hearing loss: are we there yet?

INTRODUCTION: Mammalian hair cells and auditory neurons do not show regenerative capacity. Hence, damage to these cell types is permanent and leads to hearing loss. However, there is no treatment that re-establishes auditory function. Regenerative therapies using stem cells represent a promising alternative. OBJECTIVE: This article aims to review the current literature about the main types of stem cells with potential for application in cell therapy for sensorineural hearing loss, the most relevant experiments already performed in animals, as well as the advances that have been recently made in the field. METHODS: Research included the databases PubMed/MEDLINE, Web of Science, Science Direct and SciELO, as well as gray literature. Search strategy included the following main terms: "stem cells", "hair cells" and "auditory neurons". Additionally, the main terms were combined with the following secondary terms: "mesenchymal", "iPS", "inner ear", "auditory". The research was conducted independently by three researchers. RESULTS: Differentiation of stem cells into hair cells and auditory neurons has a high success rate, reaching up to 82% for the first and 100% for the latter. Remarkably, these differentiated cells are able to interact with hair cells and auditory neurons of cochlear explants through formation of new synapses. When transplanted into the cochlea of animals with hearing loss, auditory restoration has been documented to date only in deafferented animals. CONCLUSION: Advances have been more prominent in cases of auditory neuropathy, since partial improvement of auditory nerve conditions through cell-based therapy may increase the number of patients who can successfully receive cochlear implants.