RESUMO
KCNQ4 is a voltage-gated K+ channel was reported to distribute over the basolateral surface of type 1 vestibular hair cell and/or inner surface of calyx and heminode of the vestibular nerve connected to the type 1 vestibular hair cells of the inner ear. However, the precise localization of KCNQ4 is still controversial and little is known about the vestibular phenotypes caused by KCNQ4 dysfunction or the specific role of KCNQ4 in the vestibular organs. To investigate the role of KCNQ4 in the vestibular organ, 6-g hypergravity stimulation for 24 h, which represents excessive mechanical stimulation of the sensory epithelium, was applied to p.W277S Kcnq4 transgenic mice. KCNQ4 was detected on the inner surface of calyx of the vestibular afferent in transmission electron microscope images with immunogold labelling. Vestibular function decrease was more severe in the Kcnq4p.W277S/p.W277S mice than in the Kcnq4+/+ and Kcnq4+/p.W277S mice after the stimulation. The vestibular function loss was resulted from the loss of type 1 vestibular hair cells, which was possibly caused by increased depolarization duration. Retigabine, a KCNQ activator, prevented hypergravity-induced vestibular dysfunction and hair cell loss. Patients with KCNQ4 mutations also showed abnormal clinical vestibular function tests. These findings suggest that KCNQ4 plays an essential role in calyx and afferent of type 1 vestibular hair cell preserving vestibular function against excessive mechanical stimulation.
Assuntos
Células Ciliadas Vestibulares , Canais de Potássio KCNQ , Camundongos Transgênicos , Animais , Canais de Potássio KCNQ/metabolismo , Canais de Potássio KCNQ/genética , Células Ciliadas Vestibulares/metabolismo , Células Ciliadas Vestibulares/patologia , Camundongos , Fenilenodiaminas/farmacologia , Carbamatos/farmacologia , Vestíbulo do Labirinto/metabolismo , Vestíbulo do Labirinto/patologia , Vestíbulo do Labirinto/fisiopatologiaRESUMO
Hair cell (HC) loss by epithelial extrusion has been described to occur in the rodent vestibular system during chronic 3,3'-iminodipropionitrile (IDPN) ototoxicity. This is preceded by dismantlement of the calyceal junction in the contact between type I HC (HCI) and calyx afferent terminals. Here, we evaluated whether these phenomena have wider significance. First, we studied rats receiving seven different doses of streptomycin, ranging from 100 to 800 mg/kg/day, for 3-8 weeks. Streptomycin caused loss of vestibular function associated with partial loss of HCI and decreased expression of contactin-associated protein (CASPR1), denoting calyceal junction dismantlement, in the calyces encasing the surviving HCI. Additional molecular and ultrastructural data supported the conclusion that HC-calyx detachment precede HCI loss by extrusion. Animals allowed to survive after the treatment showed functional recuperation and rebuilding of the calyceal junction. Second, we evaluated human sensory epithelia obtained during therapeutic labyrinthectomies and trans-labyrinthine tumour excisions. Some samples showed abnormal CASPR1 label strongly suggestive of calyceal junction dismantlement. Therefore, reversible dismantlement of the vestibular calyceal junction may be a common response triggered by chronic stress, including ototoxic stress, before HCI loss. This may partly explain clinical observations of reversion in function loss after aminoglycoside exposure.
Assuntos
Células Ciliadas Vestibulares , Vestíbulo do Labirinto , Humanos , Ratos , Animais , Estreptomicina/toxicidade , Vestíbulo do Labirinto/patologia , Epitélio/patologia , Células Ciliadas Vestibulares/patologia , Células Ciliadas Auditivas/patologiaRESUMO
Spag6 encodes an axoneme central apparatus protein that is required for normal flagellar and cilia motility. Recent findings suggest that Spag6 plays a role in hearing and planar cell polarity (PCP) in the cochlea of the inner ear. However, a role for Spag6 in the vestibule has not yet been explored. In the present study, the function of Spag6 in the vestibule of the inner ear was examined using Spag6-deficient mice. Our results demonstrate a vestibular disorder in the Spag6 mutants, associated with abnormal ultrastructures of vestibular hair cells and Scarpa's ganglion cells, including swollen stereocilia, decreased crista in mitochondria and swollen Scarpa's ganglion cells. Immunostaining data suggests existence of caspase-dependent apoptosis in vestibular sensory epithelium and Scarpa's ganglion cells. Our observations reveal new functions for Spag6 in vestibular function and apoptosis in the mouse vestibule.
Assuntos
Apoptose/genética , Proteínas dos Microtúbulos/genética , Mutação , Doenças Vestibulares/genética , Animais , Polaridade Celular/genética , Cóclea/citologia , Cóclea/fisiologia , Feminino , Células Ciliadas Vestibulares/patologia , Audição/genética , Masculino , Camundongos Transgênicos , Doenças Vestibulares/patologia , Nervo Vestibular/citologia , Nervo Vestibular/patologiaRESUMO
Vestibular hair cells are mechanosensory receptors that are capable of detecting changes in head position and thereby allow animals to maintain their posture and coordinate their movement. Vestibular hair cells are susceptible to ototoxic drugs, aging, and genetic factors that can lead to permanent vestibular dysfunction. Vestibular dysfunction mainly results from the injury of hair cells, which are located in the vestibular sensory epithelium. This review summarizes the mechanisms of different factors causing vestibular hair cell damage and therapeutic strategies to protect vestibular hair cells.
Assuntos
Células Ciliadas Vestibulares/fisiologia , Doenças Vestibulares/prevenção & controle , Envelhecimento/fisiologia , Animais , Epitélio/fisiologia , Células Ciliadas Vestibulares/patologia , Humanos , Ototoxicidade/prevenção & controle , Doenças Vestibulares/etiologiaRESUMO
BACKGROUND: Vestibulo-ocular reflex (VOR) function is expected to be normal in patients with presbycusis during sudden head rotations. AIM: This study aimed to determine whether presbycusis was accompanied by vestibular system pathologies. In addition, it was examined whether there was a difference existed between the patients with and without presbycusis in terms of normative data. MATERIALS AND METHODS: A total of 40 individuals were included in the study: 20 in the presbycusis group and 20 in the control group. The vestibular systems of both groups were evaluated using the video head impulse test and videonystagmography. RESULTS: The right and left lateral VOR gain values were decreased in the group with presbycusis compared to the control group. The difference between the two groups in the mean VOR gains in the right lateral canal and left lateral canal were statistically significant (p = .040 and p = .050, respectively). The air caloric tests of all individuals were found to be normal. CONCLUSIONS: This result suggests that the loss of vestibular hair cells and vestibular nerve degeneration in the lateral semicircular canal may be more severe in presbycusis than in the same age group with normal hearing.
Assuntos
Células Ciliadas Vestibulares/patologia , Presbiacusia/fisiopatologia , Reflexo Vestíbulo-Ocular , Canais Semicirculares/fisiologia , Doenças Vestibulares/complicações , Nervo Vestibular/fisiologia , Idoso , Estudos de Casos e Controles , Feminino , Teste do Impulso da Cabeça , Humanos , Masculino , Pessoa de Meia-Idade , Nistagmo Patológico/complicações , Presbiacusia/complicações , Presbiacusia/patologia , Testes de Função Vestibular , Nervo Vestibular/fisiopatologia , Vestíbulo do LabirintoRESUMO
Loss of hair cells from vestibular epithelium results in balance dysfunction. The current therapeutic regimen for vestibular diseases is limited. Upon injury or Atoh1 overexpression, hair cell replacement occurs rapidly in the mammalian utricle, suggesting a promising approach to induce vestibular hair cell regeneration. In this study, we applied simultaneous gentamicin-mediated hair cell ablation and Atoh1 overexpression to induce neonatal utricular hair cell formation in vitro. We confirmed that type I hair cells were the primary targets of gentamicin. Furthermore, injury and Atoh1 overexpression promoted hair cell regeneration in a timely and efficient manner through robust viral transfection. Hair cells regenerated with type II characteristics in the striola and type I/II characteristics in non-sensory regions. Rare EdU+/myosin7a+ cells in sensory regions and robust EdU+/myosin7a+ signals in ectopic regions indicate that transdifferentiation of supporting cells in situ, and mitosis and differentiation of non-sensory epithelial cells in ectopic regions, are sources of regenerative hair cells. Distinct regeneration patterns in in situ and ectopic regions suggested robust plasticity of vestibular non-sensory epithelium, generating more developed hair cell subtypes and thus providing a promising stem cell-like source of hair cells. These findings suggest that simultaneously causing injury and overexpressing Atoh1 promotes hair cell regeneration efficacy and maturity, thus expanding the understanding of ectopic plasticity in neonatal vestibular organs.
Assuntos
Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Gentamicinas/farmacologia , Células Ciliadas Vestibulares/efeitos dos fármacos , Sáculo e Utrículo/efeitos dos fármacos , Animais , Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Células Ciliadas Vestibulares/metabolismo , Células Ciliadas Vestibulares/patologia , Camundongos , Camundongos Endogâmicos C57BL , Sáculo e Utrículo/metabolismo , Sáculo e Utrículo/patologiaRESUMO
BACKGROUND: Cervical vestibular evoked myogenic potential (cVEMP) testing is a strong tool that enables objective determination of balance functions in humans. However, it remains unknown whether cVEMP correctly expresses vestibular disorder in mice. OBJECTIVE: In this study, correlations of cVEMP with scores for balance-related behavior tests including rotarod, beam, and air-righting reflex tests were determined in ICR mice with vestibular disorder induced by 3,3'-iminodipropiontrile (IDPN) as a mouse model of vestibular disorder. METHODS: Male ICR mice at 4 weeks of age were orally administered IDPN in saline (28 mmol/kg body weight) once. Rotarod, beam crossing, and air-righting reflex tests were performed before and 3-4 days after oral exposure one time to IDPN to determine balance functions. The saccule and utricles were labeled with fluorescein phalloidin. cVEMP measurements were performed for mice in the control and IDPN groups. Finally, the correlations between the scores of behavior tests and the amplitude or latency of cVEMP were determined with Spearman's rank correlation coefficient. Two-tailed Student's t test and Welch's t test were used to determine a significant difference between the two groups. A difference with p < 0.05 was considered to indicate statistical significance. RESULTS: After oral administration of IDPN at 28 mmol/kg, scores of the rotarod, beam, and air-righting reflex tests in the IDPN group were significantly lower than those in the control group. The numbers of hair cells in the saccule, utricle, and cupula were decreased in the IDPN group. cVEMP in the IDPN group was significantly decreased in amplitude and increased in latency compared to those in the control group. cVEMP amplitude had significant correlations with the numbers of hair cells as well as scores for all of the behavior tests in mice. CONCLUSIONS: This study demonstrated impaired cVEMP and correlations of cVEMP with imbalance determined by behavior tests in a mouse model of vestibular disorder.
Assuntos
Equilíbrio Postural/fisiologia , Transtornos de Sensação/fisiopatologia , Doenças Vestibulares/fisiopatologia , Potenciais Evocados Miogênicos Vestibulares/fisiologia , Animais , Comportamento Animal/efeitos dos fármacos , Comportamento Animal/fisiologia , Modelos Animais de Doenças , Células Ciliadas Vestibulares/patologia , Masculino , Camundongos , Camundongos Endogâmicos ICR , Nitrilas/efeitos adversos , Equilíbrio Postural/efeitos dos fármacos , Sáculo e Utrículo/patologia , Transtornos de Sensação/induzido quimicamente , Doenças Vestibulares/induzido quimicamente , Doenças Vestibulares/diagnóstico , Doenças Vestibulares/patologia , Potenciais Evocados Miogênicos Vestibulares/efeitos dos fármacos , Testes de Função VestibularRESUMO
Brg1 is an ATPase subunit of the SWI/SNF chromatin-remodeling complex, and it is indispensable for the development and homeostasis of various organs. Conditional deletion of Brg1 in cochlea hair cells (HCs) leads to multiple structural defects and profound deafness. However, the premature death of Brg1-deficient cochlea HCs hindered further study of the role of Brg1. In contrast to cochlea HCs, Brg1-deficient vestibular HCs survived for a long time. Therefore, HC apical structure and vestibular function were examined in inner HC-specific conditional Brg1 knockout mice. Vestibular HCs exhibited fused and elongated stereocilia bundles after deletion of Brg1, and the cuticular plate was absent in most HCs with fused stereocilia bundles. HC loss was observed in conditional Brg1 knockout mice at the age of 12 months. Morphological defects and HC loss were primarily restricted in the striolar region of the utricle and saccule and in the central region of ampulla. The behavioral tests revealed that Brg1 deletion in HCs caused vestibular dysfunction in older adult mice. These results suggest that Brg1 may play specific roles in the maintenance of the HC stereocilia bundle and the cuticular plate.
Assuntos
Deleção de Genes , Células Ciliadas Vestibulares/enzimologia , Proteínas de Neoplasias/deficiência , Sáculo e Utrículo/metabolismo , Estereocílios/enzimologia , Animais , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Comportamento Animal , Genótipo , Células Ciliadas Vestibulares/patologia , Camundongos Knockout , Proteínas de Neoplasias/genética , Fenótipo , Sáculo e Utrículo/anormalidades , Sáculo e Utrículo/fisiopatologia , Estereocílios/patologiaRESUMO
BACKGROUND: Waardenburg syndrome (WS) is the consequence of an inherited autosomal dominant mutation which causes the early degeneration of intermediate cells of cochlear stria vascularis (SV) and profound hearing loss. Patients with WS may also experience primary vestibular symptoms. Most of the current WS studies did not discuss the relationship between WS and abnormal vestibular function. Our study found that a spontaneous mutant pig showed profound hearing loss and depigmentation. MITF-M, a common gene mutation causes type WS which affect the development of the intermediate cell of SV, was then identified for animal modeling. RESULTS: In this study, the degeneration of vestibular hair cells was found in pigs with MITF-M. The morphology of hair cells in vestibular organs of pigs was examined using electron microscopy from embryonic day E70 to postnatal two weeks. Significant hair cell loss in the mutant saccule was found in this study through E95 to P14. Conversely, there was no hair cell loss in either utricle or semi-circular canals. CONCLUSIONS: Our study suggested that MITF-M gene mutation only affects hair cells of the saccule, but has no effect on other vestibular organs. The study also indicated that the survival of cochlear and saccular hair cells was dependent on the potassium release from the cochlear SV, but hair cells of the utricle and semi-circular canals were independent on SV.
Assuntos
Doenças Cocleares/genética , Células Ciliadas Vestibulares/patologia , Perda Auditiva/genética , Fator de Transcrição Associado à Microftalmia/genética , Transtornos da Pigmentação/genética , Sáculo e Utrículo/patologia , Síndrome de Waardenburg/genética , Animais , Doenças Cocleares/patologia , Doenças Cocleares/fisiopatologia , Modelos Animais de Doenças , Perda Auditiva/fisiopatologia , Sáculo e Utrículo/diagnóstico por imagem , Suínos , Potenciais Evocados Miogênicos Vestibulares/fisiologia , Síndrome de Waardenburg/patologia , Síndrome de Waardenburg/fisiopatologiaRESUMO
The cellular and molecular events that precede hair cell (HC) loss in the vestibular epithelium during chronic ototoxic exposure have not been widely studied. To select a study model, we compared the effects of sub-chronic exposure to different concentrations of 3,3'-iminodipropionitrile (IDPN) in the drinking water of two strains of mice and of both sexes. In subsequent experiments, male 129S1/SvImJ mice were exposed to 30 mM IDPN for 5 or 8 weeks; animals were euthanized at the end of the exposure or after a washout period of 13 weeks. In behavioral tests, IDPN mice showed progressive vestibular dysfunction followed by recovery during washout. In severely affected animals, light and electron microscopy observations of the vestibular epithelia revealed HC extrusion towards the endolymphatic cavity. Comparison of functional and ultrastructural data indicated that animals with fully reversible dysfunction did not have significant HC loss or stereociliary damage, but reversible dismantlement of the calyceal junctions that characterize the contact between type I HCs (HCI) and their calyx afferents. Immunofluorescent analysis revealed the loss of calyx junction proteins, Caspr1 and Tenascin-C, during exposure and their recovery during washout. Synaptic uncoupling was also recorded, with loss of pre-synaptic Ribeye and post-synaptic GluA2 puncta, and differential reversibility among the three different kinds of synaptic contacts existing in the epithelium. qRT-PCR analyses demonstrated that some of these changes are at least in part explained by gene expression modifications. We concluded that calyx junction dismantlement and synaptic uncoupling are early events in the mouse vestibular sensory epithelium during sub-chronic IDPN ototoxicity.
Assuntos
Células Ciliadas Auditivas/efeitos dos fármacos , Células Ciliadas Vestibulares/efeitos dos fármacos , Nitrilas/toxicidade , Ototoxicidade/patologia , Animais , Comportamento Animal/efeitos dos fármacos , Peso Corporal/efeitos dos fármacos , Epitélio/efeitos dos fármacos , Epitélio/patologia , Epitélio/ultraestrutura , Feminino , Células Ciliadas Auditivas/patologia , Células Ciliadas Vestibulares/metabolismo , Células Ciliadas Vestibulares/patologia , Masculino , Proteínas de Membrana/metabolismo , Camundongos Endogâmicos , Proteínas do Tecido Nervoso/metabolismo , Ototoxicidade/etiologia , Sinapses/efeitos dos fármacos , Sinapses/metabolismo , Sinapses/patologia , Tenascina/metabolismo , Testes de Toxicidade Subcrônica , Vestíbulo do Labirinto/efeitos dos fármacos , Vestíbulo do Labirinto/patologia , Vestíbulo do Labirinto/fisiopatologiaRESUMO
Excessive noise exposure damages sensory hair cells, leading to permanent hearing loss. Zebrafish are a highly tractable model that have advanced our understanding of drug-induced hair cell death, yet no comparable model exists for noise exposure research. We demonstrate the utility of zebrafish as model to increase understanding of hair cell damage from acoustic trauma and develop protective therapies. We created an acoustic trauma system using underwater cavitation to stimulate lateral line hair cells. We found that acoustic stimulation resulted in exposure time- and intensity-dependent lateral line and saccular hair cell damage that is maximal at 48-72 h post-trauma. The number of TUNEL+ lateral line hair cells increased 72 h post-exposure, whereas no increase was observed in TUNEL+ supporting cells, demonstrating that acoustic stimulation causes hair cell-specific damage. Lateral line hair cells damaged by acoustic stimulation regenerate within 3 d, consistent with prior regeneration studies utilizing ototoxic drugs. Acoustic stimulation-induced hair cell damage is attenuated by pharmacological inhibition of protein synthesis or caspase activation, suggesting a requirement for translation and activation of apoptotic signaling cascades. Surviving hair cells exposed to acoustic stimulation showed signs of synaptopathy, consistent with mammalian studies. Finally, we demonstrate the feasibility of this platform to identify compounds that prevent acoustic trauma by screening a small redox library for protective compounds. Our data suggest that acoustic stimulation results in lateral line hair cell damage consistent with acoustic trauma research in mammals, providing a highly tractable model for high-throughput genetic and drug discovery studies.
Assuntos
Células Ciliadas Vestibulares , Perda Auditiva Provocada por Ruído , Sistema da Linha Lateral , Regeneração Nervosa/fisiologia , Estimulação Acústica , Animais , Animais Geneticamente Modificados , Modelos Animais de Doenças , Células Ciliadas Vestibulares/patologia , Células Ciliadas Vestibulares/fisiologia , Perda Auditiva Provocada por Ruído/etiologia , Perda Auditiva Provocada por Ruído/patologia , Perda Auditiva Provocada por Ruído/fisiopatologia , Larva , Sistema da Linha Lateral/lesões , Sistema da Linha Lateral/patologia , Sistema da Linha Lateral/fisiologia , Regeneração Nervosa/efeitos dos fármacos , Peixe-ZebraRESUMO
Human vestibular sensory epithelia in explant culture were incubated in gentamicin to ablate hair cells. Subsequent transduction of supporting cells with ATOH1 using an Ad-2 viral vector resulted in generation of highly significant numbers of cells expressing the hair cell marker protein myosin VIIa. Cells expressing myosin VIIa were also generated after blocking the Notch signalling pathway with TAPI-1 but less efficiently. Transcriptomic analysis following ATOH1 transduction confirmed up-regulation of 335 putative hair cell marker genes, including several downstream targets of ATOH1. Morphological analysis revealed numerous cells bearing dense clusters of microvilli at the apical surfaces which showed some hair cell-like characteristics confirming a degree of conversion of supporting cells. However, no cells bore organised hair bundles and several expected hair cell markers genes were not expressed suggesting incomplete differentiation. Nevertheless, the results show a potential to induce conversion of supporting cells in the vestibular sensory tissues of humans.
Assuntos
Epitélio/fisiologia , Células Ciliadas Vestibulares/fisiologia , Regeneração/fisiologia , Adenoviridae/metabolismo , Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Epitélio/ultraestrutura , Regulação da Expressão Gênica , Gentamicinas/efeitos adversos , Proteínas de Fluorescência Verde/metabolismo , Células Ciliadas Vestibulares/patologia , Células Ciliadas Vestibulares/ultraestrutura , Humanos , Miosina VIIa , Miosinas/metabolismo , Receptores Notch/metabolismo , Sáculo e Utrículo/fisiologia , Sáculo e Utrículo/ultraestrutura , Transdução de Sinais , Transdução GenéticaRESUMO
Backgroundï¼ Atoh1, also named Math1, is essential for the development of inner ear hair cells. Many studies have confirmed that the absence of Atoh1 resulted in a total loss of inner ear hair cells, which indicates that Atoh1 plays very similar roles in the development of hair cells in the cochlea and vestibule. Objectiveï¼ The aim of this study was to evaluate whether Atoh1 plays different roles in the cochlea and vestibule. MATERIAL AND METHODS: We generated Atoh1-null mice by inbreeding Atoh1cre/+ heterozygous mice and compared with the epithelial cell status of the cochlea and vestibule. RESULTS: We found that no inner ear hair cells were detected in Atoh1-null mice. However, a different cell status was found in the mutant cochlea and vestibule on the last embryonic day (E18.5). In the Atoh1-null cochlea, the epithelial cells that should develop into hair cells were totally absent, while in the Atoh1-null vestibule, most of the epithelial cells that should develop into hair cells still survived. CONCLUSIONS: Our data indicate that Atoh1 may have similar but partially different functions in the development of hair cells in the cochlea and vestibule.
Assuntos
Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Regulação da Expressão Gênica no Desenvolvimento/genética , Células Ciliadas Auditivas Internas/metabolismo , Células Ciliadas Vestibulares/metabolismo , Animais , Diferenciação Celular/genética , Genótipo , Células Ciliadas Auditivas Internas/patologia , Células Ciliadas Vestibulares/patologia , Hibridização In Situ/métodos , Camundongos , Camundongos Knockout , Modelos Animais , Reação em Cadeia da Polimerase/métodos , RNA Mensageiro/genética , Sensibilidade e EspecificidadeRESUMO
BACKGROUND: Deterioration in vestibular function occurs with ageing and is linked to age-related falls. Sensory hair cells located in the inner ear vestibular labyrinth are critical to vestibular function. Vestibular hair cells rely predominantly on oxidative phosphorylation (OXPHOS) for energy production and contain numerous mitochondria. Mitochondrial DNA (mtDNA) mutations and perturbed energy production are associated with the ageing process. OBJECTIVE: We investigated the effects of ageing on mtDNA in vestibular hair and support cells, and vestibular organ gene expression, to better understand mechanisms of age-related vestibular deficits. METHODS: Vestibular hair and supporting cell layers were microdissected from young and old rats, and mtDNA was quantified by qPCR. Additionally, vestibular organ gene expression was analysed by microarray and gene set enrichment analyses. RESULTS: In contrast to most other studies, we found no evidence of age-related mtDNA deletion mutations. However, we found an increase in abundance of major arc genes near the mtDNA control region. There was also a marked age-related reduction in mtDNA copy number in both cell types. Vestibular organ gene expression, gene set enrichment analysis showed the OXPHOS pathway was down regulated in old animals. CONCLUSION: Given the importance of mtDNA to mitochondrial OXPHOS and hair cell function, our findings suggest the vestibular organs are potentially on the brink of an energy crisis in old animals.
Assuntos
Envelhecimento/genética , Senescência Celular/genética , DNA Mitocondrial/genética , Metabolismo Energético/genética , Células Ciliadas Vestibulares/metabolismo , Mitocôndrias/genética , Fatores Etários , Envelhecimento/metabolismo , Envelhecimento/patologia , Animais , Variações do Número de Cópias de DNA , DNA Mitocondrial/metabolismo , Dosagem de Genes , Perfilação da Expressão Gênica/métodos , Células Ciliadas Vestibulares/patologia , Masculino , Mitocôndrias/metabolismo , Mitocôndrias/patologia , Mutação , Análise de Sequência com Séries de Oligonucleotídeos , Fosforilação Oxidativa , Ratos Endogâmicos F344 , TranscriptomaRESUMO
BACKGROUND: Hair cell loss in the cochlea is caused by ototoxic drugs, aging, and environmental stresses and could potentially lead to devastating pathophysiological effects. In adult mammals, hair cell loss is irreversible and may result in hearing and balance deficits. In contrast, nonmammalian vertebrates, including birds, can regenerate hair cells through differentiation of supporting cells and restore inner ear function, suggesting that hair cell progenitors are present in the population of supporting cells. RESULTS: In the present study, we aimed to identify novel genes related to regeneration in the chicken utricle by gene expression profiling of supporting cell and hair cell populations obtained by laser capture microdissection. The volcano plot identified 408 differentially expressed genes (twofold change, p = 0.05, Benjamini-Hochberg multiple testing correction), 175 of which were well annotated. Among these genes, we focused on Musashi-1 (MSI1), a marker of neural stem cells involved in Notch signaling, and the downstream genes in the Notch pathway. Higher expression of these genes in supporting cells compared with that in hair cells was confirmed by quantitative reverse transcription polymerase chain reaction. Immunohistochemistry analysis demonstrated that MSI1 was mainly localized at the basal side of the supporting cell layer in normal chick utricles. During the regeneration period following aminoglycoside antibiotic-induced damage of chicken utricles, the expression levels of MSI1, hairy and enhancer of split-5, and cyclin D1 were increased, and BrdU labeling indicated that cell proliferation was enhanced. CONCLUSIONS: The findings of this study suggested that MSI1 played an important role in the proliferation of supporting cells in the inner ear during normal and damaged conditions and could be a potential therapeutic target in the treatment of vestibular defects.
Assuntos
Proteínas Aviárias/metabolismo , Células Ciliadas Vestibulares/metabolismo , Regeneração Nervosa/fisiologia , Células-Tronco Neurais/metabolismo , Neurogênese/fisiologia , Fatores de Transcrição/metabolismo , Aminoglicosídeos , Animais , Bromodesoxiuridina , Galinhas , Modelos Animais de Doenças , Expressão Gênica , Perfilação da Expressão Gênica , Células Ciliadas Vestibulares/patologia , Imuno-Histoquímica , Análise em Microsséries , Proteínas do Tecido Nervoso/metabolismo , Células-Tronco Neurais/patologia , Reação em Cadeia da Polimerase em Tempo RealRESUMO
Our study aimed to evaluate pathologic changes in the cochlear (inner and outer hair cells and stria vascularis) and vestibular (vestibular hair cells, dark, and transitional cells) sensorial elements in temporal bones from donors who had otitis media. We studied 40 temporal bones from such donors, which were categorized in serous otitis media (SOM), serous-purulent otitis media (SPOM), mucoid/mucoid-purulent otitis media (MOM/MPOM), and chronic otitis media (COM); control group comprised 10 nondiseased temporal bones. We found significant loss of inner and outer cochlear hair cells in the basal turn of the SPOM, MOM/MPOM and COM groups; significant loss of vestibular hair cells was observed in the MOM/MPOM and COM groups. All otitis media groups had smaller mean area of the stria vascularis in the basal turn of the cochlea when compared to controls. In conclusion, our study demonstrated more severe pathologic changes in the later stages of the continuum of otitis media (MOM/MPOM and COM). Those changes seem to progress from the basal turn of the cochlea (stria vascularis, then inner and outer hair cells) to the middle turn of the cochlea and to the saccule and utricle in the MOM/MPOM and COM stages.
Assuntos
Cóclea/patologia , Otite Média com Derrame/patologia , Otite Média Supurativa/patologia , Osso Temporal/patologia , Vestíbulo do Labirinto/patologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Casos e Controles , Cóclea/fisiopatologia , Feminino , Células Ciliadas Auditivas Internas/patologia , Células Ciliadas Auditivas Externas/patologia , Células Ciliadas Vestibulares/patologia , Humanos , Masculino , Pessoa de Meia-Idade , Otite Média com Derrame/fisiopatologia , Otite Média Supurativa/fisiopatologia , Osso Temporal/fisiopatologia , Vestíbulo do Labirinto/fisiopatologia , Adulto JovemRESUMO
OBJECTIVE: To determine whether intralabyrinthine hemorrhage affects vestibular hair cells, dark cells, and transitional cells in human temporal bones. METHODS: We examined 9 temporal bone specimens from 9 deceased donors with unilateral intralabyrinthine hemorrhage (the hemorrhage group) along with their 9 contralateral temporal bone specimens without hemorrhage (the control group). We estimated the density of type I and type II hair cells in all peripheral sensorial organs (including the cristae of the superior, lateral, and posterior semicircular canals, as well as the maculae of the saccule and utricle). We also estimated the density of dark and transitional cells in the lateral and posterior semicircular canals. RESULTS: The loss of type I hair cells in the cristae of the superior, lateral, and posterior semicircular canals and in the maculae of the saccule and utricle was significantly higher in the hemorrhage group, as compared with the control group ( P < .05). The density of type II hair cells in the cristae of the superior and posterior canals and in the macula of the saccule significantly differed between the hemorrhage group and the control group ( P < .05). CONCLUSION: The loss of vestibular hair cells might be the cause of vestibular symptoms in patients with intralabyrinthine hemorrhage.
Assuntos
Células Epiteliais/patologia , Células Ciliadas Vestibulares/patologia , Hemorragia/patologia , Doenças do Labirinto/patologia , Osso Temporal/patologia , Vestíbulo do Labirinto/patologia , Adolescente , Adulto , Idoso , Criança , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Fotomicrografia , Canais Semicirculares/patologia , Adulto JovemRESUMO
Vertigo is a common symptom in the clinic and impacts life quality of patients. It is closely related to the damage of vestibular hair cells. So far, there is no available approach which can facilitate abundant regeneration of mammalian vestibular hair cells, so as to recover the impaired vestibular function. Illuminating the mechanisms underlying vestibular hair cell damage and developing potential therapeutic strategies for vestibular hair cell regeneration are of great significance for the prevention and treatment of vertigo. In this study, we summarized research advances in the damage and regeneration of mammalian vestibular hair cells.
Assuntos
Pesquisa Biomédica/tendências , Células Ciliadas Vestibulares/fisiologia , Regeneração , Vertigem/terapia , Animais , Células Ciliadas Auditivas , Células Ciliadas Vestibulares/patologia , Vertigem/etiologiaRESUMO
OBJECTIVES/HYPOTHESIS: In this study, our objective was to histopathologically analyze the peripheral vestibular system in patients with Mondini dysplasia. STUDY DESIGN: Comparative human temporal bone study. METHODS: We assessed the sensory epithelium of the human vestibular system with a focus on the number of type I and type II hair cells, as well as the total number of hair cells. We compared those numbers in our Mondini dysplasia group versus our control group. RESULTS: The loss of type I and type II hair cells in the cristae of the superior, lateral, and posterior semicircular canals, as well as in the saccular and utricular macula, was significantly higher in our Mondini dysplasia group than in our control group. The total number of hair cells significantly decreased in the cristae of the superior, lateral, and posterior semicircular canals, as well as in the saccular and utricular macula, in our Mondini dysplasia group. CONCLUSION: Loss of vestibular hair cells can lead to vestibular dysfunction in patients with Mondini dysplasia. LEVEL OF EVIDENCE: NA Laryngoscope, 127:206-209, 2017.
Assuntos
Cóclea/anormalidades , Células Ciliadas Vestibulares/patologia , Osso Temporal/patologia , Anormalidades Múltiplas , Cadáver , Pré-Escolar , Feminino , Humanos , Lactente , Recém-Nascido , MasculinoRESUMO
OBJECTIVE: To quantitatively assess the effect of serous labyrinthitis, suppurative labyrinthitis, and labyrinthitis ossificans on vestibular hair cells, dark cells, and transitional cells. METHODS: We examined human temporal bone specimens with serous labyrinthitis, suppurative labyrinthitis, and labyrinthitis ossificans, then compared them with age-matched control groups without labyrinthitis. We evaluated the density of type I and II vestibular hair cells, dark cells, and transitional cells in the peripheral sensorial organs. RESULTS: The mean density of type I vestibular hair cells in the maculae of the saccule significantly differed between the serous labyrinthitis group and its control group. The loss of type I and II vestibular hair cells in all of the peripheral sensorial organs was significantly higher in the suppurative labyrinthitis group than in its control group. The mean density of dark cells in the lateral and posterior semicircular canals was significantly lower in the suppurative labyrinthitis group than in its control group. The mean density of type I and II vestibular hair cells, dark cells, and transitional cells was significantly lower in the labyrinthitis ossificans group than in its control group. CONCLUSION: The loss of vestibular hair cells and degenerative changes in dark cells and transitional cells could affect vestibular function in patients with labyrinthitis.