Cotransfection of Pax2 and Math1 promote in situ cochlear hair cell regeneration after neomycin insult.
Ontology highlight
ABSTRACT:
SUBMITTER: Chen Y
PROVIDER: S-EPMC3801138 | biostudies-other | 2013
REPOSITORIES: biostudies-other
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Project description:Ferroptosis is a recently discovered iron-dependent form of oxidative programmed cell death distinct from caspase-dependent apoptosis. In this study, we investigated the effect of ferroptosis in neomycin-induced hair cell loss by using selective ferroptosis inhibitor liproxstatin-1 (Lip-1). Cell viability was identified by CCK8 assay. The levels of reactive oxygen species (ROS) were determined by DCFH-DA and cellROX green staining. The mitochondrial membrane potential (ΔΨm) was evaluated by TMRM staining. Intracellular iron and lipid peroxides were detected with Mito-FerroGreen and Liperfluo probes. We found that ferroptosis can be induced in both HEI-OC1 cells and neonatal mouse cochlear explants, as evidenced by Mito-FerroGreen and Liperfluo staining. Further experiments showed that pretreatment with Lip-1 significantly alleviated neomycin-induced increased ROS generation and disruption in ΔΨm in the HEI-OC1 cells. In parallel, Lip-1 significantly attenuated neomycin-induced hair cell damage in neonatal mouse cochlear explants. Collectively, these results suggest a novel mechanism for neomycin-induced ototoxicity and suggest that ferroptosis inhibition may be a new clinical intervention to prevent hearing loss.
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Project description:Aging, noise, and ototoxic drug-induced hair cell (HC) loss are the major causes of sensorineural hearing loss. Aminoglycoside antibiotics are commonly used in the clinic, but these often have ototoxic side effects due to the accumulation of oxygen-free radicals and the subsequent induction of HC apoptosis. Blebbistatin is a myosin II inhibitor that regulates microtubule assembly and myosin-actin interactions, and most research has focused on its ability to modulate cardiac or urinary bladder contractility. By regulating the cytoskeletal structure and reducing the accumulation of reactive oxygen species (ROS), blebbistatin can prevent apoptosis in many different types of cells. However, there are no reports on the effect of blebbistatin in HC apoptosis. In this study, we found that the presence of blebbistatin significantly inhibited neomycin-induced apoptosis in HC-like HEI-OC-1 cells. We also found that blebbistatin treatment significantly increased the mitochondrial membrane potential (MMP), decreased ROS accumulation, and inhibited pro-apoptotic gene expression in both HC-like HEI-OC-1 cells and explant-cultured cochlear HCs after neomycin exposure. Meanwhile, blebbistatin can protect the synaptic connections between HCs and cochlear spiral ganglion neurons. This study showed that blebbistatin could maintain mitochondrial function and reduce the ROS level and thus could maintain the viability of HCs after neomycin exposure and the neural function in the inner ear, suggesting that blebbistatin has potential clinic application in protecting against ototoxic drug-induced HC loss.
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Project description:ObjectivesTo investigate the role of dibenzazepine (DBZ) in promoting supporting cell (SC) proliferation and hair cell (HC) regeneration in the inner ear.Materials and methodsPostnatal day 1 wild-type or neomycin-damaged mouse cochleae were cultured with DBZ. Immunohistochemistry and scanning electron microscopy were used to examine the morphology of cochlear cells, and high-throughput RNA-sequencing was used to measure gene expression levels.ResultsWe found that DBZ promoted SC proliferation and HC regeneration in a dose-dependent manner in both normal and damaged cochleae. In addition, most of the newly regenerated HCs induced by DBZ had visible and relatively mature stereocilia bundle structures. Finally, RNA sequencing detected the differentially expressed genes between DBZ treatment and controls, and interaction networks were constructed for the most highly differentially expressed genes.ConclusionsOur study demonstrates that DBZ can significantly promote SC proliferation and increase the number of mitotically regenerated HCs with relatively mature stereocilia bundles in the neonatal mouse cochlea by inhibiting Notch signalling and activating Wnt signalling, suggesting the DBZ might be a new therapeutic target for stimulating HC regeneration.
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Project description:Hearing loss due to damage to auditory hair cells is normally irreversible because mammalian hair cells do not regenerate. Here, we show that new hair cells can be induced and can cause partial recovery of hearing in ears damaged by noise trauma, when Notch signaling is inhibited by a ?-secretase inhibitor selected for potency in stimulating hair cell differentiation from inner ear stem cells in vitro. Hair cell generation resulted from an increase in the level of bHLH transcription factor Atoh1 in response to inhibition of Notch signaling. In vivo prospective labeling of Sox2-expressing cells with a Cre-lox system unambiguously demonstrated that hair cell generation resulted from transdifferentiation of supporting cells. Manipulating cell fate of cochlear sensory cells in vivo by pharmacological inhibition of Notch signaling is thus a potential therapeutic approach to the treatment of deafness.
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Project description:Recent studies have reported the role of Wnt/β-catenin signaling in hair cell (HC) development, regeneration, and differentiation in the mouse cochlea; however, the role of Wnt/β-catenin signaling in HC protection remains unknown. In this study, we took advantage of transgenic mice to specifically knockout or overactivate the canonical Wnt signaling mediator β-catenin in HCs, which allowed us to investigate the role of Wnt/β-catenin signaling in protecting HCs against neomycin-induced damage. We first showed that loss of β-catenin in HCs made them more vulnerable to neomycin-induced injury, while constitutive activation of β-catenin in HCs reduced HC loss both in vivo and in vitro. We then showed that loss of β-catenin in HCs increased caspase-mediated apoptosis induced by neomycin injury, while β-catenin overexpression inhibited caspase-mediated apoptosis. Finally, we demonstrated that loss of β-catenin in HCs led to increased expression of forkhead box O3 transcription factor (Foxo3) and Bim along with decreased expression of antioxidant enzymes; thus, there were increased levels of reactive oxygen species (ROS) after neomycin treatment that might be responsible for the increased aminoglycoside sensitivity of HCs. In contrast, β-catenin overexpression reduced Foxo3 and Bim expression and ROS levels, suggesting that β-catenin is protective against neomycin-induced HC loss. Our findings demonstrate that Wnt/β-catenin signaling has an important role in protecting HCs against neomycin-induced HC loss and thus might be a new therapeutic target for the prevention of HC death.
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Project description:Hearing loss is a debilitating disease that affects 10% of adults worldwide. Most sensorineural hearing loss is caused by the loss of mechanosensitive hair cells in the cochlea, often due to aging, noise, and ototoxic drugs. The identification of genes that can be targeted to slow aging and reduce the vulnerability of hair cells to insults is critical for the prevention of sensorineural hearing loss. Our previous cell-specific transcriptome analysis of adult cochlear hair cells and supporting cells showed that Clu, encoding a secreted chaperone that is involved in several basic biological events, such as cell death, tumor progression, and neurodegenerative disorders, is expressed in hair cells and supporting cells. We generated Clu-null mice (C57BL/6) to investigate its role in the organ of Corti, the sensory epithelium responsible for hearing in the mammalian cochlea. We showed that the deletion of Clu did not affect the development of hair cells and supporting cells; hair cells and supporting cells appeared normal at 1 month of age. Auditory function tests showed that Clu-null mice had hearing thresholds comparable to those of wild-type littermates before 3 months of age. Interestingly, Clu-null mice displayed less hair cell and hearing loss compared to their wildtype littermates after 3 months. Furthermore, the deletion of Clu is protected against aminoglycoside-induced hair cell loss in both in vivo and in vitro models. Our findings suggested that the inhibition of Clu expression could represent a potential therapeutic strategy for the alleviation of age-related and ototoxic drug-induced hearing loss.
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Project description:Significant changes in the expression of synaptic and inflammatory genes were observed early after damage, during regeneration of the fibers and synapses, and after completion of in vitro regeneration between afferent neurons and cochlear hair cells.
2020-09-14 | GSE130495 | GEO
Project description:Aminoglycosides are toxic to sensory hair cells (HCs). Macroautophagy/autophagy is an essential and highly conserved self-digestion pathway that plays important roles in the maintenance of cellular function and viability under stress. However, the role of autophagy in aminoglycoside-induced HC injury is unknown. Here, we first found that autophagy activity was significantly increased, including enhanced autophagosome-lysosome fusion, in both cochlear HCs and HEI-OC-1 cells after neomycin or gentamicin injury, suggesting that autophagy might be correlated with aminoglycoside-induced cell death. We then used rapamycin, an autophagy activator, to increase the autophagy activity and found that the ROS levels, apoptosis, and cell death were significantly decreased after neomycin or gentamicin injury. In contrast, treatment with the autophagy inhibitor 3-methyladenine (3-MA) or knockdown of autophagy-related (ATG) proteins resulted in reduced autophagy activity and significantly increased ROS levels, apoptosis, and cell death after neomycin or gentamicin injury. Finally, after neomycin injury, the antioxidant N-acetylcysteine could successfully prevent the increased apoptosis and HC loss induced by 3-MA treatment or ATG knockdown, suggesting that autophagy protects against neomycin-induced HC damage by inhibiting oxidative stress. We also found that the dysfunctional mitochondria were not eliminated by selective autophagy (mitophagy) in HEI-OC-1 cells after neomycin treatment, suggesting that autophagy might not directly target the damaged mitochondria for degradation. This study demonstrates that moderate ROS levels can promote autophagy to recycle damaged cellular constituents and maintain cellular homeostasis, while the induction of autophagy can inhibit apoptosis and protect the HCs by suppressing ROS accumulation after aminoglycoside injury.
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