Single-cell transcriptomic profiling of the mouse cochlea: An atlas for targeted therapies

Proceedings of the National Academy of Sciences, Год журнала: 2023, Номер 120(26)

Опубликована: Июнь 20, 2023

Functional molecular characterization of the cochlea has mainly been driven by deciphering genetic architecture sensorineural deafness. As a result, search for curative treatments, which are sorely lacking in hearing field, become potentially achievable objective, particularly via cochlear gene and cell therapies. To this end, complete inventory types, with an in-depth their expression profiles right up to final differentiation, is indispensable. We therefore generated single-cell transcriptomic atlas mouse based on analysis more than 120,000 cells postnatal day 8 (P8), during prehearing period, P12, corresponding onset, P20, when maturation almost complete. By combining whole-cell nuclear transcript analyses extensive situ RNA hybridization assays, we characterized signatures covering nearly all types developed type–specific markers. Three were discovered; two them contribute modiolus houses primary auditory neurons blood vessels, third one consists lining scala vestibuli. The results also shed light basis tonotopic gradient biophysical characteristics basilar membrane that critically underlies passive sound frequency analysis. Finally, overlooked deafness genes several was unveiled. This paves way regulatory networks controlling differentiation maturation, essential development effective targeted treatments.

Язык: Английский

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Increased mitophagy protects cochlear hair cells from aminoglycoside-induced damage

Autophagy, Год журнала: 2022, Номер 19(1), С. 75 - 91

Опубликована: Апрель 26, 2022

Aminoglycosides exhibit ototoxicity by damaging mitochondria, which in turn generate reactive oxygen species that induce hair cell death and subsequent hearing loss. It is well known damaged mitochondria are degraded mitophagy, an important mitochondrial quality control system maintains homeostasis ensures survival. However, it unclear whether dysregulation of mitophagy contributes to aminoglycoside-induced injury. In the current study, we found PINK1-PRKN-mediated was impaired neomycin-treated cells. Our data suggested recruitment PRKN phagophore recognition during were blocked following neomycin treatment. addition, degradation lysosomes significantly decreased as indicated mitophagic flux reporter mt-mKeima. Moreover, demonstrated disrupted through transcriptional inhibition Pink1 expression, key initiator mitophagy. inducing ATF3 expression. Importantly, treatment with a activator could rescue cells increasing indicating genetic modulation or drug intervention may have therapeutic potential for

Язык: Английский

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Molecular and cytological profiling of biological aging of mouse cochlear inner and outer hair cells

Cell Reports, Год журнала: 2022, Номер 39(2), С. 110665 - 110665

Опубликована: Апрель 1, 2022

Age-related hearing loss (ARHL) negatively impacts quality of life in the elderly population. The prevalent cause ARHL is mechanosensitive cochlear hair cells (HCs). molecular and cellular mechanisms HC degeneration remain poorly understood. Using RNA-seq transcriptomic analyses inner outer HCs isolated from young aged mice, we show that aging associated with changes key processes, including transcription, DNA damage, autophagy, oxidative stress, as well genes related to specialization. At level, characterized by stereocilia, shrinkage soma, reduction mechanical properties, suggesting functional decline mechanotransduction amplification precedes contributes ARHL. Our study reveals cytological profiles identifies such Sod1, Sirt6, Jund, Cbx3 biomarkers potential therapeutic targets for ameliorating

Язык: Английский

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Single-cell transcriptomic Atlas of mouse cochlear aging

Protein & Cell, Год журнала: 2022, Номер unknown

Опубликована: Ноя. 11, 2022

Progressive functional deterioration in the cochlea is associated with age-related hearing loss (ARHL). However, cellular and molecular basis underlying cochlear aging remains largely unknown. Here, we established a dynamic single-cell transcriptomic landscape of mouse aging, which characterized aging-associated changes 27 different cell types across five time points. Overall, our analysis pinpoints proteostasis elevated apoptosis as hallmark features highlights unexpected transcriptional fluctuations intermediate cells localized stria vascularis (SV) demonstrates that upregulation endoplasmic reticulum (ER) chaperon protein HSP90AA1 mitigates ER stress-induced damages aging. Our work suggests targeting unfolded response pathways may help alleviate aging-related SV atrophy hence delay progression ARHL.

Язык: Английский

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Genome-wide association meta-analysis identifies 48 risk variants and highlights the role of the stria vascularis in hearing loss

The American Journal of Human Genetics, Год журнала: 2022, Номер 109(6), С. 1077 - 1091

Опубликована: Май 16, 2022

Hearing loss is one of the top contributors to years lived with disability and a risk factor for dementia. Molecular evidence on cellular origins hearing in humans growing. Here, we performed genome-wide association meta-analysis clinically diagnosed self-reported impairment 723,266 individuals identified 48 significant loci, 10 which are novel. A large proportion associations comprised missense variants, half lie within known familial loci. We used single-cell RNA-sequencing data from mouse cochlea brain mapped common-variant genomic results spindle, root, basal cells stria vascularis, structure necessary normal hearing. Our findings indicate importance vascularis mechanism impairment, providing future paths developing targets therapeutic intervention loss.

Язык: Английский

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Spatial patterns of noise-induced inner hair cell ribbon loss in the mouse mid-cochlea

iScience, Год журнала: 2024, Номер 27(2), С. 108825 - 108825

Опубликована: Янв. 8, 2024

In the mammalian cochlea, moderate acoustic overexposure leads to loss of ribbon-type synapse between inner hair cell (IHC) and its postsynaptic spiral ganglion neuron (SGN), causing a reduced dynamic range hearing but not permanent threshold elevation. A prevailing view is that such ribbon (known as synaptopathy) selectively impacts low-spontaneous-rate high-threshold SGN fibers contacting predominantly modiolar IHC face. However, spatial pattern synaptopathy remains scarcely characterized in most sensitive mid-cochlear region, where two morphological subtypes with distinct size gradients coexist. Here, we used volume electron microscopy investigate noise exposure-related changes mouse IHCs without loss. Our quantifications reveal differ worst-hit area synaptopathy. Moreover, show relative enrichment mitochondria surviving terminals, providing key experimental evidence for long-proposed role SGN-terminal synaptic vulnerability.

Язык: Английский

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Inner ear immunity

Hearing Research, Год журнала: 2022, Номер 419, С. 108518 - 108518

Опубликована: Май 11, 2022

Язык: Английский

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Hair Cell Regeneration: From Animals to Humans

Clinical and Experimental Otorhinolaryngology, Год журнала: 2024, Номер 17(1), С. 1 - 14

Опубликована: Янв. 19, 2024

Cochlear hair cells convert sound into electrical signals that are relayed via the spiral ganglion neurons to central auditory pathway. Hair vulnerable damage caused by excessive noise, aging, and ototoxic agents. Non-mammals can regenerate lost mitotic regeneration direct transdifferentiation of surrounding supporting cells. However, in mature mammals, damaged not replaced, resulting permanent hearing loss. Recent studies have uncovered mechanisms which sensory organs non-mammals neonatal mammalian cochlea cells, outlined possible why this ability declines rapidly with age mammals. Here, we review similarities differences between avian, zebrafish, cell regeneration. Moreover, discuss advances limitations their potential applications human

Язык: Английский

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KSR1 knockout mouse model demonstrates MAPK pathway's key role in cisplatin- and noise-induced hearing loss

Journal of Neuroscience, Год журнала: 2024, Номер unknown, С. e2174232024 - e2174232024

Опубликована: Март 28, 2024

Hearing loss is a major disability in everyday life and therapeutic interventions to protect hearing would benefit large portion of the world population. Here we found that mice devoid protein kinase suppressor RAS 1 (KSR1) their tissues (germline KO mice) exhibit resistance both cisplatin- noise-induced permanent compared wild-type KSR1 littermates. scaffold brings proximity mitogen-activated (MAPK) proteins BRAF, MEK1/2 ERK1/2 assists activation through phosphorylation cascade induced by cisplatin noise insults cochlear cells. KSR1, MEK1/2, are all ubiquitously expressed cochlea. Deleting tempered down MAPK cells following conferred protection up 30 dB SPL three tested frequencies male female mice. Treatment with dabrafenib, an FDA-approved oral BRAF inhibitor, protected from loss. Dabrafenib treatment did not enhance mice, providing evidence dabrafenib works primarily pathway. Thus, either elimination gene expression or drug inhibition cellular pathway resulted profound noise-induce Inhibition pathway, responds damage cells, can prove valuable strategy treat Significance Statement Ten percent population suffers but this impairment may be preventable. We show (KO) littermates harbor protein. Removing tempers BRAF-MEK-ERK cochlea insults. and, importantly, confer additional Hence, has unique role responding removing results protection.

Язык: Английский

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Profiling mouse cochlear cell maturation using 10× Genomics single-cell transcriptomics

Frontiers in Cellular Neuroscience, Год журнала: 2022, Номер 16

Опубликована: Авг. 18, 2022

Juvenile and mature mouse cochleae contain various low-abundant, vulnerable sensory epithelial cells embedded in the calcified temporal bone, making it challenging to profile dynamic transcriptome changes of these during maturation at single-cell level. Here we performed 10x Genomics RNA sequencing (scRNA-seq) postnatal days 14 (P14) 28. We attained transcriptomes multiple cell types, including hair cells, supporting spiral ganglia, stria fibrocytes, immune cells. Our scRNA-seq datasets are consistent with published transcripts from bulk RNA-seq. also mapped known deafness genes corresponding cochlear types. Importantly, pseudotime trajectory analysis revealed that inner peaks P14 while outer continue development until P28. further identified confirmed a long non-coding gene Miat be expressed ganglia neurons, Pcp4 juvenile provide sequel those previously late embryonic early ages will valuable resources investigate resolution.

Язык: Английский

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