Ototoxicity-induced c-Fos activation underlies regenerative capacity in vestibular sensory epithelia
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE295480 | GEO | 2025/12/02
REPOSITORIES: GEO
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Project description:Ototoxicity-induced c-Fos activation underlies regenerative capacity in vestibular sensory epithelia
| PRJNA1254763 | ENA
Project description: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.
| S-EPMC6078492 | biostudies-literature
Project description:The inner ear utilizes sensory hair cells as mechano-electric transducers for sensing sound and balance. In mammals, these hair cells lack the capacity for regeneration. Unlike mammals, hair cells from non-mammalian vertebrates, such as birds, can be regenerated throughout the life of the organism making them a useful model for studying inner ear genetics pathways. The zinc finger transcription factor GATA3 is required for inner ear development and mutations cause sensory neural deafness in humans. In the avian cochlea GATA3 is expressed throughout the sensory epithelia; however, expression is limited to the striola of the utricle. The striola corresponds to an abrupt change in morphologically distinct hair cell types and a 180° shift in hair cell orientation. We used 3 complimentary approaches to identify potential downstream targets of GATA3 in the avian utricle. Specifically we used microarray expression profiling of GATA3 knockdown by siRNA and GATA3 over-expression treatments as well as direct comparisons of GATA3 expressing cells from the striola and non GATA3 expressing cells from the extra-striola. Whole utricle specimens were treated with streptomycin for 24 hrs, rinsed and allowed to recover for an additional 24 hrs. Whole utricles were transfected with either GATA3 or GFP 21mer synthetic siRNAs for an additional 48 hrs and pure sensory epithelia were isolated. There are 2 biological samples and experiments include technical replicates as well as dye-switches for a total of 8 microarrays.
2010-06-24 | E-GEOD-14785 | biostudies-arrayexpress
Project description:To investigate alterations in gene expression after Ad2-ATOH1-GFP transduction of human supporting cells, we measured transcriptome changes by RNA-seq. We compared gentamicin-treated tissue (to kill the hair cells) transduced with Ad2-ATOH1-GFP (to promote hair cell production) cultured for 5 days, versus control tissues only treated with gentamicin (cultured for 2 days, 8 days and 14-18 days).
2018-07-16 | GSE109320 | GEO
Project description:The afferent encoding of vestibular stimuli depends on molecular mechanisms that regulate membrane potential, concentration gradients, and ion and neurotransmitter clearance at both afferent and efferent relays. In many cell types, the Na,K-ATPase (NKA) is essential for establishing hyperpolarized membrane potentials and mediating both primary and secondary active transport required for ion and neurotransmitter clearance. In vestibular sensory epithelia, a calyx nerve ending envelopes each type I hair cell, isolating it over most of its surface from support cells and posing special challenges for ion and neurotransmitter clearance. We used immunofluorescence and high-resolution confocal microscopy to examine the cellular and subcellular patterns of NKA? subunit expression within the sensory epithelia of semicircular canals as well as an otolith organ (the utricle). Results were similar for both kinds of vestibular organ. The neuronal NKA?3 subunit was detected in all afferent endings-both the calyx afferent endings on type I hair cells and bouton afferent endings on type II hair cells-but was not detected in efferent terminals. In contrast to previous results in the cochlea, the NKA?1 subunit was detected in hair cells (both type I and type II) but not in supporting cells. The expression of distinct NKA? subunits by vestibular hair cells and their afferent endings may be needed to support and shape the high rates of glutamatergic neurotransmission and spike initiation at the unusual type I-calyx synapse.
| S-EPMC4164683 | biostudies-literature
Project description:Background & aimsLimited understanding of pruritus mechanisms in cholestatic liver diseases hinders development of antipruritic treatments. Previous studies implicated lysophosphatidic acid (LPA) as a potential mediator of cholestatic pruritus.MethodsPruritogenicity of lysophosphatidylcholine (LPC), LPA's precursor, was examined in naïve mice, cholestatic mice, and nonhuman primates. LPC's pruritogenicity involving keratinocyte TRPV4 was studied using genetic and pharmacologic approaches, cultured keratinocytes, ion channel physiology, and structural computational modeling. Activation of pruriceptor sensory neurons by microRNA-146a (miR-146a), secreted from keratinocytes, was identified by in vitro and ex vivo Ca2+ imaging assays. Sera from patients with primary biliary cholangitis were used for measuring the levels of LPC and miR-146a.ResultsLPC was robustly pruritic in mice. TRPV4 in skin keratinocytes was essential for LPC-induced itch and itch in mice with cholestasis. Three-dimensional structural modeling, site-directed mutagenesis, and channel function analysis suggested a TRPV4 C-terminal motif for LPC binding and channel activation. In keratinocytes, TRPV4 activation by LPC induced extracellular release of miR-146a, which activated TRPV1+ sensory neurons to cause itch. LPC and miR-146a levels were both elevated in sera of patients with primary biliary cholangitis with itch and correlated with itch intensity. Moreover, LPC and miR-146a were also increased in sera of cholestatic mice and elicited itch in nonhuman primates.ConclusionsWe identified LPC as a novel cholestatic pruritogen that induces itch through epithelia-sensory neuron cross talk, whereby it directly activates skin keratinocyte TRPV4, which rapidly releases miR-146a to activate skin-innervating TRPV1+ pruriceptor sensory neurons. Our findings support the new concept of the skin, as a sensory organ, playing a critical role in cholestatic itch, beyond liver, peripheral sensory neurons, and central neural pathways supporting pruriception.
| S-EPMC9093619 | biostudies-literature
Project description:RNA-Seq analysis of adult mouse cultured utricles exposed to 43C heat shock for 30 minutes and recovered for 2 hours in order to generate a heat shock signature for cultured mouse inner ear tissue
2018-12-31 | GSE116515 | GEO
Project description:Tendons are essential, frequently injured connective tissues that transmit forces from muscle to bone. Their unique highly ordered, matrix-rich structure is critical for proper function. While adult mammalian tendons heal after acute injuries, endogenous tendon cells, or tenocytes, fail to respond appropriately, resulting in the formation of disorganized fibrovascular scar tissue with impaired function and increased propensity for re-injury. Here, we show that, unlike mammals, adult zebrafish tenocytes activate upon injury and fully regenerate the tendon. Using a full tear injury model in the adult zebrafish craniofacial tendon, we defined the hallmark stages and cellular basis of tendon regeneration through multiphoton imaging, lineage tracing, and transmission electron microscopy approaches. Remarkably, we observe that zebrafish tendons regenerate and restore normal collagen matrix ultrastructure by 6 months post-injury (mpi). Tendon regeneration progresses in three main phases: inflammation within 24 h post-injury (hpi), cellular proliferation and formation of a cellular bridge between the severed tendon ends at 3-5 days post-injury (dpi), and re-differentiation and matrix remodeling beginning from 5 dpi to 6 mpi. Importantly, we demonstrate that pre-existing tenocytes are the main cellular source of regeneration, proliferating and migrating upon injury to ultimately bridge the tendon ends. Finally, we show that TGF-β signaling is required for tenocyte recruitment and bridge formation. Collectively, our work debuts and aptly positions the adult zebrafish tendon as an invaluable comparative system to elucidate regenerative mechanisms that may inspire new therapeutic strategies.
| S-EPMC10509205 | biostudies-literature
Project description:Hair cells in the mammalian inner ear sensory epithelia are surrounded by supporting cells which are essential for function of cochlear and vestibular systems. In mice, support cells exhibit spontaneous intracellular Ca2+ transients in both auditory and vestibular organs during the first postnatal week before the onset of hearing. We recorded long lasting (>200 ms) Ca2+ transients in cochlear and vestibular support cells in neonatal mice using the genetic calcium indicator GCaMP5. Both cochlear and vestibular support cells exhibited spontaneous intracellular Ca2+ transients (GCaMP5 ΔF/F), in some cases propagating as waves from the apical (endolymph facing) to the basolateral surface with a speed of ∼25 μm per second, consistent with inositol trisphosphate dependent calcium induced calcium release (CICR). Acetylcholine evoked Ca2+ transients were observed in both inner border cells in the cochlea and vestibular support cells, with a larger change in GCaMP5 fluorescence in the vestibular support cells. Adenosine triphosphate evoked robust Ca2+ transients predominantly in the cochlear support cells that included Hensen's cells, Deiters' cells, inner hair cells, inner phalangeal cells and inner border cells. A Ca2+ event initiated in one inner border cells propagated in some instances longitudinally to neighboring inner border cells with an intercellular speed of ∼2 μm per second, and decayed after propagating along ∼3 cells. Similar intercellular propagation was not observed in the radial direction from inner border cell to inner sulcus cells, and was not observed between adjacent vestibular support cells.
| S-EPMC8455828 | biostudies-literature
Project description:Regenerating hair cells in human vestibular sensory epithelia
| PRJNA430413 | ENA