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In Vivo and Ex Vivo Utricles treated with ATOH1 under different promoters

ABSTRACT: Vestibular hair cells are mechanoreceptors critical for detecting head position and motion. In mammals, hair cell loss causes vestibular dysfunction as spontaneous regeneration is nearly absent. Constitutive expression of exogenous ATOH1, a hair cell transcription factor, increases regeneration of hair cells, but these cells fail to mature. With the aim of developing an optimized AAV-based ATOH1 gene therapy, we used single-cell RNA-Seq and explored the impact of defined promoters on ATOH1 transgene expression level, timing, effects in distinct cell types, and the maturity of regenerated vestibular hair cells ex vivo and in vivo.

ORGANISM(S): Mus musculus

PROVIDER: GSE240846 | GEO | 2024/09/24

REPOSITORIES: GEO

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Developmental Timecourse of Mouse Utricles

Project description:Vestibular hair cells are mechanoreceptors critical for detecting head position and motion. In mammals, hair cell loss causes vestibular dysfunction as spontaneous regeneration is nearly absent. Constitutive expression of exogenous ATOH1, a hair cell transcription factor, increases regeneration of hair cells, but these cells fail to mature. With the aim of developing an optimized AAV-based ATOH1 gene therapy, we used single-cell RNA-Seq and explored the impact of defined promoters on ATOH1 transgene expression level, timing, effects in distinct cell types, and the maturity of regenerated vestibular hair cells ex vivo and in vivo.

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Transcriptomic and epigenetic regulation of hair cell regeneration in the mouse utricle and its potentiation by Atoh1

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Project description:Strategies to overcome irreversible cochlear hair cell (HC) damage and loss are of vital importance to develop a treatment for hearing loss. HC regeneration in adult cochlea relies on a two-phase process: 1) Reprogramming mature cochlear (SCs) to regain the properties of their younger selves; 2) Activating Atoh1, a gene responsible for HC fate-determining, in the reprogrammed adult SCs for HC regeneration. We have shown that, by transient co-activation of Myc and NICD (Notch1 intracellular domain), the adult mouse cochlea can be successfully reprogrammed to a relatively younger stage and regain progenitor capacity, with the regeneration of HCs following Atoh1 overexpression in vitro and in vivo. To identify molecules to reprogram mature cochlear SCs and HC regeneration, we utilized single-cell RNA sequencing and uncovered the pathways and their target genes underlying MYC/NICD-mediated reprogramming. We used an in-house adult cochlea explant culture system and carried out single-cell RNA sequencing to examine the gene expression profiles of cochlear explants from a transgenic mouse model, rtTa/tet-Myc/-tet-NICD, in response to Dox-induced MYC/NICD co-activation. We compared gene expression profiles between Atoh1 activation vs. MYC/NICD/Atoh1 co-activation.

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Breaking the Atoh1 autoregulatory loop in hair cells: the repression of Atoh1 by Neurogenin1 during ear development

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