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Reprogramming of cochlear supporting cells by MYC/NICD co-activation.

ABSTRACT: 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, 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 have shown that a 4-day treatment by Dox in cultured adult rtTa/tetMyc/-tet-NICD cochleae was sufficient to reprogram adult SCs for HC regeneration.

ORGANISM(S): Mus musculus

PROVIDER: GSE205187 | GEO | 2022/06/03

REPOSITORIES: GEO

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Single cell gene expression profile of adult cochlear explants over the course of hair cell regeneration stimulated by Atoh1 activation [DoxVehicleAtoh1]

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.

2023-06-01 | GSE218325 | GEO

Single cell gene expression profile of adult cochlear explants over the course of hair cell regeneration stimulated by chemical reprogramming [CocktailVehicleAtoh1]

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Dual expression of Atoh1 and Ikzf2 promotes transformation of adult cochlear supporting cells into outer hair cells

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Mapping out genome wide binding sites of Prox1 by CUT&RUN approach in mouse cochlea

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Identification of intermediate transcriptome states and synergistic effects of Isl1 in Atoh1-mediated cochlear hair cell conversion

Project description:Ectopic expression of Atoh1 in non-sensory supporting cells (SCs) in mouse cochleae induces their conversion to hair cells (HCs) in vivo. cHCs in multiple intermediate states of the conversion process that most closely resembled neonatal differentiating HCs, but differed from the progenitors. We further identified 52 transcription factors that are differentially expressed in cHCs, SCs, and mature HCs and confirmed that Isl1 synergistically enhanced the efficiency of Atoh1-mediated HC conversion in cochlear explants. Our results demonstrate that direct HC conversion from SCs in vivo follows a different path from normal development and requires multiple factors for maximum efficiency and completion.

2018-07-23 | GSE85983 | GEO

Characterizing adult cochlear supporting cell transcriptional diversity using single-cell RNA-Seq: Validation in the adult mouse and translational implications for the adult human cochlea

Project description:Characterizing adult cochlear supporting cell transcriptional diversity using scRNA-Seq Hearing loss is a significant disability that impacts 432 million people worldwide. A significant proportion of these individuals are dissatisfied with or do not have access to available treatment options which include hearing aids and cochlear implants. An alternative approach to restore hearing would be to regenerate lost cells, including hair cells in the adult cochlea. Such therapy would require restoration of the organ of Corti’s complex architecture, necessitating regeneration of both mature hair cells and supporting cells. We characterize the first single-cell adult cochlear supporting cell transcriptomes with the goals of: (1) demonstrating their transcriptional distinctiveness from perinatal cochlear supporting cells, (2) providing a metric for future attempts at regenerating mature cochlear supporting cells by identifying both cell type-specific and regional-specific expression, and (3) identify cell cycle gene expression present in adult supporting cells at the single cell level which may establish a basis for targeting cell cycle regulation pathways to force these cells out of quiescence.

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2017-09-18 | PXD006240 | Pride

Comprehensive analysis on the signaling pathway of Norrie disease protein (Ndp)

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2021-09-04 | GSE173393 | GEO

Reprogramming of cochlear supporting cells by MYC/NICD co-activation.

Project description:Reprogramming of cochlear supporting cells by MYC/NICD co-activation.

| PRJNA844057 | ENA

Single cell RNA sequencing analysis of mouse cochlear supporting cell transcriptomes with activated ERBB2 receptor, a candidate mediator of hearing restoration mechanisms

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