Reprogramming of cochlear supporting cells by MYC/NICD co-activation.
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ABSTRACT:
PROVIDER: PRJNA844057 | ENA |
REPOSITORIES: ENA
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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, 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.
2022-06-03 | GSE205187 | GEO
Project description:This study examined transcripts that are enriched in neonatal mouse cochlear supporting cells at postnatal day 1 and postnatal day 6. Supporting cells were purified by FACS sorting for GFP fluorescence from the cochleas of transgenic mice in which a BAC including the LFng locus drives the expression of GFP. Two replicates of GFP+ supporting cells were compared with all other cochlear cell types that were GFP-. We performed this experiment at two different ages, postnatal day 1 and postnatal day 6. mRNA profiles of supporting cells (GFP+) and all other cochlear cell types (GFP-), two replicates each, at P1 and P6 mice were generated by deep sequencing using Illumna TruSeq.
2016-07-01 | E-GEOD-83356 | biostudies-arrayexpress
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
Project description:This study examined transcripts that are enriched in neonatal mouse cochlear supporting cells at postnatal day 1 and postnatal day 6 after inhibition of the Notch signaling pathway. Cochleas from postnatal day 0 and postnatal day 5 were cultured for 24 hours in the gamma secretase inhibitor DAPT or DMSO as a vehicle control. Supporting cells were purified by FACS sorting for GFP fluorescence from the cochleas of transgenic mice in which a BAC including the LFng locus drives the expression of GFP. Two replicates of GFP+ supporting cells were compared with all other cochlear cell types that were GFP-. We performed this experiment at two different ages, postnatal day 0+24 hours culture and postnatal day 5 + 24 hours culture. (corresponding to P1 and P6). mRNA profiles of P0 and P5 supporting cells (GFP+) and all other cochlear cell types (GFP-) treated with DAPT or DMSO, two replicates each, were generated by deep sequencing using Illumna TruSeq.
2016-07-01 | E-GEOD-83340 | biostudies-arrayexpress
Project description:This study examined transcripts that are enriched in neonatal mouse cochlear supporting cells at postnatal day 1 and postnatal day 6. Supporting cells were purified by FACS sorting for GFP fluorescence from the cochleas of transgenic mice in which a BAC including the LFng locus drives the expression of GFP. Two replicates of GFP+ supporting cells were compared with all other cochlear cell types that were GFP-. We performed this experiment at two different ages, postnatal day 1 and postnatal day 6.
2016-07-01 | GSE83356 | GEO
Project description:This study examined transcripts that are enriched in neonatal mouse cochlear supporting cells at postnatal day 1 and postnatal day 6 after inhibition of the Notch signaling pathway. Cochleas from postnatal day 0 and postnatal day 5 were cultured for 24 hours in the gamma secretase inhibitor DAPT or DMSO as a vehicle control. Supporting cells were purified by FACS sorting for GFP fluorescence from the cochleas of transgenic mice in which a BAC including the LFng locus drives the expression of GFP. Two replicates of GFP+ supporting cells were compared with all other cochlear cell types that were GFP-. We performed this experiment at two different ages, postnatal day 0+24 hours culture and postnatal day 5 + 24 hours culture. (corresponding to P1 and P6).
2016-07-01 | GSE83340 | GEO
Project description:RNA-seq analysis of neonatal mouse cochlear supporting cells
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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. We identified a combination (the cocktail) of drug-like molecules composing of small molecules and siRNAs to activate the pathways of Myc, Notch1, Wnt and cAMP. 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 chemical-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, in response to chemical-induced reprogramming. We compared gene expression profiles between Vehicle/ad.Atoh1 activation vs. Cocktail (chemical reprogramming)/ad.Atoh1 activation.
2023-06-01 | GSE218324 | GEO
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.
2020-02-19 | GSE135703 | GEO
Project description:Role of Jagged1 in cochlear supporting cell differentiation and maintenance
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