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RNA-sequence facilitates analyze changes of signaling pathways after drug treatment

ABSTRACT: Mammalian cochlear hair cells cannot regenerate after damage, which was a cause of hearing loss. Due to the small number of cochlear hair cells, we were unable to collect enough cells for research. Therefore, we have established a inner ear organoid model in this way, which greatly expands the number of supporting cells, Lgr5 and gradually mature hair cells. It can be used in high-throughput screening experiments. Using this model for high-throughput screening of FDA small molecule Drug, we found that Regorafenib can promote hair cell regeneration in vitro and get more mature regenerated hair cells. And we found that Regorfenib was though a new VEGF-TGFB axis to regulate hair cell regeneration.

ORGANISM(S): Mus musculus

PROVIDER: GSE139485 | GEO | 2019/10/29

REPOSITORIES: GEO

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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.

2020-02-19 | GSE135703 | GEO

Characterization of the transcriptomes of Atoh1-induced hair cells in the mouse cochlea

Project description:Mammalian cochlea hair cells can be regenerated from the adjacent supporting cells in many ways, however, the newly hair cells are immature and without hearing function almost. The expression of Atoh1 is an important maker of the appearance of newly hair cells, many approaches of inner ear hair cells’ regeneration are concerned with the transcription factor Atoh1. However, most new HCs are immature HCs, and they do not have the function of mature HCs and eventually die a few weeks after regeneration. Thus promoting the maturation and survival of new HCs is the primary focus of HC regeneration field. We used RNA-Seq analysis to compare the differences between the transcriptomes of Atoh1 overexpression-induced new HCs and the original HCs, and to define the factors that might help to promote the maturation and survival of new HCs.

2019-04-10 | GSE129533 | GEO

Array analysis of wound induced hair neogenesis (late stage)

Project description:Mice were wounded and measured for regeneration starting 4 days after wound closure with simultaneous measurement of hair follicle neogenesis and biopsing. At each time point, RNA was collected from one mouse with high number of regenerated follicles and one without regenerated follicles. Whole skin biopsies of wound scars were submitted for Affymetrix Exon arrays. 3 replicates of mice with high number of regenerated follicles, 3 replicates of mice with no regenerated follicles; each pair taken at a different date after wound closure.

2015-08-05 | E-GEOD-50419 | biostudies-arrayexpress

Insights into the Biology of Hearing and Deafness Revealed by Single-Cell RNA Sequencing

Project description:The goal of this study was to isolate individual cochlear hair cells and supporting cells from wild type animals in order to characterize the transcriptome of functionally mature auditory hair cells in the mammalian cochlea.

2019-03-12 | GSE114157 | GEO

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

Gene expression during synaptic regeneration between cochlear hair cells and neurons

Project description:Significant changes in the expression of synaptic and inflammatory genes were observed early after damage, during regeneration of the fibers and synapses, and after completion of in vitro regeneration between afferent neurons and cochlear hair cells.

2020-09-14 | GSE130495 | GEO

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

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

2022-08-19 | GSE202920 | GEO

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

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

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

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

Array analysis of wound induced hair neogenesis (late stage)

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