Mapping the developmental potential of mouse inner ear organoids at single-cell resolution
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ABSTRACT:
PROVIDER: PRJNA1014008 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR25946375_1.fastq.gz | Fastqsanger.gz | |||
| SRR25946375_2.fastq.gz | Fastqsanger.gz | |||
| SRR25946376_1.fastq.gz | Fastqsanger.gz | |||
| SRR25946376_2.fastq.gz | Fastqsanger.gz | |||
| SRR25946377_1.fastq.gz | Fastqsanger.gz |
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Project description:Inner ear organoids recapitulate development and are intended to generate cell types of the otic lineage for applications such as basic science research and cell replacement strategies. Here, we use single-cell sequencing to study the cellular heterogeneity of late-stage mouse inner ear organoid sensory epithelia, which we validated by comparison with data sets of the mouse cochlea and vestibular epithelia. We resolved supporting cell sub-types, cochlear like hair cells, and vestibular Type I and Type II like hair cells. While cochlear like hair cells aligned best with an outer hair cell trajectory, vestibular like hair cells followed developmental trajectories similar to in vivo programs branching into Type II and then Type I extrastriolar hair cells. These results highlight the transcriptional accuracy of the organoid developmental program but will also inform future strategies to improve synaptic connectivity and regional specification.
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Project description:The inner ear sensory epithelia contain mechanosensitive hair cells and supporting cells. Both cell types arise from SOX2-expressing prosensory cells, but the mechanisms underlying the diversification of these cell lineages remain unclear. To determine the transcriptional trajectory of prosensory cells, we established a SOX2-2A-ntdTomato human ES cell line using CRISPR/Cas9, and performed single-cell RNA-sequencing analysis with SOX2-positive cells isolated from inner ear organoids at various time points between differentiation days 20 and 60. Our pseudotime analysis suggests that hair cells arise primarily from supporting cells, rather than bi-fated transitional cells in organoids. Moreover, ion channel- and ion transporter-related gene sets were enriched in supporting cells vs. prosensory cells, whereas Wnt signaling-related gene sets were enriched in hair cells vs. supporting cells. These findings provide valuable insights into how prosensory cells give rise to hair cells and supporting cells during human inner ear development, and may provide a clue to promote hair cell regeneration from resident supporting cells in individuals with hearing loss and balance disorders.
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Project description:In 2014, a method was introduced to differentiate mouse embryonic stem cells into inner ear vestibular-like sensory epithelia in vitro. The resulting inner ear organoids represent a potentially inexhaustible source of tissues for investigating mechanosensory hair cell development, function, and responses to ototoxic and regenerative treatments. However, there has been limited exploration into how closely the molecular characteristics of organoid-derived hair cells match those that develop in vivo. To address this gap, we have employed single-cell RNA sequencing (scRNA-seq) to generate a comprehensive atlas of inner ear organoid development at six stages, spanning the formation of definitive ectoderm to the emergence of sensory hair cells. Here, we specifically utilize our inner ear organoid atlas to define the dynamic changes in gene expression that occur during otic vesicle cell maturation into sensory epithelial supporting cells and hair cells.
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Project description:We report the application of single cell RNA sequencing for determining cell type and quantity in developing inner ear organoids derived from human pluripotent stem cells. By obtaining samples from multiple time points throughout differentiation, we developed a roadmap at single cell resolution of the multiple cell lineages which give rise to in vitro inner ear tissue as well as 'off-target' tissue types. We find that the cells in the day 0 sample contained primarily a homogenous population of pluripotent stem cells. On day 3, after treatment with BMP4, we find that the cells have differentiated into a split between surface ectoderm, the progenitor of the inner ear tissue, and neuroectoderm. On day 6 and 8, we observed the emergence of cranial placode tissue, both anterior and posterior. Then, after treatment starting on day 8 with a WNT agonist, CHIR, we observed the maturation of inner ear tissue into hair cells and neurons, starting on day 18 and increasing through the last time point collected, day 36. This study provides an atlas of inner ear organoid differentiation from human pluripotent stem cells.
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Project description:The role of TMPRSS3 in hair cell (HC) remains unclear. Nelson and colleagues generated stem cell-derived inner ear organoids with Tmprss3-mutations to show that 1) inner ear organoids exhibit comparative effects of the genetic abnormality to its in vivo counterparts, 2) Tmprss3-mutations lead to apoptosis and reduced BK channels in HCs, and 3) cell membrane-bound TMPRSS3 is localized in HCs.
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