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Derivation of cochlear organoids from human pluripotent stem cells reveals tight transcriptome-structure coupling during organogenesis

ABSTRACT: A balance of morphogen gradients during embryogenesis is thought to determine the identity of inner ear end organs. We applied this developmental principle to aggregates of human pluripotent stem cells and found that modulations of Sonic Hedgehog and WNT signaling promote stem cell-derived otic progenitors to express ventral otic markers. Strikingly, these ventralized otic progenitors gave rise to hair cells with short hair bundles comprised of stereocilia arrayed in a geometry reminiscent of cochlear hair cells. Moreover, these ventralized hair cells expressed multiple markers defining outer or inner hair cells in the cochlea. These results reveal that early morphogenic signals are sufficient for not only establishing cochlear gene expression, but also defining structural properties pertaining to the cochlear sensory epithelium.

ORGANISM(S): Homo sapiens

PROVIDER: GSE200629 | GEO | 2022/04/14

REPOSITORIES: GEO

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Mapping the developmental potential of mouse inner ear organoids at single-cell resolution

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:Mutations in the chromatin remodeling enzyme CHD7 cause CHARGE syndrome, which affects multiple organs including the inner ear. We investigated how CHD7 mutations affect otic development in human inner ear organoids. We found loss of CHD7 or its chromatin remodeling activity leads to complete absence of hair cells and supporting cells, which can be explained by dysregulation of key otic development-associated genes in mutant otic progenitors. Further analysis of the mutant otic progenitors suggested that CHD7 can regulate otic genes through a chromatin remodeling-independent mechanism. Results from transcriptome profiling of hair cells revealed disruption of deafness gene expression as a potential underlying mechanism of CHARGE-associated sensorineural hearing loss. Notably, co-differentiating CHD7 knockout and wild-type cells in chimeric organoids partially rescued mutant phenotypes by restoring otherwise severely dysregulated otic genes. Taken together, our results suggest that CHD7 plays a critical role in regulating human otic lineage differentiation and deafness gene expression.

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Project description:Stem cells, with their potential to generate different lineages, could offer a solution by replacing damaged or lost cells within the inner ear. We have shown that human embryonic stem cells can be induced to differentiate into otic progenitors, and then into hair cell-like cells and neurons that display expected electrophysiological properties. More importantly, once these otic progenitors are transplanted into animals with induced hearing loss, they differentiate and elicit a significant recovery of auditory function. The generation of otic progenitors is triggered by FGF signalling. In this dataset we have analysed the global gene expression profile of undifferentiated hESCs and compared with cultures that have been treated with FGF3 and 10, the two ligands involved in otic induction, or cultures that have been allowed to differentiate under basal conditions without FGF (DFNB). Global gene expression profiles were obtained from hESC lines H14, Shef3 and Shef1 by hybridizing samples from undifferentiated cells (Day 0) and cells exposed to either FGF3+10- or DFNB medium for 14 days. Three experimental conditions are therefore produced: hESC, FGF3+10 and DFNB.

2012-09-12 | E-GEOD-36754 | biostudies-arrayexpress

Gene expression of differentiating hESCs into otic progenitors

2012-09-12 | GSE36754 | GEO

RNA-seq analysis of Barhl1 locus mutant mouse embryonic stem cell (mESC)-derived hair cell-like cells

Project description:Although Barhl1 has been known to be essential for the maintenance of cochlear hair cells, the precise molecular function of Barhl1 in hair cells has not been well studied. This study examined differentially expressed genes in Barhl1 locus mutant hair cell-like cells relative to wild type hair cell-like cells. We detected the critical expression time and period of Barhl1 in our in vitro hair cell induction system, and used the day 9 cultures during induction of otic progenitors towards hair cell-like cells to perform RNA-seq. The known hair cell-specific genes that were significantly downregulated in Barhl1 locus mutant hair cell-like cells are associated with hair cell functions and development, such as neurotransmitter secretion, calcium ion transport, intermediate filament bundle assembly, synaptic potential and sensory perception of sound.

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Human Pluripotent stem cells-derived Inner ear organoids recapitulate otic development in vitro

Project description:The molecular characterization of early stages of human inner ear development is limited by the difficulty in accessing samples at early gestational stages. Some aspects of inner ear morphogenesis can be recapitulated using pluripotent stem cell directed differentiation in inner ear organoids (IEOs). Once validated and benchmarked, these models could provide a unique tool to complement and refine our understanding of human otic differentiation and could be used to model developmental defects.Here we provide a first characterization of early human embryonic otocyst development and compare the primary tissue to the iPSC-derived inner ear cell types. Multiplex immunostaining and single cell RNA sequencing were used to characterize human iPSC-derived IEOs at 3 key developmental steps, providing a new and unique signature of in vitro derived otic- placode, epithelium, neuroblasts and sensory epithelia. The expression and localization of key markers were further evaluated in human embryos. We show that the otic placode derived in vitro (day 8-12) matches marker expression of Carnegie Stage (CS) 11 embryos, and subsequently (day 20-40) gives rise to otic epithelia and neuroblasts comparable to the CS13 embryonic stage. Differentiation of sensory epithelia, including supporting cells and hair cells, starts in vitro at day 50-60 of culture. The maturity of these cells is equivalent to vestibular sensory epithelia at week 10 or cochlear tissue at week 12 of development, prior to functional onset. Taken together these data indicates that the current state of the art protocol enables the specification of bona fide otic tissue, supporting further application of IEOs to model inner ear biology and disease

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Identifcation of Meis2 target genes in the otic cell line VOT-E36 via ChIP analysis

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2021-03-12 | GSE166072 | GEO

Genome-wide characterization of Six1 binding in embryo and cochlea

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D10 Stereocilia Membrane Enrichment

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2016-08-16 | PXD004222 | Pride

Expression data from Pou4f3-Rb1 cKO and control inner ear

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2011-05-31 | E-GEOD-25732 | biostudies-arrayexpress

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