Recapitulating Inner Ear Development with Pluripotent Stem Cells

Koehler, Karl R.; Malone, Alexander; Hashino, Eri

doi:10.1016/b978-0-12-408088-1.00008-7

Cited by 3 publications

(4 citation statements)

References 142 publications

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Section: Introductionmentioning

confidence: 99%

“…A simplified model of SGN lineage indicates that PSCs first give rise to nonneuronal ectoderm (NNE), which develops into preplacodal ectoderm (PPE) . PPE then becomes cranial placodes, including the otic placode, which contains SGN precursors . Although developmental pathways governing commitment of precursor cells to human SGNs are not completely understood, substantial insight has been provided by studies of chick, Xenopus , and rodent nervous systems and recent studies of human embryonic stem cells (hESCs) .…”

Section: Introductionmentioning

confidence: 99%

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Directed Differentiation of Human Embryonic Stem Cells Toward Placode-Derived Spiral Ganglion-Like Sensory Neurons

Matsuoka¹,

Morrissey²,

Zhang³

et al. 2016

Stem Cells Translational Medicine

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The ability to generate spiral ganglion neurons (SGNs) from stem cells is a necessary prerequisite for development of cell-replacement therapies for sensorineural hearing loss (SNHL). We present a protocol that directs human embryonic stem cells (hESCs) toward a purified population of otic neuronal progenitors and SGN-like cells. Between 82% and 95% of these cells express SGN molecular markers, they preferentially extend neurites to the cochlear nucleus rather than non-auditory nuclei, and they generate action potentials. The protocol follows an in vitro stepwise recapitulation of developmental events inherent to normal differentiation of hESCs into SGNs, resulting in efficient sequential generation of nonneuronal ectoderm, preplacodal ectoderm, early prosensory otic neuronal progenitors (ONPs), late ONPs, and cells with cellular and molecular characteristics of human SGNs. We thus describe the sequential signaling pathways that generate the early and later lineage species in the human SGN lineage, thereby better describing key developmental processes. The results indicate that our protocol generates cells that closely replicate the phenotypic characteristics of human SGNs, advancing the process of guiding hESCs to states serving inner-ear cell-replacement therapies and possible next-generation hybrid auditory prostheses.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Directed Differentiation of Human Embryonic Stem Cells Toward Placode-Derived Spiral Ganglion-Like Sensory Neurons

Matsuoka¹,

Morrissey²,

Zhang³

et al. 2016

Stem Cells Translational Medicine

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“…Note that, in the group column of the Tables 1 and 2 , “up” indicates more targeting of a gene by miRNA in the case (CVG) vs the comparison tissue (NC or OV), and presumably downregulation of the gene itself. In the CVG vs. NC comparison, zinc finger transcription factors (ZNF213, ZNF117, and 138) at stage 13; PELP1 (EGF), PIK3R1 (FGF), SCRT1 (Zinc finger transcription factor), and SKI (TGF-β signaling) at stage 14; and SKOR1 (SMAD binding (inhibiting BMP signaling)) at stage 15 are likely to relevant for CVG development based on prior literature [ 43 , 44 ]. In the CVG vs. OV comparison, CARF (BDNF transcription), EPHA5 (axonal genesis and synapse guidance), LRP6 (Wnt/beta-catenin signaling) at stage 13; and BBS7 (Sonic hedgehog (SHH) signaling) at stage 14 are similarly relevant for CVG development.…”

Section: Resultsmentioning

confidence: 99%

Developmental profiling of microRNAs in the human embryonic inner ear

et al. 2018

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Due to the extreme inaccessibility of fetal human inner ear tissue, defining of the microRNAs (miRNAs) that regulate development of the inner ear has relied on animal tissue. In the present study, we performed the first miRNA sequencing of otic precursors in human specimens. Using HTG miRNA Whole Transcriptome assays, we examined miRNA expression in the cochleovestibular ganglion (CVG), neural crest (NC), and otic vesicle (OV) from paraffin embedded (FFPE) human specimens in the Carnegie developmental stages 13–15. We found that in human embryonic tissues, there are different patterns of miRNA expression in the CVG, NC and OV. In particular, members of the miR-183 family (miR-96, miR-182, and miR-183) are differentially expressed in the CVG compared to NC and OV at Carnegie developmental stage 13. We further identified transcription factors that are differentially targeted in the CVG compared to the other tissues from stages 13–15, and we performed gene set enrichment analyses to determine differentially regulated pathways that are relevant to CVG development in humans. These findings not only provide insight into the mechanisms governing the development of the human inner ear, but also identify potential signaling pathways for promoting regeneration of the spiral ganglion and other components of the inner ear.

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“…Transdifferentiating supporting cells into HCs or generating HCs from pluripotent stem cells has advanced since the important role of Atoh1 was first described in the ear of null mutants . Generating vestibular HC‐like cell differentiation from precursor cells to form simple mosaic driven by Delta‐Notch as found in vestibular sensory epithelia may soon be possible. However, one would need to generate distinct cochlea HC types, surrounded by distinct supporting cell types in the right numbers and in the right position and pattern to achieve lasting restoration of the OC.…”

Section: Can Developmental Insights Be Used For In Situ Regeneration?mentioning

confidence: 99%

The quest for restoring hearing: Understanding ear development more completely

et al. 2015

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Neurosensory hearing loss is a growing problem of super-aged societies. Cochlear implants can restore some hearing, but rebuilding a lost hearing organ would be superior. Research has discovered many cellular and molecular steps to develop a hearing organ but translating those insights into hearing organ restoration remains unclear. We cannot make various hair cell types and arrange them into their specific patterns surrounded by the right type of supporting cells in the right numbers. Our overview of the topologically highly organized and functionally diversified cellular mosaic of the mammalian hearing organ highlights what is known and unknown about its development. Following this analysis, we suggest critical steps to guide future attempts toward restoration of a functional OC. We argue that generating mutant mouse lines that mimic human pathology to fine-tune attempts toward long-term functional restoration are needed to go beyond the hope generated by restoring single hair cells.

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Recapitulating Inner Ear Development with Pluripotent Stem Cells

Cited by 3 publications

References 142 publications

Directed Differentiation of Human Embryonic Stem Cells Toward Placode-Derived Spiral Ganglion-Like Sensory Neurons

Directed Differentiation of Human Embryonic Stem Cells Toward Placode-Derived Spiral Ganglion-Like Sensory Neurons

Developmental profiling of microRNAs in the human embryonic inner ear

The quest for restoring hearing: Understanding ear development more completely

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