Novel cell types and developmental lineages revealed by single-cell RNA-seq analysis of the mouse crista ampullaris

Wilkerson, Brent A.; Zebroski, Heather L; Finkbeiner, Connor; Chitsazan, Alex; Beach, Kathy; Sen, Nilasha; Zhang, Renee C; Bermingham‐McDonogh, Olivia

doi:10.7554/elife.60108

Cited by 27 publications

(37 citation statements)

References 114 publications

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“…To confirm the vestibular versus the cochlear identity of the epithelial cell population, we analyzed the differential gene expression between the putative cochlear duct floor and vestibular supporting cells (Figure 3D). ADAMTSL1, MEIS2, EBF3 and ERBB4 were genes highly expressed within vestibular populations, in contrast to GATA3, NR2F1 and SULF1 which are present in cochlear populations, as has been shown on a single-cell level for the developing mouse inner ear (Wilkerson et al, 2021;Yamamoto et al, 2021). The cochlear cell types could be separated (Figure 3E) into a medial (TECTA, FGF10, JAG1), prosensory (ISL1, LGR5, SOX2, FGF20) and lateral domain of the duct floor (BMP4, GATA3) as well as the cochlear roof (OTX2, FGF9, WNT4, GSC), based on data from the developing mouse cochlea (Chai et al, 2011;Hayashi et al, 2008;Luo et al, 2013;Morsli et al, 1999;Munnamalai and Fekete, 2020;Ohyama et al, 2010;Yamamoto et al, 2021).…”

Section: Generation Of An Atlas Of Fetal and Adult Human Inner Ear Ti...mentioning

confidence: 62%

A Single-Cell Level Comparison of Human Inner Ear Organoids and the Human Cochlea and Vestibular Organs

Valk

Beelen

Steinhart

et al. 2022

Preprint

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Genetic inner ear disorders are among the most common congenital abnormalities and lead to hearing loss and balance disorders. Ideally, tissue culture models of the inner ear should contain a functional unit combining otic sensory and nonsensory cell types to recapitulate the varied etiologies of inner ear disorders. Here, we evaluated cell type diversity of late-stage human pluripotent stem cell-derived inner ear organoids using single-cell transcriptomic analysis, electron microscopy and immunohistochemistry. We observed the induction of on-target inner ear-related periotic mesenchymal cells alongside off-target induction of skeletal myocytes, endothelial cells, and ependymal cells. By constructing a single-cell transcriptomic atlas of the human fetal and adult inner ear, we show that epithelium in the inner ear organoids contains cochlear and vestibular identities similar to the developing human inner ear. Moreover, the inner ear organoids contain immature type I and type II vestibular hair cells. Within these putative inner ear cell types, we confirmed the expression of genes and proteins linked to sensorineural hearing loss. This approach using human inner ear organoids would allow for disease modeling of specific genetic inner ear pathologies in the sensory and nonsensory domains of the inner ear.

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Section: Generation Of An Atlas Of Fetal and Adult Human Inner Ear Ti...mentioning

confidence: 62%

A Single-Cell Level Comparison of Human Inner Ear Organoids and the Human Cochlea and Vestibular Organs

Valk

Beelen

Steinhart

et al. 2022

Preprint

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“…A recent single-cell study revealed distinct central versus peripheral hair cell subpopulations in postnatal mouse cristae, reminiscent of the striolar and extrastriolar populations in the maculae (Wilkerson et al, 2021). As our zebrafish cristae hair cells also separate by the expression of cabp1b and cabp2b (Figure 6A), we performed SAMap analysis between the crista cell populations of the two species to investigate cell type homology.…”

Section: Resultsmentioning

confidence: 99%

“…We used the python package SAMap (v1.0.2)(Tarashansky et al, 2021) to correlate gene expression patterns and determine cell type homology between mouse utricle (GSE155966) (Jan et al, 2021) or crista (GSE168901) (Wilkerson et al, 2021) hair cells and supporting cells and our 12 mpf zebrafish inner ear scRNA-seq data. Zebrafish lateral line hair cell sc-RNA data (GSE123241) (Lush et al, 2019) was integrated with our 12 mpf inner ear data using Seurat in order to compare to mice.…”

Section: Methodsmentioning

confidence: 99%

Single-Cell Transcriptomic Profiling of the Zebrafish Inner Ear Reveals Molecularly Distinct Hair Cell and Supporting Cell Subtypes

Shi

Beaulieu

Saunders

et al. 2022

Preprint

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A major cause of human deafness and vestibular dysfunction is permanent loss of the mechanosensory hair cells of the inner ear. In non-mammalian vertebrates such as zebrafish, regeneration of missing hair cells can occur throughout life. While a comparative approach has the potential to reveal the basis of such differential regenerative ability, the degree to which the inner ears of fish and mammals share common hair cells and supporting cell types remains unresolved. Here we perform single-cell RNA sequencing of the zebrafish inner ear at embryonic through adult stages to catalog the diversity of hair cell and non-sensory supporting cells. We identify a putative progenitor population for hair cells and supporting cells, as well as distinct hair cells and supporting cell types in the maculae versus cristae. The hair cell and supporting cell types differ from those described for the lateral line system, a distributed mechanosensory organ in zebrafish in which most studies of hair cell regeneration have been conducted. In the maculae, we identify two subtypes of hair cells that share gene expression with mammalian striolar or extrastriolar hair cells. In situ hybridization reveals that these hair cell subtypes occupy distinct spatial domains within the two major macular organs, the utricle and saccule, consistent with the reported distinct electrophysiological properties of hair cells within these domains. These findings suggest that primitive specialization of spatially distinct striolar and extrastriolar hair cells likely arose in the last common ancestor of fish and mammals. The similarities of inner ear cell type composition between fish and mammals also support using zebrafish as a relevant model for understanding inner ear-specific hair cell function and regeneration.

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“…This branch of high-throughput methods has provided the field with valuable insight into cell type gene expression dynamics, intercellular communication, and tissue composition in NAFLD [ 60 ]. Importantly, single-cell RNA-seq (scRNA-seq) profiling does not require any biological pre-knowledge as individual cells are characterized independently of cellular tagging, which has facilitated the detection of novel and rare cell types across tissues [ 90 , 91 , 92 ]. Single cells can be profiled either as whole cells or nuclei ( Figure 2 A), and the different source of bias this might lead to (discussed above) also manifests here, emphasizing the importance of careful consideration of the experimental approach prior to conducting the analysis [ 58 ].…”

Section: Emerging Technologies To Analyze the Cis-regulatory Genome A...mentioning

confidence: 99%

Cell-Type Resolved Insights into the Cis-Regulatory Genome of NAFLD

Dam

Toft

Grøntved

2022

Cells

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The prevalence of non-alcoholic fatty liver disease (NAFLD) is increasing rapidly, and unmet treatment can result in the development of hepatitis, fibrosis, and liver failure. There are difficulties involved in diagnosing NAFLD early and for this reason there are challenges involved in its treatment. Furthermore, no drugs are currently approved to alleviate complications, a fact which highlights the need for further insight into disease mechanisms. NAFLD pathogenesis is associated with complex cellular changes, including hepatocyte steatosis, immune cell infiltration, endothelial dysfunction, hepatic stellate cell activation, and epithelial ductular reaction. Many of these cellular changes are controlled by dramatic changes in gene expression orchestrated by the cis-regulatory genome and associated transcription factors. Thus, to understand disease mechanisms, we need extensive insights into the gene regulatory mechanisms associated with tissue remodeling. Mapping cis-regulatory regions genome-wide is a step towards this objective and several current and emerging technologies allow detection of accessible chromatin and specific histone modifications in enriched cell populations of the liver, as well as in single cells. Here, we discuss recent insights into the cis-regulatory genome in NAFLD both at the organ-level and in specific cell populations of the liver. Moreover, we highlight emerging technologies that enable single-cell resolved analysis of the cis-regulatory genome of the liver.

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Novel cell types and developmental lineages revealed by single-cell RNA-seq analysis of the mouse crista ampullaris

Cited by 27 publications

References 114 publications

A Single-Cell Level Comparison of Human Inner Ear Organoids and the Human Cochlea and Vestibular Organs

A Single-Cell Level Comparison of Human Inner Ear Organoids and the Human Cochlea and Vestibular Organs

Single-Cell Transcriptomic Profiling of the Zebrafish Inner Ear Reveals Molecularly Distinct Hair Cell and Supporting Cell Subtypes

Cell-Type Resolved Insights into the Cis-Regulatory Genome of NAFLD

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