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Conditional Overexpression of Serpine2 Promotes Hair Cell Regeneration from Lgr5+ Progenitors in the Neonatal Mouse Cochlea

ABSTRACT: Conditional Overexpression of Serpine2 Promotes Hair Cell Regeneration from Lgr5+ Progenitors in the Neonatal Mouse Cochlea

PROVIDER: PRJNA1223354 | ENA |

REPOSITORIES: ENA

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Conditional Overexpression of Serpine2 Promotes Hair Cell Regeneration from Lgr5+ Progenitors in the Neonatal Mouse Cochlea

Project description:Neonatal cochlear Lgr5+ progenitors can regenerate hair cells (HCs), and this process is regulated by several genes and signaling pathways. However, this regeneration ability is limited, and whether additional genes are involved in this process remains unknown. Serpine2 was shown to participate in regulating proliferation and differentiation of cochlear Lgr5+ progenitors in our previous in vitro study. Here, we explored the expression pattern and in vivo roles of Serpine2 in HC regeneration by constructing transgenic mice in which Serpine2 is conditionally overexpressed in cochlear Lgr5+ progenitors. We found that Serpine2 is expressed in the mouse cochlea after birth with a downward trend as the mice aged. In addition, Serpine2 conditional overexpression in vivo in Lgr5+ progenitors of neonatal mice cochlea resulted in an increase number of ectopic HCs in a dose-dependent manner. And Serpine2 knockdown ex vivo and in vivo can inhibit HC regeneration. EdU assay and lineage tracing assay demonstrated that these ectopic HCs likely originated from Lgr5+ progenitors through direct trans-differentiation rather than through mitotic regeneration. Moreover, snRNA-seq analysis and RT-qPCR results revealed that Serpine2 cOE likely induces HC regeneration via inhibiting sonic hedgehog (SHH) signal pathway and inducing Atoh1 and Pou4f3 transcription factor. In brief, our data indicate that Serpine2 plays a pivotal role in HC regeneration from Lgr5+ progenitors in the neonatal mouse cochlea, and this suggests a new avenue for future research into HC regeneration.

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Characterization of Lgr6+ Cells as an Enriched Population of Hair Cell Progenitors Compared to Lgr5+ Cells for Hair Cell Generation in the Neonatal Mouse Cochlea

Project description:Characterization of Lgr6+ Cells as an Enriched Population of Hair Cell Progenitors Compared to Lgr5+ Cells for Hair Cell Generation in the Neonatal Mouse Cochlea

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ChIP-seq Analysis for H3K4me3 in Neomycin-induced Lgr5+ Progenitor Cells of Neonatal Mouse Cochlea

Project description:ChIP-seq Analysis for H3K4me3 in Neomycin-induced Lgr5+ Progenitor Cells of Neonatal Mouse Cochlea

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Characterization of Lgr6+ Cells as an Enriched Population of Hair Cell Progenitors Compared to Lgr5+ Cells for Hair Cell Generation in the Neonatal Mouse Cochlea

Project description:Our previous studies showed that Lgr6+ cells are a subpopulation of Lgr5+ progenitor cells and that both Lgr6+ and Lgr5+ progenitors can regenerate Myosin7a+ HCs in vitro. Thus we hypothesized that Lgr6+ cells are an enriched population of cochlear progenitor cells. However, the detailed distinctions between the Lgr5+ and Lgr6+ progenitors have not been researched. Here, we systematically compared the proliferation, HC differentiation, and detailed transcriptome expression profiles of these two progenitor populations. We found that when isolated by flow cytometry, the same number of Lgr6+ progenitors generated significantly more Myosin7a+ HCs than Lgr5+ progenitors; however, Lgr5+ progenitors formed more epithelial colonies and more spheres than Lgr6+ progenitors in vitro. Using RNA-Seq, we compared the transcriptome differences between Lgr5+ and Lgr6+ progenitors and identified a list of significantly differential expressed genes which may regulate the proliferation and differentiation of these HC progenitors.

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Expression of Atoh1, Gfi1, and Pou4f3 in the mature cochlea reprograms non-sensory cells into hair cells

Project description:Mechanosensory hair cells of the mature mammalian organ of Corti do not regenerate, and loss of hair cells leads to permanent hearing loss. Although non-mammalian vertebrates are able to regenerate hair cells by the division and transdifferentiation of adjacent supporting cells, many humans with severe hearing loss completely lack hair cells and supporting cells, with the organ of Corti being replaced by a flat epithelium of non-sensory cells To determine if mature non-sensory cells can produce hair cells in vivo, we reprogrammed non-sensory cells of the mature cochlea with three hair cell transcription factors, Gfi1, Atoh1, and Pou4f3. We were able to generate significant numbers of hair cell-like cells in the non-sensory inner and outer sulci of the cochlea after 2 weeks of reprogramming. New hair cells continued to be added to the non-sensory regions of the cochlea over the next seven weeks, and expressed hair cell proteins such as Myosin VIIa, parvalbumin, and prestin and formed stereociliary hair bundles. We confirmed the identity of these cells by high depth single cell RNA-seq. Significantly, cells adjacent to converted hair cells expressed markers of supporting cells, suggesting that transcription factor reprogramming of non-sensory tissue in the adult animal can generate mosaics of sensory cells similar to those seen in the organ of Corti. Generating such sensory mosaics by reprogramming may represent a potential strategy for hearing restoration in humans.

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LGR5 is a conserved marker of hair follicle stem cells across species

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Gene expression profiles along the tonotopic axis of the mouse cochlea during neonatal development

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RNA-seq analysis of neonatal mouse cochlear hair cells

Project description:This study examined transcripts that are enriched in neonatal mouse cochlear hair cells. Hair cells were purified by FACS sorting for GFP fluorescence from the cochleas of transgenic mice in which the endogenous Atoh1 gene was fused with GFP Two replicates of GFP+ hair cells were compared with all other cochlear cell types that were GFP-

2015-03-01 | E-GEOD-65633 | biostudies-arrayexpress

Gene expression profiles along the tonotopic axis of the mouse cochlea during neonatal development

Project description:The cochlear duct is tonotopically organized, such that the basal cochlea responds more sensitively to high frequency sounds and the apical cochlea to low frequency sounds. In effort to understand how the tonotopic organization is established in mammals, we searched for genes that are differentially expressed along the tonotopic axis during neonatal development. Eighty temporal bones were dissected from C57BL/6 mice at P0 and P8. The cochlear tissues were divided into three equal pieces representing the basal, middle and apical turns, and pooled separately. Six total RNA from the pooled samples were applied to 6 GeneChips.

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RNA-seq analysis of neonatal mouse cochlear hair cells

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