Abstract

The vestibular sensory epithelium of humans and mice may degenerate into a layer of flat cells, known as flat epithelium (FE), after a severe lesion. However, the pathogenesis of vestibular FE remains unclear. To determine whether the epithelial–mesenchymal transition (EMT) participates in the formation of vestibular FE, we used a well-established mouse model in which FE was induced in the utricle by an injection of streptomycin into the inner ear. The mesenchymal and epithelial cell markers and cell proliferation were examined using immunofluorescence staining and quantitative reverse transcription polymerase chain reaction (qRT-PCR). The function of the EMT was assessed through transcriptome microarray analysis. The results demonstrated that mesenchymal cell markers (α-SMA, S100A4, vimentin, and Fn1) were upregulated in vestibular FE compared with the normal utricle. Robust cell proliferation, which was absent in the normal status, was observed in the formation of FE. Microarray analysis identified 1,227 upregulated and 962 downregulated genes in vestibular FE. Gene Ontology (GO) analysis revealed that differentially expressed genes (DEGs) were highly associated with several EMT-related GO terms, such as cell adhesion, cell migration, and extracellular matrix. Pathway enrichment analysis revealed that DEGs were enriched in the EMT-related signaling pathways, including extracellular matrix (ECM)-receptor interaction, focal adhesion, PI3K/Akt signaling pathway and cell adhesion molecule. Protein–protein interaction networks screened 20 hub genes, which were Akt, Casp3, Col1a1, Col1a2, Fn1, Hgf, Igf1,Il1b, Irs1, Itga2, Itga5, Jun, Mapk1, Myc, Nras, Pdgfrb, Tgfb1, Thbs1, Trp53, and Col2a1. Most of these genes are reportedly involved in the EMT process in various tissues. The mRNA expression level of hub genes was validated using qRT-PCR. In conclusion, the present study indicates that EMT plays a significant role in the formation of vestibular FE and provides an overview of transcriptome characteristics in vestibular FE.

Highlights

  • Vestibular end organs, including the utricle, saccule, and cristae ampullae, are responsible for the perception of linear acceleration and head rotation

  • Epithelial cell marker ZO-1 was significantly expressed in the normal samples but weakly expressed in flat epithelium (FE) (Figures 1E–F )

  • The present study results revealed that mesenchymal cell markers (α-SMA, S100A4, vimentin, and fibronectin 1 (Fn1)) were upregulated, and robust cell proliferation was detected, during the formation of vestibular FE

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Summary

Introduction

Vestibular end organs, including the utricle, saccule, and cristae ampullae, are responsible for the perception of linear acceleration and head rotation. Various insults to the vestibular sensory epithelium could lead to vestibular dysfunction (McCall et al, 2009; Wang et al, 2015; Brosel et al, 2016; Isgrig et al, 2017; You et al, 2018; Zhang et al, 2020; Fu et al, 2021). Severe lesions damage both vestibular HCs and SCs and induce the sensory epithelium to be replaced by a layer of flat cells, referred to as flat epithelium (FE) (Wang et al, 2017). Elucidation of the molecular mechanism underlying FE formation is significant for designing therapeutic strategies for vestibular dysfunction

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