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Spatially distinct otic mesenchyme cells show molecular and functional heterogeneity patterns before hearing onset.

ABSTRACT: The cochlea consists of diverse cellular populations working in harmony to convert mechanical stimuli into electrical signals for the perception of sound. Otic mesenchyme cells (OMCs), often considered a homogeneous cell type, are essential for normal cochlear development and hearing. Despite being the most numerous cell type in the developing cochlea, OMCs are poorly understood. OMCs are known to differentiate into spatially and functionally distinct cell types, including fibrocytes of the lateral wall and spiral limbus, modiolar osteoblasts, and specialized tympanic border cells of the basilar membrane. Here, we show that OMCs are transcriptionally and functionally heterogeneous and can be divided into four distinct populations that spatially correspond to OMC-derived cochlear structures. We also show that this heterogeneity and complexity of OMCs commences during early phases of cochlear development. Finally, we describe the cell-cell communication network of the developing cochlea, inferring a major role for OMC in outgoing signaling.

SUBMITTER: Rose KP

PROVIDER: S-EPMC10502415 | biostudies-literature | 2023 Oct

REPOSITORIES: biostudies-literature

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Spatially distinct otic mesenchyme cells show molecular and functional heterogeneity patterns before hearing onset.

Rose Kevin P KP Manilla Gabriella G Milon Beatrice B Zalzman Ori O Song Yang Y Coate Thomas M TM Hertzano Ronna R

iScience 20230829 10

The cochlea consists of diverse cellular populations working in harmony to convert mechanical stimuli into electrical signals for the perception of sound. Otic mesenchyme cells (OMCs), often considered a homogeneous cell type, are essential for normal cochlear development and hearing. Despite being the most numerous cell type in the developing cochlea, OMCs are poorly understood. OMCs are known to differentiate into spatially and functionally distinct cell types, including fibrocytes of the late ...[more]

PMID: 37720106

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Project description:BackgroundIdiopathic pulmonary fibrosis (IPF) is a heterogeneous disease that is pathologically characterized by areas of normal-appearing lung parenchyma, active fibrosis (transition zones including fibroblastic foci) and dense fibrosis. Defining transcriptional differences between these pathologically heterogeneous regions of the IPF lung is critical to understanding the distribution and extent of fibrotic lung disease and identifying potential therapeutic targets. Application of a spatial transcriptomics platform would provide more detailed spatial resolution of transcriptional signals compared to previous single cell or bulk RNA-Seq studies.MethodsWe performed spatial transcriptomics using GeoMx Nanostring Digital Spatial Profiling on formalin-fixed paraffin-embedded (FFPE) tissue from 32 IPF and 12 control subjects and identified 231 regions of interest (ROIs). We compared normal-appearing lung parenchyma and airways between IPF and controls with histologically normal lung tissue, as well as histologically distinct regions within IPF (normal-appearing lung parenchyma, transition zones containing fibroblastic foci, areas of dense fibrosis, and honeycomb epithelium metaplasia).ResultsWe identified 254 differentially expressed genes (DEGs) between IPF and controls in histologically normal-appearing regions of lung parenchyma; pathway analysis identified disease processes such as EIF2 signaling (important for cap-dependent mRNA translation), epithelial adherens junction signaling, HIF1α signaling, and integrin signaling. Within IPF, we identified 173 DEGs between transition and normal-appearing lung parenchyma and 198 DEGs between dense fibrosis and normal lung parenchyma; pathways dysregulated in both transition and dense fibrotic areas include EIF2 signaling pathway activation (upstream of endoplasmic reticulum (ER) stress proteins ATF4 and CHOP) and wound healing signaling pathway deactivation. Through cell deconvolution of transcriptome data and immunofluorescence staining, we confirmed loss of alveolar parenchymal signals (AGER, SFTPB, SFTPC), gain of secretory cell markers (SCGB3A2, MUC5B) as well as dysregulation of the upstream regulator ATF4, in histologically normal-appearing tissue in IPF.ConclusionsOur findings demonstrate that histologically normal-appearing regions from the IPF lung are transcriptionally distinct when compared to similar lung tissue from controls with histologically normal lung tissue, and that transition zones and areas of dense fibrosis within the IPF lung demonstrate activation of ER stress and deactivation of wound healing pathways.

Dataset Information

Spatially distinct otic mesenchyme cells show molecular and functional heterogeneity patterns before hearing onset.

Publications

Spatially distinct otic mesenchyme cells show molecular and functional heterogeneity patterns before hearing onset.

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