Single-nucleus profiling of mouse inner ear aging uncovers cell type heterogeneity and hair cell subtype-specific age-related signatures

Mingyu Xia; Feng Zhang; Jiaoyao Ma; Yunjie Li; Gaogan Jia; Mingxuan Wu; Yiyun Lou; Yaoqian Liu; Lingjie Li; Huawei Li; Wenyan Li

doi:10.1016/j.celrep.2025.115781

Single-nucleus profiling of mouse inner ear aging uncovers cell type heterogeneity and hair cell subtype-specific age-related signatures

Cell Rep. 2025 Jun 24;44(6):115781. doi: 10.1016/j.celrep.2025.115781. Epub 2025 May 28.

Authors

Mingyu Xia¹, Feng Zhang², Jiaoyao Ma³, Yunjie Li³, Gaogan Jia³, Mingxuan Wu³, Yiyun Lou³, Yaoqian Liu³, Lingjie Li⁴, Huawei Li⁵, Wenyan Li⁶

Affiliations

¹ ENT Institute and Otorhinolaryngology Department of Eye & ENT Hospital, State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Fudan University, Shanghai 200031, China; Institutes of Biomedical Sciences, Fudan University, Shanghai 200032, China; NHC Key Laboratory of Hearing Medicine, Fudan University, Shanghai 200031, China.
² Digital Technologies, Hainan Bielefeld University of Applied Sciences, Hainan 572400, China.
³ ENT Institute and Otorhinolaryngology Department of Eye & ENT Hospital, State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Fudan University, Shanghai 200031, China; Institutes of Biomedical Sciences, Fudan University, Shanghai 200032, China.
⁴ Department of Histoembryology, Genetics and Developmental Biology, Shanghai Key Laboratory of Reproductive Medicine, Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China. Electronic address: lingjie@shsmu.edu.cn.
⁵ ENT Institute and Otorhinolaryngology Department of Eye & ENT Hospital, State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Fudan University, Shanghai 200031, China; Institutes of Biomedical Sciences, Fudan University, Shanghai 200032, China; NHC Key Laboratory of Hearing Medicine, Fudan University, Shanghai 200031, China; The Institutes of Brain Science and the Collaborative Innovation Center for Brain Science, Fudan University, Shanghai 200032, China; Shanghai Engineering Research Centre of Cochlear Implant, Shanghai 200031, China. Electronic address: hwli@shmu.edu.cn.
⁶ ENT Institute and Otorhinolaryngology Department of Eye & ENT Hospital, State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Fudan University, Shanghai 200031, China; Institutes of Biomedical Sciences, Fudan University, Shanghai 200032, China; NHC Key Laboratory of Hearing Medicine, Fudan University, Shanghai 200031, China; The Institutes of Brain Science and the Collaborative Innovation Center for Brain Science, Fudan University, Shanghai 200032, China; Shanghai Engineering Research Centre of Cochlear Implant, Shanghai 200031, China. Electronic address: wenyan_li@fudan.edu.cn.

PMID: 40440168
DOI: 10.1016/j.celrep.2025.115781

Abstract

Degeneration of the auditory and vestibular hair cells (HCs) leads to dysfunction of two essential senses: hearing loss and decompensated balance perception. However, the cellular and molecular mechanisms governing inner ear aging and its link to dysfunctions of sensory HCs remain unclear. Here, we constructed an aging-associated cell atlas of cochlear and utricular tissues in C57BL/6J mice through single-nucleus RNA sequencing, revealing transcriptionally distinct hair cell subtypes and spatially restricted molecular markers that delineate specific cellular populations. We uncovered activation of macrophages and shaped inflamed niches in the aged inner ear. Furthermore, we demonstrated the cell type-specific signatures of aging between the two organs, with focused characterization in six HC subtypes uncovering core mechanisms like dysregulated RNA splicing underlying degeneration. Crucially, suppressing RNA splicing factor Rbm25 abolished inflammation-induced HC deterioration. Our study reveals complex, multifactorial mechanisms that underlie inner ear aging and offer potential targets for preventing HC degeneration.

Keywords: CP: Cell biology; CP: Molecular biology; RNA splicing; aging; hair cell; inflammation; inner ear.

MeSH terms

Aging* / genetics
Aging* / metabolism
Animals
Cell Nucleus* / metabolism
Ear, Inner* / metabolism
Ear, Inner* / pathology
Hair Cells, Auditory* / metabolism
Macrophages / metabolism
Mice
Mice, Inbred C57BL
RNA-Binding Proteins / genetics
RNA-Binding Proteins / metabolism
Single-Cell Analysis

Substances

RNA-Binding Proteins