耳蜗衰老的时间分辨单核图谱揭示双相炎性衰老及Tbx2依赖的内毛细胞维持
A time-resolved single-nucleus atlas of cochlear aging reveals biphasic inflammaging and Tbx2-dependent inner hair cell maintenance.
文献信息
| PMID | 42987443 |
|---|---|
| 原文 | 在 PubMed 查看原文 ↗ |
| 发表日期 | 2026 |
| 作者 | He Zhao |
| 作者单位 | Department of Otorhinolaryngology, Head and Neck Surgery, Yantai Yuhuangding Hospital, Qingdao University, Yantai 264000, Shandong, China; Shandong Provincial Key Laboratory of Neuroimmune Interaction and Regulation, Yantai 264000, Shandong, China; Shandong Provincial Clinical Research Center for Otorhinolaryngologic Diseases, Yantai 264000, Shandong, China; Shandong Engineering Research Center for Precision Diagnosis and Treatment of Airway Diseases, Yantai 264000, Shandong, China; Yantai Key Laboratory of Otorhinolaryngologic Diseases, Yantai 264000, Shandong, China; Yantai Clinical Research Center for Otorhinolaryngologic Diseases, Yantai 264000, Shandong, China. |
| 期刊 | Hearing research |
| SCI 分区 | Q1 |
| IF | 3.2 |
| 研究类型 | 基础研究 · 基础／转化 |
| 所属专科 | 耳科 |
中文摘要
背景： 年龄相关性听力损失（ARHL）是老年人中最常见的感觉缺陷，但其分子进展仍不清楚。很少有耳蜗单细胞研究将细胞间通讯、基因调控网络（GRN）重建和跨队列bulk验证整合到一个时间框架中。
方法： 我们重新分析了C57BL/6 J小鼠耳蜗在3、12和24月龄时公开可用的单核RNA测序数据，并与两个独立的bulk微阵列队列进行交叉验证。推断配体-受体相互作用，并在配体表达水平上进行验证。重建GRN并进行计算机模拟扰动；特征选择提取了跨尺度炎症特征。
结果： ARHL并不遵循线性下降。全耳蜗I型干扰素反应在12月龄达到峰值，并在24月龄消退。载脂蛋白E在螺旋神经节神经元、内毛细胞（IHC）、巨噬细胞和纤维细胞中遵循三阶段轨迹：基线、代偿性上调、崩溃。SLIT-ROBO轴突导向信号在这些细胞中关闭，同时伴随神经营养和Notch信号撤退。计算机模拟扰动确定T-box转录因子2（Tbx2）为保护性GRN节点：敲除使81.2%的IHC向衰老方向驱动，过表达使74.6%向年轻方向驱动。一个13基因炎症面板显示巨噬细胞中年激活和终末期耗竭，与干扰素峰值相呼应。
结论： 这些发现支持两阶段ARHL模型，即中年免疫激活随后终末期突触、脂质和轴突导向崩溃，将中年窗口和Tbx2依赖的IHC维持定位为候选干预靶点，尚待体内验证。
英文摘要
BACKGROUND: Age-related hearing loss (ARHL) is the most prevalent sensory deficit in older adults, yet its molecular progression remains poorly resolved. Few cochlear single-cell studies have integrated cell-cell communication, gene regulatory network (GRN) reconstruction, and cross-cohort bulk validation into one temporal framework.
METHODS: We reanalyzed publicly available single-nucleus RNA sequencing data from C57BL/6 J mouse cochleae at 3, 12, and 24 months and cross-validated against two independent bulk microarray cohorts. Ligand-receptor interactions were inferred and validated at the ligand-expression level. GRNs were reconstructed and perturbed in silico; and feature selection extracted cross-scale inflammatory features.
RESULTS: ARHL did not follow a linear decline. A cochlea-wide type I interferon response peaked at 12 months and resolved by 24. Apolipoprotein E followed a three-phase trajectory, baseline, compensatory upregulation, collapse, across spiral ganglion neurons, inner hair cells (IHCs), macrophages, and fibrocytes. SLIT-ROBO axon-guidance signaling shut down in these cells, alongside neurotrophic and Notch withdrawal. In silico perturbation identified T-box transcription factor 2 (Tbx2) as a protective GRN node: knockout drove 81.2% of IHCs toward aging and overexpression 74.6% toward youth. A 13-gene inflammatory panel showed midlife activation and end-stage exhaustion in macrophages, mirroring the interferon peak.
CONCLUSION: These findings support a two-stage ARHL model, midlife immune activation followed by end-stage synaptic, lipid, and axon-guidance collapse, positioning the midlife window and Tbx2-dependent IHC maintenance as candidate intervention targets, pending in vivo validation.