Nelson Lacey, Lovett Braeden, Johns J Dixon, Gu Shoujun, Choi Dongseok, Trune Dennis, Hoa Michael
Department of Otolaryngology-Head and Neck Surgery, Georgetown University School of Medicine, Washington, DC, United States.
Auditory Development and Restoration Program, NIDCD Otolaryngology Surgeon-Scientist Program, Division of Intramural Research, NIDCD/NIH, Bethesda, MD, United States.
Front Neurol. 2022 Jan 25;12:818157. doi: 10.3389/fneur.2021.818157. eCollection 2021.
Treatment of many types of hearing instability in humans, including sudden sensorineural hearing loss, Meniere's disease, and autoimmune inner ear disease, rely heavily on the utilization of corticosteroids delivered both by oral and transtympanic routes. Despite this use, there is heterogeneity in the response to treatment with corticosteroids in humans with these diseases. The mechanisms by which corticosteroids exert their effect and the cell types in which they exert their effects in the inner ear remain poorly characterized. In this study, we localize steroid-responsive genes to cochlear cell types using previously published transcriptome datasets from the mammalian cochlea.
Steroid-responsive genes were localized to specific cochlear cell types using existing transcriptome datasets from wild-type mammalian cochlea exposed to systemic and transtympanic steroids, as well as previously published single-cell and single-nucleus RNA-sequencing datasets from the mammalian cochlea. Gene ontology (GO) analysis of differentially expressed genes (DEGs) was performed using PANTHER to investigate cellular processes implicated in transtympanic vs. systemic steroid action in the cochlea.
Steroid-responsive genes were localized to specific cell types and regions in the cochlea including the stria vascularis, organ of Corti, and spiral ganglion neurons (SGN). Analyses demonstrate differential prevalence of steroid-responsive genes. GO analysis demonstrated steroid-responsive DEGs in the SGN to be associated with angiogenesis, apoptosis, and cytokine-mediated anti-inflammatory pathways.
Single-cell and single-nucleus transcriptome datasets localize steroid-responsive genes to specific regions in the cochlea. Further study of these regionally-specific steroid-responsive genes may provide insight into the mechanisms of and clinical response to corticosteroids in diseases of hearing instability.
多种类型的人类听力不稳定疾病的治疗，包括突发性感音神经性听力损失、梅尼埃病和自身免疫性内耳疾病，严重依赖于口服和经鼓膜途径给予的皮质类固醇。尽管有这种应用，但这些疾病患者对皮质类固醇治疗的反应存在异质性。皮质类固醇发挥作用的机制以及它们在内耳中发挥作用的细胞类型仍未得到充分表征。在本研究中，我们利用先前发表的哺乳动物耳蜗转录组数据集，将类固醇反应基因定位到耳蜗细胞类型。
利用来自暴露于全身和经鼓膜类固醇的野生型哺乳动物耳蜗的现有转录组数据集，以及先前发表的来自哺乳动物耳蜗的单细胞和单细胞核RNA测序数据集，将类固醇反应基因定位到特定的耳蜗细胞类型。使用PANTHER对差异表达基因（DEG）进行基因本体（GO）分析，以研究耳蜗中经鼓膜与全身类固醇作用相关的细胞过程。
类固醇反应基因定位于耳蜗的特定细胞类型和区域，包括血管纹、柯蒂氏器和螺旋神经节神经元（SGN）。分析表明类固醇反应基因的分布存在差异。GO分析表明，SGN中的类固醇反应性DEG与血管生成、细胞凋亡和细胞因子介导的抗炎途径相关。
单细胞和单细胞核转录组数据集将类固醇反应基因定位到耳蜗的特定区域。对这些区域特异性类固醇反应基因的进一步研究可能有助于深入了解听力不稳定疾病中皮质类固醇的作用机制和临床反应。
