Molecular and Cellular Manifestations of Biological Aging of Cochlear Inner and Outer Hair Cells
Molecular and Cellular Manifestations of Biological Aging of Cochlear Inner and Outer Hair Cells
复制标题
耳蜗内外毛细胞生物衰老的分子和细胞表现
DOI：
10.2139/ssrn.3960259
复制
发表时间：
2021
期刊：
影响因子：
8.8
通讯作者：
David Z.Z. He
中科院分区：
文献类型：
--
作者：
Huizhan Liu;Kimberlee P Giffen;Lei Chen;Heidi J Henderson;Talia A. Cao;Grant A. Kozeny;Yi Li;David Z.Z. He
听力损失（ARHL）对老年人的生活质量产生负面影响。ARHL的普遍原因是机械敏感耳蜗毛细胞（HC）的损失。HC变性的分子和细胞机制仍然知之甚少。使用从年轻和老年小鼠分离的内部和外部HC的RNA-seq转录组学分析，我们表明HC衰老是由关键分子过程的变化驱动的，包括转录，DNA损伤/修复，炎症，自噬和氧化应激，以及与HC独特形态和功能相关的基因。在细胞水平上，HC老化的特征在于静纤毛的丧失、HC索马的收缩和外部HC机械性能的降低，这表明机械转导和耳蜗放大的功能下降是ARHL的基础，并且先于HC丧失。我们的研究揭示了老化HC的新分子和细胞学特征，鉴定了包括Foxo 3，Jund和Cbx 3在内的几种生物标志物，并提出了改善ARHL的潜在治疗靶点。
Age-related hearing loss (ARHL) negatively impacts quality of life in the elderly population. The prevalent cause of ARHL is loss of mechanosensitive cochlear hair cells (HCs). The molecular and cellular mechanisms of HC degeneration remain poorly understood. Using RNA-seq transcriptomic analysis of inner and outer HCs isolated from young and aged mice, we show that HC aging is driven by changes in key molecular processes, including transcription, DNA damage/repair, inflammation, autophagy, and oxidative stress, as well as genes related to HC unique morphology and function. At the cellular level, HC aging is characterized by loss of stereocilia, shrinkage of HC soma and reduction in outer HC mechanical properties, suggesting that functional decline in mechanotransduction and cochlear amplification underlie ARHL and precede HC loss. Our study reveals novel molecular and cytological profiles of aging HCs, identifies several biomarkers including Foxo3, Jund and Cbx3 , and suggests potential therapeutic targets for ameliorating ARHL.