MiR-210 promotes sensory hair cell formation in the organ of corti.
MiR-210 promotes sensory hair cell formation in the organ of corti.
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DOI：
10.1186/s12864-016-2620-7
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发表时间：
2016-04-27
期刊：
影响因子：
4.4
通讯作者：
Kinzel B
中科院分区：
文献类型：
--
作者：
Riccardi S;Bergling S;Sigoillot F;Beibel M;Werner A;Leighton-Davies J;Knehr J;Bouwmeester T;Parker CN;Roma G;Kinzel B
听力损失是最常见的感觉缺陷，困扰着全世界数亿人。在大多数情况下，无论最初的原因是什么，听力损失都与毛细胞及其相关的螺旋神经节神经元的变性和死亡有关。尽管有这些知识，但相对较少的研究报道了听觉系统的再生。我们对听觉功能的分子机制的理解仍然存在重大差距，包括感觉细胞再生所需的因素。最近，毛细胞命运的转录激活因子和抑制因子的鉴定已经被与听力损失相关的microRNA（miRNAs）的发现所增强。由于miRNAs是分化和细胞命运的主要参与者，因此miRNAs及其基因靶点的鉴定可能揭示毛细胞再生的新途径，从而为治疗听力损失提供新途径。为了鉴定能够使内耳感觉毛细胞再生的新遗传元件，使用下一代miRNA测序（miRSeq）来鉴定小鼠胚胎内耳细胞系UB/OC-1在向毛细胞样表型分化期间表达的最主要的miRNA。基于这些miRSeq结果，选择8种差异表达最多的miRNA用于进一步表征。在UB/OC-1中，miR-210的体外沉默导致毛细胞标志物表达，而miR-210的异位表达导致耳蜗外植体中新毛细胞形成。使用谱系追踪小鼠模型，支持上皮细胞的转分化被鉴定为这种新毛细胞形成的可能机制。潜在的miR-210靶标通过计算机模拟预测，并使用miR-陷阱方法进行实验验证。MiRSeq随后的离体验证揭示了miR-210是驱动支持上皮细胞向感觉毛细胞转分化的新因子，这表明miR-210可能是听力损失治疗的潜在新因子。此外，对miR-210调控的内耳通路的鉴定确定了治疗听力损失的潜在新药靶点。本文的在线版本（doi：10.1186/s12864-016-2620-7）包含补充材料，可供授权用户使用。
Hearing loss is the most common sensory defect afflicting several hundred million people worldwide. In most cases, regardless of the original cause, hearing loss is related to the degeneration and death of hair cells and their associated spiral ganglion neurons. Despite this knowledge, relatively few studies have reported regeneration of the auditory system. Significant gaps remain in our understanding of the molecular mechanisms underpinning auditory function, including the factors required for sensory cell regeneration. Recently, the identification of transcriptional activators and repressors of hair cell fate has been augmented by the discovery of microRNAs (miRNAs) associated with hearing loss. As miRNAs are central players of differentiation and cell fate, identification of miRNAs and their gene targets may reveal new pathways for hair cell regeneration, thereby providing new avenues for the treatment of hearing loss. In order to identify new genetic elements enabling regeneration of inner ear sensory hair cells, next-generation miRNA sequencing (miRSeq) was used to identify the most prominent miRNAs expressed in the mouse embryonic inner ear cell line UB/OC-1 during differentiation towards a hair cell like phenotype. Based on these miRSeq results eight most differentially expressed miRNAs were selected for further characterization. In UB/OC-1, miR-210 silencing in vitro resulted in hair cell marker expression, whereas ectopic expression of miR-210 resulted in new hair cell formation in cochlear explants. Using a lineage tracing mouse model, transdifferentiation of supporting epithelial cells was identified as the likely mechanism for this new hair cell formation. Potential miR-210 targets were predicted in silico and validated experimentally using a miR-trap approach. MiRSeq followed by ex vivo validation revealed miR-210 as a novel factor driving transdifferentiation of supporting epithelial cells to sensory hair cells suggesting that miR-210 might be a potential new factor for hearing loss therapy. In addition, identification of inner ear pathways regulated by miR-210 identified potential new drug targets for the treatment of hearing loss. The online version of this article (doi:10.1186/s12864-016-2620-7) contains supplementary material, which is available to authorized users.