Transcriptome-wide comparison of the impact of Atoh1 and miR-183 family on pluripotent stem cells and multipotent otic progenitor cells.
Transcriptome-wide comparison of the impact of Atoh1 and miR-183 family on pluripotent stem cells and multipotent otic progenitor cells.
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DOI：
10.1371/journal.pone.0180855
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发表时间：
2017
期刊：
影响因子：
3.7
通讯作者：
Soukup GA
中科院分区：
文献类型：
--
作者：
Ebeid M;Sripal P;Pecka J;Beisel KW;Kwan K;Soukup GA
超过5%的全球人口患有由多种因素引起的致残性听力损失，包括衰老、噪声暴露、遗传易感性或使用耳毒性药物。感觉神经性听力损失通常是由内耳的感觉毛细胞(HC)的丧失引起的。HC丧失后听力恢复的一个障碍是哺乳动物听觉HC自发再生的能力有限。了解协调HC发展的分子机制有望促进细胞替代疗法。已知多种事件对HC的正常发育是必不可少的，包括Atoh1转录因子和miR-183家族的表达。我们已经开发了一系列表达miR-183家族和/或Atoh1的载体，用于转染两种不同的发育细胞模型：代表高级发育阶段的多能小鼠胚胎干细胞(MESCs)和永生化多能外周血祖细胞(IMOP)。对转基因细胞的转录组分析表明，Atoh1的影响与iMOP细胞上更多的HC特异性作用有关。MIR-183家族的表达与Atoh1的结合不仅似乎微调了有利于HC命运的基因表达，而且也是一些HC特异性基因表达所必需的。总体而言，这项工作为Atoh1和miR-183家族在HC发育过程中的联合作用提供了新的见解，最终可能为促进HC再生或维护的策略提供信息。
Over 5% of the global population suffers from disabling hearing loss caused by multiple factors including aging, noise exposure, genetic predisposition, or use of ototoxic drugs. Sensorineural hearing loss is often caused by the loss of sensory hair cells (HCs) of the inner ear. A barrier to hearing restoration after HC loss is the limited ability of mammalian auditory HCs to spontaneously regenerate. Understanding the molecular mechanisms orchestrating HC development is expected to facilitate cell replacement therapies. Multiple events are known to be essential for proper HC development including the expression of Atoh1 transcription factor and the miR-183 family. We have developed a series of vectors expressing the miR-183 family and/or Atoh1 that was used to transfect two different developmental cell models: pluripotent mouse embryonic stem cells (mESCs) and immortalized multipotent otic progenitor (iMOP) cells representing an advanced developmental stage. Transcriptome profiling of transfected cells show that the impact of Atoh1 is contextually dependent with more HC-specific effects on iMOP cells. miR-183 family expression in combination with Atoh1 not only appears to fine tune gene expression in favor of HC fate, but is also required for the expression of some HC-specific genes. Overall, the work provides novel insight into the combined role of Atoh1 and the miR-183 family during HC development that may ultimately inform strategies to promote HC regeneration or maintenance.
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