Hair cell regeneration after ATOH1 gene therapy in the cochlea of profoundly deaf adult guinea pigs.
Hair cell regeneration after ATOH1 gene therapy in the cochlea of profoundly deaf adult guinea pigs.
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DOI：
10.1371/journal.pone.0102077
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发表时间：
2014
期刊：
影响因子：
3.7
通讯作者：
Richardson RT
中科院分区：
文献类型：
--
作者：
Atkinson PJ;Wise AK;Flynn BO;Nayagam BA;Richardson RT
哺乳动物耳蜗毛细胞的退化导致永久性感音神经性听力丧失。本研究旨在通过引入已知毛细胞发育必需的转录因子ATOH1和神经营养因子，促进成熟耳蜗感觉毛细胞的再生及其与听觉神经元的重新连接。在耳毒性耳聋后4天，将单独含有ATOH1或同时含有神经营养因子-3和脑源性神经营养因子的腺病毒载体注射到豚鼠耳蜗下部基底介质中。单独接受ATOH1基因治疗的豚鼠在治疗3周后接受检查时，与未接受治疗的对侧耳蜗相比，表达毛细胞标记物的细胞数量显著增加。然而，这种增加并没有导致听力阈值的相应改善，也没有突触带的增加，这是单独使用ATOH1治疗或与神经营养素联合使用时通过CtBP2点测量的。然而，与ATOH1和神经营养因子共同处理后的毛细胞形成和突触发生仍然不确定，因为当样品组合时，病毒滴度减半，病毒转导减少。总的来说，这些数据表明，虽然ATOH1单独可以驱动成熟耳蜗中的非感觉细胞向未成熟的感觉毛细胞表型发展，但这不会导致氨基糖苷性耳聋后的功能改善。
The degeneration of hair cells in the mammalian cochlea results in permanent sensorineural hearing loss. This study aimed to promote the regeneration of sensory hair cells in the mature cochlea and their reconnection with auditory neurons through the introduction of ATOH1, a transcription factor known to be necessary for hair cell development, and the introduction of neurotrophic factors. Adenoviral vectors containing ATOH1 alone, or with neurotrophin-3 and brain derived neurotrophic factor were injected into the lower basal scala media of guinea pig cochleae four days post ototoxic deafening. Guinea pigs treated with ATOH1 gene therapy, alone, had a significantly greater number of cells expressing hair cell markers compared to the contralateral non-treated cochlea when examined 3 weeks post-treatment. This increase, however, did not result in a commensurate improvement in hearing thresholds, nor was there an increase in synaptic ribbons, as measured by CtBP2 puncta after ATOH1 treatment alone, or when combined with neurotrophins. However, hair cell formation and synaptogenesis after co-treatment with ATOH1 and neurotrophic factors remain inconclusive as viral transduction was reduced due to the halving of viral titres when the samples were combined. Collectively, these data suggest that, whilst ATOH1 alone can drive non-sensory cells towards an immature sensory hair cell phenotype in the mature cochlea, this does not result in functional improvements after aminoglycoside-induced deafness.
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影响因子：
16.2
作者：
Mizutari K;Fujioka M;Hosoya M;Bramhall N;Okano HJ;Okano H;Edge AS
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