miR-431 secreted by human vestibular schwannomas increases the mammalian inner ear's vulnerability to noise trauma.
miR-431 secreted by human vestibular schwannomas increases the mammalian inner ear's vulnerability to noise trauma.
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DOI：
10.3389/fneur.2023.1268359
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发表时间：
2023
影响因子：
3.4
通讯作者：
中科院分区：
文献类型：
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前庭神经鞘瘤是一种发生于第八颅神经前庭分支的颅内肿瘤，通常表现为感音神经性听力损失。据推测，这种SNHL的机制涉及由VS分泌的细胞外囊泡（EV）的遗传货物介导的内耳微环境的改变。我们的目的是确定与听力差相关的EV货物，并确定其交付是否导致体内小鼠模型的听力损失和耳蜗损伤。VS组织是从术前听力好（VS-GH）或差（VS-PH）的患者常规切除的肿瘤中收集的，通过纯音平均值和单词识别评分进行测量。对从培养的原代人VS细胞和来自VS条件培养基的EV分离的RNA进行下一代测序，根据患者的听力能力分层。比较VS-PH和VS-GH样品之间的微小RNA表达水平，以鉴定差异表达的候选物，用于包装到合成的腺相关病毒载体（Anc 80 L 65）中。将含有候选microRNA的病毒载体注入小鼠的半规管，以评估对听力的影响，包括噪音暴露后。差异表达的microRNA包括hsa-miR-431- 5 p（在VS-PH中富集）和hsa-miR-192- 5 p（在VS-GH中富集）。接受过表达hsa-miR-431-GFP、hsa-miR-192-GFP或仅GFP（对照）的病毒载体脑内注射的新生小鼠在注射后6周具有相似的听力。然而，在声创伤后，miR-431组显示出比对照组显著更差的听力，以及在声创伤耳蜗区域中每个内毛细胞的突触带的更大损失。我们的研究结果表明，miR-431有助于耳蜗应力后VS相关的听力损失。需要进一步研究以确定miR-431是否是SNHL的潜在治疗靶点。
Vestibular schwannoma (VS) is an intracranial tumor that arises on the vestibular branch of cranial nerve VIII and typically presents with sensorineural hearing loss (SNHL). The mechanisms of this SNHL are postulated to involve alterations in the inner ear’s microenvironment mediated by the genetic cargo of VS-secreted extracellular vesicles (EVs). We aimed to identify the EV cargo associated with poor hearing and determine whether its delivery caused hearing loss and cochlear damage in a mouse model in vivo. VS tissue was collected from routinely resected tumors of patients with good (VS-GH) or poor (VS-PH) pre-surgical hearing measured via pure-tone average and word recognition scores. Next-generation sequencing was performed on RNA isolated from cultured primary human VS cells and EVs from VS-conditioned media, stratified by patients’ hearing ability. microRNA expression levels were compared between VS-PH and VS-GH samples to identify differentially expressed candidates for packaging into a synthetic adeno-associated viral vector (Anc80L65). Viral vectors containing candidate microRNA were infused to the semicircular canals of mice to evaluate the effects on hearing, including after noise exposure. Differentially expressed microRNAs included hsa-miR-431-5p (enriched in VS-PH) and hsa-miR-192-5p (enriched in VS-GH). Newborn mice receiving intracochlear injection of viral vectors over-expressing hsa-miR-431-GFP, hsa-miR-192-GFP, or GFP only (control) had similar hearing 6 weeks post-injection. However, after acoustic trauma, the miR-431 group displayed significantly worse hearing, and greater loss of synaptic ribbons per inner hair cell in the acoustically traumatized cochlear region than the control group. Our results suggest that miR-431 contributes to VS-associated hearing loss following cochlear stress. Further investigation is needed to determine whether miR-431 is a potential therapeutic target for SNHL.
1978 - 1985年，洛杉矶县男性声学神经瘤病因的噪音创伤。
影响因子：
8.8
作者：
Preston-Martin, S;Thomas, D C;Wright, W E;Henderson, B E
通讯作者：
Henderson, B E
影响因子：
4.6
作者：
Yamamoto-Fukuda, Tomomi;Pinto, Filipa;Pitt, Keshia;Senoo, Makoto
通讯作者：
Senoo, Makoto