内耳毛细胞自发再生的转录组分析揭示dlx5a的关键作用

文献信息

中文摘要

感觉毛细胞（HCs）易受损伤，由于再生能力有限，通常在哺乳动物中导致永久性听力和平衡缺陷。理解非哺乳动物模型中的自发再生为恢复感觉功能提供了关键见解。在此，我们建立了斑马鱼半规管壶腹嵴HC损伤模型，并表征了随后的再生和功能恢复过程。谱系追踪表明，再生的壶腹嵴HC来源于损伤后通过有丝分裂和非有丝分裂机制出现的预先存在和新形成的支持细胞（SCs）。跨再生时间线的耳囊单细胞转录组测序揭示，转录组动态在损伤后24小时达到峰值，并揭示了协调的多细胞反应，包括免疫细胞中激活的炎症信号和SC群体中的再生通路。最后，我们确定dlx5a是壶腹嵴HC再生所需的关键转录因子。在这项工作中，我们提供了一个理解前庭HC再生的框架，可能为感觉恢复的再生疗法提供信息。

英文摘要

Sensory hair cells (HCs) are susceptible to damage, typically causing permanent hearing and balance deficits in mammals due to limited regeneration. Understanding spontaneous regeneration in non-mammalian models offers key insights for restoring sensory function. Here, we establish a zebrafish semicircular canal crista HC injury model and characterize subsequent regeneration and functional recovery processes. Lineage tracing demonstrates that regenerated crista HCs derive from preexisting and newly formed supporting cells (SCs) that emerged after crista HC injury via both mitotic and non-mitotic mechanisms. Single-cell transcriptomic sequencing of otic vesicles across a regeneration timeline reveals that transcriptomic dynamics peak at 24 h post-injury and uncovers a coordinated multicellular response, including activated inflammatory signaling in immune cells and regenerative pathways in SC populations. Finally, we identify dlx5a as a key transcription factor required for crista HC regeneration. In this work, we provide a framework for understanding vestibular HC regeneration that may inform regenerative therapies for sensory restoration.