Xia Mingyu, Wu Mingxuan, Zhao Liping, Ma Jiaoyao, Li Wenyan, Li Huawei
Department of the Affiliated Eye and ENT Hospital, State Key Laboratory of Medical Neurobiology, ENT Institute and Otorhinolaryngology, Fudan University, Room 613, Building 9, No. 83, Fenyang Road, Shanghai 200031, China; Institutes of Biomedical Sciences, Fudan University, Shanghai 200032, China.
Department of the Affiliated Eye and ENT Hospital, State Key Laboratory of Medical Neurobiology, ENT Institute and Otorhinolaryngology, Fudan University, Room 613, Building 9, No. 83, Fenyang Road, Shanghai 200031, China; Institutes of Biomedical Sciences, Fudan University, Shanghai 200032, China.
Hear Res. 2021 Aug;407:108275. doi: 10.1016/j.heares.2021.108275. Epub 2021 May 23.
Loss of hair cells (HCs) accounts for most sensorineural hearing loss, and regeneration of cochlear HCs is considered as the ultimate strategy for restoring hearing. Several lines of evidence have shown that Lgr5+ progenitor cells can spontaneously regenerate new HCs after HC loss at the neonatal stage, and most of which are immature. IHCs are resistant to ototoxic drugs and noise and cannot be ablated efficiently in order to precisely investigate IHC regeneration in existing hearing injury models, and thus we generated a new transgenic mouse model by inserting diphtheria toxin receptor (DTR) under the control of the Vglut3 promoter. In this model, IHCs were selectively ablated in a dose-dependent manner after the injection of diphtheria toxin (DT) at the neonatal stage, while OHCs remained intact with normal hair bundle structures until adulthood. With this IHC-specific injury model, we observed HC regeneration from Lgr5+ progenitors after IHC ablation at the neonatal stage. Some of the newly generated HCs replaced the lost IHCs in-situ and re-build the structure of the organ of Corti through the asymmetrical mitosis of progenitor cells. While, the majority of the regenerated HCs did not survive until adulthood, and the loss of spiral ganglion neurons was observed after the IHC ablation, which led to profound hearing loss after DT injection in Vglut3 mice at the neonatal stage. The model presented here shows promise for investigating the mechanisms behind IHC loss and subsequent regeneration.
毛细胞（HCs）的丧失是大多数感音神经性听力损失的原因，而耳蜗毛细胞的再生被认为是恢复听力的最终策略。多项证据表明，Lgr5 +祖细胞在新生期毛细胞丧失后可自发再生新的毛细胞，且其中大多数是不成熟的。在现有的听力损伤模型中，为了精确研究内毛细胞（IHCs）的再生，内毛细胞对耳毒性药物和噪音具有抗性且无法有效消融，因此我们通过在Vglut3启动子的控制下插入白喉毒素受体（DTR）构建了一种新的转基因小鼠模型。在该模型中，新生期注射白喉毒素（DT）后，内毛细胞以剂量依赖性方式被选择性消融，而外毛细胞（OHCs）在成年前保持完整且毛束结构正常。利用这种内毛细胞特异性损伤模型，我们观察到新生期内毛细胞消融后Lgr5 +祖细胞的毛细胞再生。一些新生成的毛细胞原位替代了丢失的内毛细胞，并通过祖细胞的不对称有丝分裂重建了柯蒂氏器的结构。然而，大多数再生的毛细胞在成年前未能存活，并且在内毛细胞消融后观察到螺旋神经节神经元的丧失，这导致新生期注射DT的Vglut3小鼠在注射后出现严重的听力损失。本文提出的模型为研究内毛细胞丧失及后续再生背后的机制提供了希望。
