Selective ablation of inner hair cells and subsequent in-situ hair cell regeneration in the neonatal mouse cochlea

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 DTR+ mice at the neonatal stage. The model presented here shows promise for investigating the mechanisms behind IHC loss and subsequent regeneration. (c) 2021 The Author(s). Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND license ( http://creativecommons.org/licenses/by-nc-nd/4.0/ )

Automated summary

Loss of hair cells is a major factor in sensorineural hearing loss, and regeneration of cochlear hair cells is seen as a way to restore hearing. A new transgenic mouse model was created to selectively ablate inner hair cells (IHCs) in a dose-dependent manner, leading to the observation of regeneration from Lgr5+ progenitors. However, most regenerated hair cells did not survive to adulthood, and loss of spiral ganglion neurons resulted in profound hearing loss after the ablation of IHCs. This model shows promise for studying mechanisms of IHC loss and regeneration.