Pcolce2 overexpression promotes supporting cell reprogramming in the neonatal mouse cochlea

Hair cell (HC) damage is a leading cause of sensorineural hearing loss, and in mammals supporting cells (SCs) are unable to divide and regenerate HCs after birth spontaneously. Procollagen C‐endopeptidase enhancer 2 (Pcolce2), which encodes a glycoprotein that acts as a functional procollagen C protease enhancer, was screened as a candidate regulator of SC plasticity in our previous study. In the current study, we used adeno‐associated virus (AAV)‐ie (a newly developed adeno‐associated virus that targets SCs) to overexpress Pcolce2 in SCs. AAV‐Pcolce2 facilitated SC re‐entry into the cell cycle both in cultured cochlear organoids and in the postnatal cochlea. In the neomycin‐damaged model, regenerated HCs were detected after overexpression of Pcolce2, and these were derived from SCs that had re‐entered the cell cycle. These findings reveal that Pcolce2 may serve as a therapeutic target for the regeneration of HCs to treat hearing loss. Our study found that AAV‐Pcolce2 promoted the re‐entry of SCs into the cell cycle in cultured cochlear organ tissues and in the postnatal cochlea, and regenerating HCs were detected in a neomycin injury model after overexpression of Pcolce2, which were derived from re‐entering cell cycle SCs.