Single-cell atlas comparison across vertebrates reveals auditory cell evolution and mechanisms for hair cell regeneration.

Mammals suffer permanent hearing impairment from the loss of auditory hair cells due to their inability to regenerate. In contrast, lower vertebrates exhibit extraordinary capacity for hair cell regeneration and hearing restoration, but the mechanisms remain unclear. Here we characterize the single-cell atlas of Xenopus laevis inner ear and perform a comprehensive comparison with mouse model. An exceptionally conserved inner ear neuronal cell type is discovered. The results reveal that the outer hair cells (OHCs) exist exclusively in mammals. Importantly, our analyses reveal an orchestrated gene expression program in Xenopus, characterized by upregulation of hair cell regeneration-related genes, coupled with downregulation of proliferation inhibitory genes. These findings unveil a natural feature of regenerative capacity in Xenopus, and provide molecular and evolutionary evidences for differential regenerative capacities across vertebrates. This work offers insights from amphibians into developing strategies to solve the challenges of hair cell regeneration in humans.