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

The loss of auditory hair cell in mammals including humans results in permanent hearing impairment, as they lack the inherent capacity for regeneration. In contrast, the lower vertebrates exhibit remarkable capacity for hair cell regeneration and hearing restoration, however, the mechanisms remain unclear. In this work, we characterized the first single-cell atlas of inner ear from the high regenerative species Xenopus laevis and further performed a comprehensive comparison with mouse model. An exceptionally conserved inner ear neuronal cell type was discovered and confirmed across species. Comprehensive characterization of the auditory hair cell across species revealed that the outer hair cells (OHCs) represent a newly evolved subtype, existing exclusively in mammals. Importantly, our analyses revealed an orchestrated gene expression program of the highly regenerative capacity in Xenopus , characterized by upregulation of genes associated with hair cell regeneration, coupled with downregulation of proliferation inhibitory genes. These findings unveil a natural feature of the highly regenerative capacity in Xenopus , and provide molecular and evolutionary evidences for the regulatory mechanisms for differential regenerative capacities across vertebrates. This work offers novel insights from amphibian into developing strategies to solve the challenges of hair cell regeneration and hearing repair in humans.