Dual mechanisms of supporting cell regeneration in the neonatal mouse cochlea

Cochlear supporting cells are glia-like cells critical for development, homeostasis, and regeneration. In the neonatal mouse cochlea, inner phalangeal cells (IPhCs), a supporting cell subtype surrounding inner hair cells, are uniquely regenerated by greater epithelial ridge (GER) cells. Here, we used fate-mapping and single-cell transcriptomic analysis to show that GER cells both mitotically and non-mitotically regenerate IPhCs. Mechanisms of regeneration are spatially distinct, with non-mitotic regeneration found throughout the cochlear spiral and mitotic regeneration restricted to the apical and middle turns. By profiling the regenerating cochlea at four time points, we revealed a damage-induced loss of medial-to-lateral specialization of GER cells. Moreover, in silico analysis predicted distinct lineages and associated pathways where mitotic and non-mitotic IPhC progenitors emerge in the lateral GER. Finally, inhibiting proliferation eliminated mitotic IPhC regeneration while sparing non-mitotic regeneration in vitro. Together, our study reveals dual mechanisms and molecular targets governing supporting cell regeneration.