Live imaging and multimodal profiling reveal transdifferentiation of a cochlear supporting cell subpopulation upon Notch inhibition.

Summary

The cochlear sensory epithelium has strikingly limited regenerative capacity. Using live imaging and single-cell multiomics of cochlear explants, this study found that Notch repression silences key supporting-cell genes broadly, but only a rare subpopulation of Deiters' cells (dubbed transdifferentiating DCs) actually goes on to convert into hair cells, undergoing distinct transcriptional and enhancer remodeling that other, molecularly similar supporting cells never do. That gives a molecular definition of which cells are regeneration-competent, and why most supporting cells stay refractory even when the same Notch-inhibition signal reaches all of them.

Key findings

• Live imaging and single-cell multiomics of neonatal mouse cochlear explants mapped the cellular and molecular heterogeneity behind limited cochlear regeneration.
• Notch repression broadly silenced key supporting-cell genes, but only a rare subpopulation of Deiters' cells initiated transdifferentiation into hair cells.
• These regeneration-competent cells underwent coordinated transcriptional and enhancer remodeling not seen in other supporting cells exposed to the same signal.
• The study provides a molecular definition of an early transitional supporting-cell-to-hair-cell state and identifies Notch inhibition as a selective trigger that unmasks rare regenerative competence.