biostudies-literatureLi XJRNIDNIDCD NIH HHSU.S. Department of Health & Human Services | NIH | National Institute on Deafness and Other Communication Disorders (NIDCD)8169https://www.ebi.ac.uk/biostudies/studies/S-EPMC12402437biostudies-literatureUnknown16(1)Hair cells within the inner ear cochlea are specialized mechanoreceptors required for hearing. Hair cells are not regenerated in mammals, and their loss is a leading cause of deafness in humans. Cochlear supporting cells in newborn mice have the capacity to regenerate hair cells, but persistent Notch signaling, presumably activated by the Notch ligand Jagged1, prevents supporting cells from converting into hair cells. Employing a cochlear organoid platform, we show that while Jagged1 participates in hair cell-fate repression, Jagged1's primary function is to preserve the progenitor-like characteristics of supporting cells. Transcriptomic and mechanistic studies reveal that Jagged1/Notch signaling maintains progenitor and metabolic gene expression in supporting cells and sustains pro-growthNature communicationsThe Notch ligand Jagged1 plays a dual role in cochlear hair cell regeneration.PMC12402437DC020882R01DC011571R01 DC011571Discovery Grant G99G99R01DC019359R01 DC019359F31 DC020882Doetzlhofer AZhang WYMorgan CLi XJLi LChrysostomou EfalseThe Notch ligand Jagged1 plays a dual role in cochlear hair cell regeneration.Hair cells within the inner ear cochlea are specialized mechanoreceptors required for hearing. Hair cells are not regenerated in mammals, and their loss is a leading cause of deafness in humans. Cochlear supporting cells in newborn mice have the capacity to regenerate hair cells, but persistent Notch signaling, presumably activated by the Notch ligand Jagged1, prevents supporting cells from converting into hair cells. Employing a cochlear organoid platform, we show that while Jagged1 participates in hair cell-fate repression, Jagged1's primary function is to preserve the progenitor-like characteristics of supporting cells. Transcriptomic and mechanistic studies reveal that Jagged1/Notch signaling maintains progenitor and metabolic gene expression in supporting cells and sustains pro-growth2025-01-01T00:00:00Z2025 Sep2026-06-03T06:36:29.665Z2026-04-25T03:20:49.244ZS-EPMC124024374089010410.1038/s41467-025-63053-6