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bioRxiv · 10.1101/2025.03.02.640998

The Notch ligand Jagged1 plays a dual role in cochlear hair cell regeneration.

Li, X.-J.·Morgan, C.·Li, L.·Zhang, W.-Y.·Chrysostomou, E.·Doetzlhofer, A.
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Abstract

Hair cells (HCs) within the inner ear cochlea are specialized mechanoreceptors required for hearing. Cochlear HCs are not regenerated in mammals, and their loss is a leading cause of deafness in humans. Cochlear supporting cells (SCs) in newborn mice have the capacity to regenerate HCs, but persistent Notch signaling, presumably activated by SC-specific Notch ligand Jagged1 (JAG1), prevents SCs from converting into HCs. Here, employing an organoid platform, we show that while JAG1 participates in HC-fate repression, JAG1s primary function is to preserve the "progenitor-like characteristics" of cochlear SCs. Transcriptomic and mechanistic studies reveal that JAG1/Notch signaling maintains the expression of progenitor and metabolic genes in cochlear SCs and sustains pro-growth pathways, including PI3K-Akt-mTOR signaling, a function that is mediated by Notch1 and Notch2. Finally, we show that JAG1/Notch signaling stimulation with JAG1-Fc peptide enhances the HC-forming capacity of cochlear SCs undergoing maturation in cochlear explants and in vivo.

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Li, X.-J., Morgan, C., Li, L., Zhang, W.-Y., Chrysostomou, E., Doetzlhofer, A.. 2025-03-04. The Notch ligand Jagged1 plays a dual role in cochlear hair cell regeneration.. https://doi.org/10.1101/2025.03.02.640998

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