Li Xiao-Jun, Morgan Charles, Li Lin, Zhang Wan-Yu, Chrysostomou Elena, Doetzlhofer Angelika
bioRxiv. 2025 Mar 4:2025.03.02.640998. doi: 10.1101/2025.03.02.640998.
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, JAG1's 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 .
内耳耳蜗中的毛细胞（HCs）是听力所需的特殊机械感受器。哺乳动物的耳蜗毛细胞不会再生，其损失是人类耳聋的主要原因。新生小鼠的耳蜗支持细胞（SCs）具有再生毛细胞的能力，但持续的Notch信号传导（可能由SCs特异性Notch配体Jagged1（JAG1）激活）会阻止支持细胞转化为毛细胞。在这里，利用类器官平台，我们表明，虽然JAG1参与了对毛细胞命运的抑制，但其主要功能是维持耳蜗支持细胞的“祖细胞样特征”。转录组学和机制研究表明，JAG1/Notch信号传导维持耳蜗支持细胞中祖细胞和代谢基因的表达，并维持包括PI3K-Akt-mTOR信号传导在内的促生长途径，该功能由Notch1和Notch2介导。最后，我们表明用JAG1-Fc肽刺激JAG1/Notch信号传导可增强耳蜗外植体中正在成熟的耳蜗支持细胞形成毛细胞的能力。
