Li Xiao-Jun, Morgan Charles, Li Lin, Zhang Wan-Yu, Chrysostomou Elena, Doetzlhofer Angelika
The Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA.
Frontier Institute of Science and Technology, Xi'an Jiaotong University, Xi'an, 710049, China.
Nat Commun. 2025 Sep 1;16(1):8169. doi: 10.1038/s41467-025-63053-6.
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-growth pathways, including phosphoinositide-3-kinase/Akt /mammalian target of rapamycin signaling, a function that is Notch1 and Notch2-receptor mediated. Finally, we show that Jagged1/Notch signaling stimulation with Jagged1-Fc peptide enhances the hair cell-forming capacity of supporting cells in cochlear explants and in vivo.
内耳耳蜗中的毛细胞是听力所需的特殊机械感受器。毛细胞在哺乳动物中不会再生，其损失是人类耳聋的主要原因。新生小鼠的耳蜗支持细胞具有再生毛细胞的能力，但持续的Notch信号传导（可能由Notch配体Jagged1激活）会阻止支持细胞转化为毛细胞。利用耳蜗类器官平台，我们发现虽然Jagged1参与毛细胞命运抑制，但其主要功能是维持支持细胞的祖细胞样特征。转录组学和机制研究表明，Jagged1/Notch信号传导维持支持细胞中的祖细胞和代谢基因表达，并维持促生长途径，包括磷酸肌醇-3-激酶/蛋白激酶B/雷帕霉素哺乳动物靶标信号传导，该功能由Notch1和Notch2受体介导。最后，我们表明用Jagged1-Fc肽刺激Jagged1/Notch信号传导可增强耳蜗外植体和体内支持细胞形成毛细胞的能力。
