Notch 抑制与 Wnt 激活的时机和剂量增强耳器官样体中毛细胞样细胞生成与静纤毛延长
Timing and Dosage of Notch Inhibition and Wnt Activation Enhanced Hair Cell-Like Cell Generation and Stereocilia Elongation in Otic Organoids
内耳毛细胞受损后无法再生，是听力损失难以恢复的关键原因。研究用小鼠胚胎干细胞培育出耳器官样体（模拟内耳发育的三维细胞团），在不同时间段分别加入抑制 Notch 通路的药物 DAPT 和激活 Wnt 通路的药物 CHIR99021。结果显示，在培养后期用较低剂量处理，毛细胞标志物 MyoVIIa 和 Atoh1 表达更强，电镜观察到静纤毛样结构更长更明显；早期处理则形态更稳定但诱导效果较弱。这提示精确控制信号调控的时间和剂量，可提高毛细胞样细胞的成熟度，为内耳再生研究提供平台。
为什么推荐给您：在类器官中优化信号调控时机剂量改善毛细胞成熟，属方法学进展，尚未进入人体。
不需要生物学背景，多打比方
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摘要Abstract
The modulation of Notch and Wnt signaling was evaluated for its ability to promote the differentiation and maturation of hair cell (HC)-like cells in otic organoids derived from mouse embryonic stem cells (mESCs). Using R1/E mESCs, we generated otic organoids and treated them with the Notch pathway inhibitor (γ-secretase inhibitor, DAPT) and the Wnt signaling agonist (CHIR99021) during two-time windows: days (D) D12-D18 (early treatment) or D28-D34 (late treatment). Among the late treatment conditions, lower concentration (5 μM DAPT and 2.5 μM CHIR99021) yielded greater expression of MyoVIIa and Atoh1 compared with higher doses (10 and 5 μM, respectively). Ultrastructural analysis by transmission electron microscopy further demonstrated that late treatment with lower-dose DAPT and CHIR99021 generated HC-like cells harboring longer and more prominent stereocilia-like bundles than those observed in other conditions. In contrast, early treatment produced HCs arranged in a typical otic organoid pattern, resulting in a more morphologically stable but less robustly induced HC-like population. These findings indicate that temporally and dose-controlled modulation of Notch and Wnt signaling efficiently enhances HC-like cell differentiation and stereocilia maturation in mESC-derived otic organoids, providing a useful platform for future studies in inner ear regeneration and cell-based therapies.