外部微环境的机械线索已被认为是驱动细胞行为的重要线索。尽管在感觉上皮发育过程中调节细胞命运的细胞内信号已被充分了解，但感觉上皮形成的驱动力仍然难以捉摸。在这里，我们为耳蜗类器官培养制造了一种具有可调机械性能的混合水凝胶，并揭示了细胞外基质（ECM）通过以阶段依赖的模式改变刚度来驱动感觉上皮的形成。作为驱动力，适度的 ECM 硬度通过调节整合素 α3 (ITGA3)/F-肌动蛋白细胞骨架/YAP 信号传导激活耳蜗祖细胞 (CPC) 来源的上皮类器官的扩张。较高的刚度通过增加 PIEZO2 介导的细胞内 Ca2 信号传导，然后激活 KLF2 来完成细胞规范，诱导 CPC 转变为感觉毛细胞 (HC)。我们的结果确定了 ECM 机械力引导的感觉上皮形成的分子机制，并有助于开发 HC 再生的治疗方法。

The mechanical cues of the external microenvironment have been recognized as essential clues driving cell behavior. Although intracellular signals modulating cell fate during sensory epithelium development is well understood, the driving force of sensory epithelium formation remains elusive. Here, we manufactured a hybrid hydrogel with tunable mechanical properties for the cochlear organoids culture and revealed that the extracellular matrix (ECM) drives sensory epithelium formation through shifting stiffness in a stage-dependent pattern. As the driving force, moderate ECM stiffness activated the expansion of cochlear progenitor cell (CPC)-derived epithelial organoids by modulating the integrin α3 (ITGA3)/F-actin cytoskeleton/YAP signaling. Higher stiffness induced the transition of CPCs into sensory hair cells (HCs) through increasing the intracellular Ca2+ signaling mediated by PIEZO2 and then activating KLF2 to accomplish the cell specification . Our results identify the molecular mechanism of sensory epithelium formation guided by ECM mechanical force and contribute to developing therapeutic approaches for HC regeneration.