Hearing loss is a chronic disease affecting millions of people worldwide, yet no restorative treatment options are available. Although non-mammalian species can regenerate their auditory sensory hair cells, mammals cannot. Birds retain facultative stem cells known as supporting cells that engage in proliferative regeneration when surrounding hair cells die. Here, we investigated gene expression changes in chicken supporting cells during auditory hair cell death. This identified a pathway involving the receptor F2RL1, HBEGF, EGFR, and ERK signaling. We propose a cascade starting with the proteolytic activation of F2RL1, followed by matrix-metalloprotease-mediated HBEGF shedding, and culminating in EGFR-mediated ERK signaling. Each component of this cascade is essential for supporting cell S-phase entry in vivo and is integral for hair cell regeneration. Furthermore, STAT3-phosphorylation converges with this signaling toward upregulation of transcription factors ATF3, FOSL2, and CREM. Our findings could provide a basis for designing treatments for hearing and balance disorders.

听力损失是一种慢性疾病，影响着全世界数百万人，但目前尚无恢复性治疗方案。尽管非哺乳动物物种可以再生听觉毛细胞，但哺乳动物却不能。鸟类保留了被称为支持细胞的兼性干细胞，当周围的毛细胞死亡时，它们会参与增殖再生。在这里，我们研究了听毛细胞死亡过程中鸡支持细胞的基因表达变化。这确定了一条涉及受体 F2RL1、HBEGF、EGFR 和 ERK 信号传导的途径。我们提出了一个级联反应，从 F2RL1 的蛋白水解激活开始，然后是基质金属蛋白酶介导的 HBEGF 脱落，最终导致 EGFR 介导的 ERK 信号传导。该级联的每个组成部分对于支持体内细胞进入 S 期至关重要，并且是毛细胞再生不可或缺的部分。此外，STAT3 磷酸化与该信号转导一致，导致转录因子 ATF3 、FOSL2 和 CREM 上调。我们的研究结果可以为设计听力和平衡障碍的治疗方法提供基础。