Laboratory of Developmental Cell Biology and Disease, School of Ophthalmology and Optometry and Eye Hospital, Wenzhou Medical University, Wenzhou, China.
State Key Laboratory of Ophthalmology, Optometry and Vision Science, Wenzhou, China.
J Cell Mol Med. 2020 Oct;24(20):12020-12031. doi: 10.1111/jcmm.15830. Epub 2020 Sep 11.
Homeostasis and function of limbal epithelial stem cells (LESCs) rely on the limbal niche, which, if dysfunctional, leads to limbal epithelial stem cell deficiency (LSCD) and impaired vision. Hence, recovery of niche function is a principal therapeutic goal in LSCD, but the molecular mechanisms of limbal niche homeostasis are still largely unknown. Here, we report that the neural crest transcription factor SOX10, which is expressed in neural crest-derived limbal niche cells (LNCs), is required for LNCs to promote survival of LESCs both in vivo and in vitro. In fact, using mice with a Sox10 mutation and in vitro coculture experiments, we show that SOX10 in LNCs stimulates the production of KIT ligand (KITL), which in turn activates in LESCs the KIT-AKT signalling pathway that protects the cells against activated CASPASE 3-associated cell death. These results suggest that SOX10 and the KITL/KIT-AKT pathway play key roles in limbal niche homeostasis and LESC survival. These findings provide molecular insights into limbal niche function and may point to rational approaches for therapeutic interventions in LSCD.
角膜缘上皮干细胞（LESCs）的稳态和功能依赖于角膜缘龛，如果功能失调，会导致角膜缘上皮干细胞缺乏（LSCD）和视力受损。因此，恢复龛功能是 LSCD 的主要治疗目标，但角膜缘龛稳态的分子机制在很大程度上仍不清楚。在这里，我们报告说，神经嵴转录因子 SOX10 在神经嵴衍生的角膜缘龛细胞（LNCs）中表达，对于 LNCs 在体内和体外促进 LESCs 的存活是必需的。事实上，我们使用 Sox10 突变的小鼠和体外共培养实验表明，LNCs 中的 SOX10 刺激 KIT 配体（KITL）的产生，反过来又激活 LESCs 中的 KIT-AKT 信号通路，保护细胞免受激活的 CASPASE 3 相关细胞死亡。这些结果表明，SOX10 和 KITL/KIT-AKT 通路在角膜缘龛稳态和 LESC 存活中发挥关键作用。这些发现为角膜缘龛功能提供了分子见解，并可能为 LSCD 的治疗干预指明合理的方法。
