Lin Sijie, Cai Minqing, Zhang Lingyu, Mao Yi, Wu Han, Liu Xiaodong, Li Yixuan, Liang Minghui, Cheng Xinxuan, Yu Fei, He Hui, Zong Rongrong, Wu Huping, Liu Zuguo, Ou Shangkun, Li Wei
Eye Institute of Xiamen University and affiliated Xiamen Eye Center, School of Medicine, Xiamen, China; Fujian Provincial Key Laboratory of Ophthalmology and Visual Science, Xiamen, China.
Eye Institute of Xiamen University and affiliated Xiamen Eye Center, School of Medicine, Xiamen, China; Fujian Provincial Key Laboratory of Ophthalmology and Visual Science, Xiamen, China; Fujian Provincial Key Laboratory of Corneal & Ocular Surface Diseases, Xiamen, China.
Am J Pathol. 2023 Nov;193(11):1863-1878. doi: 10.1016/j.ajpath.2023.08.003. Epub 2023 Aug 26.
Severe dry eye (SDE) can cause grievous damage to the ocular surface and result in vision impairment and even blindness. To investigate the fate of limbal stem cells in SDE and the underlying mechanism, the current study established an SDE rat model by removing the extraorbital and infraorbital lacrimal glands and maintaining them in a low-humidity environment. One month after the surgery, aqueous tear secretion was reduced dramatically, blood vessels invaded into the central cornea, and inflammatory cells infiltrated into the limbal stroma. The expressions of keratin 12 and paired box gene 6 were down-regulated dramatically, while those of keratin 10, small proline-rich protein 1b, and mucin 5AC were up-regulated in the corneal epithelium of the SDE rats. Cell proliferation in the limbal epithelium was up-regulated, while the stem/progenitor marker adenosine 5'-triphosphate-binding cassette member 2 and the limbal epithelial colony-forming efficiency were decreased in the SDE condition. Furthermore, the p38 mitogen-activated protein kinase signaling pathway was activated in the limbal corneal epithelium of SDE rats. The abnormal differentiation and stemness loss in the corneal epithelium could be reversed upon treatment with a p38 inhibitor in a SDE in vivo model and in vitro hyperosmolar corneal epithelial culture conditions. These data suggest that SDE can lead to limbal stem cell dysfunction, and p38 mitogen-activated protein kinase signaling pathway activation plays an essential role in this process.
严重干眼（SDE）可对眼表造成严重损害，导致视力受损甚至失明。为了研究SDE中角膜缘干细胞的命运及其潜在机制，本研究通过切除眶外和眶下泪腺并将大鼠置于低湿度环境中建立了SDE大鼠模型。手术后1个月，泪液分泌显著减少，血管侵入角膜中央，炎症细胞浸润至角膜缘基质。在SDE大鼠的角膜上皮中，角蛋白12和配对盒基因6的表达显著下调，而角蛋白10、富含脯氨酸的小分子蛋白1b和黏蛋白5AC的表达上调。角膜缘上皮中的细胞增殖上调，而在SDE条件下，干细胞/祖细胞标志物三磷酸腺苷结合盒成员2和角膜缘上皮集落形成效率降低。此外，SDE大鼠角膜缘上皮中的p38丝裂原活化蛋白激酶信号通路被激活。在SDE体内模型和体外高渗角膜上皮培养条件下，用p38抑制剂治疗可逆转角膜上皮的异常分化和干性丧失。这些数据表明，SDE可导致角膜缘干细胞功能障碍，p38丝裂原活化蛋白激酶信号通路激活在此过程中起重要作用。
