Department of Ophthalmology, Chang Gung Memorial Hospital, Keelung, Taiwan; School of Medicine, College of Medicine, Chang Gung University, Taoyuan, Taiwan.
Department of Ophthalmology, Chang Gung Memorial Hospital, Keelung, Taiwan.
EBioMedicine. 2021 Nov;73:103654. doi: 10.1016/j.ebiom.2021.103654. Epub 2021 Oct 29.
Age-related changes affecting the ocular surface cause vision loss in the elderly. Cisd2 deficiency drives premature aging in mice as well as resulting in various ocular surface abnormalities. Here we investigate the role of CISD2 in corneal health and disease.
We studied the molecular mechanism underlying the ocular phenotypes brought about by Cisd2 deficiency using both Cisd2 knockout (KO) mice and a human corneal epithelial cell (HCEC) cell line carrying a CRISPR-mediated CISD2KO background. We also develop a potential therapeutic strategy that targets the Ca signaling pathway, which has been found to be dysregulated in the corneal epithelium of subjects with ocular surface disease in order to extend the mechanistic findings into a translational application.
Firstly, in patients with corneal epithelial disease, CISD2 is down-regulated in their corneal epithelial cells. Secondly, using mouse cornea, Cisd2 deficiency causes a cycle of chronic injury and persistent repair resulting in exhaustion of the limbal progenitor cells. Thirdly, in human corneal epithelial cells, CISD2 deficiency disrupts intracellular Ca homeostasis, impairing mitochondrial function, thereby retarding corneal repair. Fourthly, cyclosporine A and EDTA facilitate corneal epithelial wound healing in Cisd2 knockout mice. Finally, cyclosporine A treatment restores corneal epithelial erosion in patients with dry eye disease, which affects the ocular surface.
These findings reveal that Cisd2 plays an essential role in the cornea and that Ca signaling pathways are potential targets for developing therapeutics of corneal epithelial diseases.
This study was supported by the Ministry of Science and Technology (MOST) and Chang Gung Medical Research Foundation, Taiwan.
与年龄相关的眼表变化导致老年人视力丧失。Cisd2 缺乏会导致小鼠早衰，并导致各种眼表异常。在这里，我们研究了 CISD2 在角膜健康和疾病中的作用。
我们使用 Cisd2 敲除 (KO) 小鼠和携带 CRISPR 介导的 CISD2KO 背景的人角膜上皮细胞 (HCEC) 细胞系，研究了 Cisd2 缺乏引起的眼部表型的分子机制。我们还开发了一种针对钙信号通路的潜在治疗策略，该通路在患有眼表疾病的受试者的角膜上皮中发现失调，旨在将机制研究结果转化为转化应用。
首先，在患有角膜上皮疾病的患者中，CISD2 在其角膜上皮细胞中下调。其次，在小鼠角膜中，Cisd2 缺乏会导致慢性损伤和持续修复的循环，从而耗尽角膜缘祖细胞。第三，在人角膜上皮细胞中，Cisd2 缺乏会破坏细胞内 Ca 稳态，损害线粒体功能，从而阻碍角膜修复。第四，环孢素 A 和 EDTA 促进 Cisd2 敲除小鼠的角膜上皮伤口愈合。最后，环孢素 A 治疗可恢复干燥性眼病患者的角膜上皮糜烂，这会影响眼表。
这些发现表明 Cisd2 在角膜中发挥着重要作用，钙信号通路是开发角膜上皮疾病治疗药物的潜在靶点。
本研究得到科技部和台湾长庚医学研究基金会的支持。
