Cisd2 plays an essential role in corneal epithelial regeneration
Chi-Chin Sun,
Shao-Yun Lee,
Cheng-Heng Kao,
Li-Hsien Chen,
Zhao-Qing Shen,
Chia-Hui Lai,
Tsai-Yu Tzeng,
Jong-Hwei Su Pang,
Wen-Tai Chiu,
Ting-Fen Tsai
Affiliations
Chi-Chin Sun
Department of Ophthalmology, Chang Gung Memorial Hospital, Keelung, Taiwan; School of Medicine, College of Medicine, Chang Gung University, Taoyuan, Taiwan
Shao-Yun Lee
Department of Ophthalmology, Chang Gung Memorial Hospital, Keelung, Taiwan
Cheng-Heng Kao
Center of General Education, Chang Gung University, Taoyuan, Taiwan
Li-Hsien Chen
Department of Pharmacology, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Taiwan
Zhao-Qing Shen
Department of Life Sciences and Institute of Genome Sciences, National Yang Ming Chiao Tung University, Taipei, Taiwan
Chia-Hui Lai
Graduate Institute of Clinical Medical Sciences, Chang Gung University, Kwei-shan, Taoyuan, Taiwan
Tsai-Yu Tzeng
Cancer Progression Research Center, National Yang Ming Chiao Tung University, Taipei, Taiwan
Jong-Hwei Su Pang
Graduate Institute of Clinical Medical Sciences, Chang Gung University, Kwei-shan, Taoyuan, Taiwan
Wen-Tai Chiu
Department of Biomedical Engineering, College of Engineering, National Cheng Kung University, Tainan, Taiwan; Corresponding Authors. Wen-Tai Chiu, Ph.D., No. 1, University Rd., Tainan City 701, Taiwan
Ting-Fen Tsai
Department of Life Sciences and Institute of Genome Sciences, National Yang Ming Chiao Tung University, Taipei, Taiwan; Aging and Health Research Center, National Yang Ming Chiao Tung University, Taipei, Taiwan; Institute of Molecular and Genomic Medicine, National Health Research Institutes, Zhunan, Taiwan; Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, Zhunan, Taiwan; Corresponding Authors. Ting-Fen Tsai, Ph.D., 155 Li-Nong St., Sec. 2, Beitou, Taipei 11221, Taiwan
Background: 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. Methods: 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 Ca2+ 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. Findings: 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 Ca2+ 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. Interpretation: These findings reveal that Cisd2 plays an essential role in the cornea and that Ca2+ signaling pathways are potential targets for developing therapeutics of corneal epithelial diseases. Funding: This study was supported by the Ministry of Science and Technology (MOST) and Chang Gung Medical Research Foundation, Taiwan.
