Cisd2 Plays an Essential Role in Corneal Epithelial Regeneration

Abstract

Age-related changes affecting the cornea and ocular surface cause vision loss in the elderly. We investigated the role of Cisd2 in corneal health and disease. Five major discoveries were made. 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. 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 disease. Keywords: corneal wound healing; Cisd2; calcium homeostasis; limbal stem cell deficiency; EDTA; cyclosporine A. Funding: We acknowledge the support provided by grants from the Ministry of Science and Technology (MOST104-2314-B-182-070, MOST105-2314-B-182-066-MY3, and MOST108-2314-B-182-049- MY3 to CCS; MOST 109-2327-B-010-002, MOST 109-2320-B-010-043 and MOST 107-2320-B-010- 037-MY3 to TFT), and from Chang Gung Medical Research Foundation (CORPG2L0011 to CCS). Declaration of Interest: None to declare. Ethical Approval: This study has been approved by the Institutional Review Board (#201509558B0, #201900646B0, #20200799B0, #202001685B0) at Chang Gung Memorial Hospital, Taiwan. The animal protocols were approved by the Institutional Animal Care and Use Committee of Chang Gung Memorial Hospital (approval no. 2015121606, 2020092211)and National Yang-Ming University (approval no. 1021218).