Work

CYR61/CCN1: A novel mediator of redox response in corneal stromal cells of keratoconus

Year: 2024

Type: article

Abstract: Keratoconus (KC) is a progressive, multifactorial and ectatic corneal disorder that characterized by steepening thinning of the cornea. It was previously demonstrated that oxidative stress has a strong link with KC progression. However, the molecular mechanism underlying oxidative stress response in KC remains unclear. Hence, the present study analyzed the heterogeneity of response of corneal stromal cells (CSCs) to oxidative stress in order to further illustrate how oxidative shape the pathophysiology of KC. Single-cell transcriptomics analysis revealed that CSCs demonstrated significant higher oxidative stress score in the KC group compared to the Ctrl group. The expression of oxidative markers verified by experiments illustrated elevated oxidative stress levels and insufficient antioxidant levels in CSCs of KC. In further single-cell transcriptomics analysis, we identified CYR61 to distinguish different subgroups of CSCs responding to oxidative stress. The cornea stroma cells in KC could be differentiated into CYR61 high cells and CYR61 low cells. Of note, the CYR61 high cells showed lower score in collagen production process and higher score in collagen catabolic process. Further experiments illustrated that CYR61 was elevated in KC and associated with collagen production. • Keratoconus (KC) is the most common blinding eye disease in young adults. Oxidative stress has long been suspected to shape the pathophysiology of KC, however, the pathophysiology remains poorly understood. • In this study, for the first time, we utilize single cell analysis to acquire the differentially expressed genes and different cellular heterogeneity associated with oxidative stress response between KC and healthy samples. • Here, we identify CYR61 as a pivotal gene for discerning the heterogeneity among corneal stromal cells in response to oxidative stress. • In addition to the redox stress response, we have also discovered that CYR61 high cells exhibit a decreased potential of collagen production and elevated collagen catabolic ability. • These findings uncover a specific marker in KC and further establish redox stress-induced extracellular matrix remodeling as a mechanism for controlling corneal thinning in KC progression.

Source: Experimental Eye Research

DOI: 10.1016/j.exer.2024.110093