Single-cell atlas of keratoconus corneas revealed aberrant transcriptional signatures and implicated mechanical stretch as a trigger for keratoconus pathogenesis

作者：Shengqian Dou, Qun Wang, Bin Zhang, Chao Wei, Huijun Wang, Ting Liu, Haoyun Duan, Hui Jiang, Mingna Liu, Xiaolin Qi, Qingjun Zhou, Lixin Xie, Weiyun Shi, Hua Gao · 发表于：Cell Discovery · 年份：2022 · DOI：10.1038/s41421-022-00397-z · 被引用次数：95 · 研究领域：Corneal surgery and disorders、Corneal Surgery and Treatments、Skin Protection and Aging

Keratoconus is a common ectatic corneal disorder in adolescents and young adults that can lead to progressive visual impairment or even legal blindness. Despite the high prevalence, its etiology is not fully understood. In this study, we performed single-cell RNA sequencing (scRNA-Seq) analysis on 39,214 cells from central corneas of patients with keratoconus and healthy individuals, to define the involvement of each cell type during disease progression. We confirmed the central role of corneal stromal cells in this disease, where dysregulation of collagen and extracellular matrix (ECM) occurred. Differential gene expression and histological analyses revealed two potential novel markers for keratoconus stromal cells, namely CTSD and CTSK. Intriguingly, we detected elevated levels of YAP1 and TEAD1, the master regulators of biomechanical homeostasis, in keratoconus stromal cells. Cyclical mechanical experiments implicated the mechanical stretch in prompting protease production in corneal stromal cells during keratoconus progression. In the epithelial cells of keratoconus corneas, we observed reduced basal cells and abnormally differentiated superficial cells, unraveling the corneal epithelial lesions that were usually neglected in clinical diagnosis. In addition, several elevated cytokines in immune cells of keratoconus samples supported the involvement of inflammatory response in the progression of keratoconus. Finally, we revealed the dysregulated cell-cell communications in...