Single-cell transcriptome combined with genetic tracing reveals a roadmap of fibrosis formation during proliferative vitreoretinopathy

• 成果类型: Article
• 署名作者: Liao, Mengyu; Ye, Zhisheng; Zhao, Yumeng; Nan, Jiaying; Liu, Yuming; Yao, Xueming; Yang, Tianjing; Guo, Ju; Jin, Xin; Zhang, Hong; You, Caiyun; Xu, Heping; Yu, Jinguo; Chen, Yupeng; Wang, Xiaohong; Yan, Hua
• 署名单位: Tianjin Medical University; Tianjin Medical University; Nankai University; Harbin Medical University; Queens University Belfast; Tianjin Medical University; Tianjin Medical University
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-12419
• DOI: 10.1073/pnas.2424487122
• 发表日期: 2025-09-16
• 关键词: retinal-pigment epithelium; myofibroblast; outcomes; disease; eyes

摘要

Ocular fibrosis, a severe consequence of excessive retinal wound healing, can lead to vision loss following retinal injury. Proliferative vitreoretinopathy (PVR), a common form of ocular fibrosis, is a major cause of blindness, characterized by the formation of extensive fibrous proliferative membranes. Understanding the cellular origins of PVR-associated fibroblasts (PAFs) is essential to decipher the mechanisms of ocular wound healing. In this study, we combined single-cell transcriptomics with genetic lineage tracing to map the contributions of retinal pigment epithelial (RPE) cells, immune cells, and M & uuml;ller cells to disease progression. RPE cells were found to constitute the largest fraction of cells within PVR lesions, transitioning through metabolic, proliferative, and epithelial-to-mesenchymal transition stages during their conversion to PAFs. These cells exhibited remarkable plasticity and heterogeneity. Notably, Pdgfrb+RPE cells demonstrated significant morphological plasticity, transitioning toward a fibroblast-like phenotype, while macrophage-like RPE cells acquired inflammation-related functions post-PVR. Cell communication network analysis identified Thbs1 (encoding TSP-1) as a key hub gene driving RPE cell fate transitions during PVR. Importantly, therapeutic antibodies targeting TSP-1 significantly mitigated PVR progression. This study provides a detailed roadmap of fibrosis formation during ocular wound healing and highlights the therapeutic potential of targeting TSP-1 in the management of PVR.