Surviving Fibroblasts After Treatment With Mitomycin C Exhibit SASP-Like Phenotype After Glaucoma Filtration Surgery.

Abstract

The clinical outcomes of trabeculectomy, a standard glaucoma filtration surgery (GFS), have dramatically improved with the introduction of mitomycin C (MMC), an antimetabolite widely used to inhibit postoperative scarring. MMC exerts anti-scarring effects primarily by promoting apoptosis and suppressing fibroblast proliferation at the surgical site. However, despite these beneficial effects, MMC also induces the production of inflammatory cytokines, and its full mechanism of action remains incompletely understood. Moreover, a subset of patients continues to experience poor surgical outcomes even after MMC application, highlighting the need for complementary therapeutic strategies. Comprehensive transcriptomic analysis of postoperative GFS tissues revealed that MMC promoted the expression of genes associated with cellular senescence and inflammatory responses. Supporting this, in vitro experiments suggested that the transcriptional changes were associated with MMC-induced senescence-associated secretory phenotype (SASP)-like changes in the fibroblasts. Single-cell RNA sequencing (scRNA-Seq) analyses of postoperative GFS tissues also revealed that fibroblasts after GFS with MMC secrete SASP factors. Furthermore, Cell-Cell communication analysis identified CCL7 as one of the key molecules involved in inflammatory cell migration and the promotion of fibrosis. Importantly, we demonstrated that fibroblasts exhibiting SASP-like features can be selectively eliminated by a specific senolytic agent, suggesting a novel and promising therapeutic approach that may improve long-term surgical outcomes after GFS.