Trabeculectomy's gold-standard adjunct mitomycin C (MMC) kills most fibroblasts to prevent scarring—but single-cell RNA sequencing of postoperative glaucoma filtration surgery tissues reveals that surviving fibroblasts acquire a senescence-associated secretory phenotype (SASP). Transcriptomic analysis identified upregulated senescence and inflammatory gene programs, while cell-cell communication modelling pinpointed CCL7 as a key paracrine signal driving inflammatory cell recruitment and fibrosis. Critically, these SASP-like fibroblasts were selectively cleared by a senolytic agent in vitro, suppressing the pro-fibrotic cascade.
This finding reframes a 30-year-old clinical puzzle: why do a meaningful proportion of trabeculectomy patients fail even with MMC? The prevailing model assumed MMC's incomplete apoptotic kill was simply insufficient; this work proposes an actively harmful survivor population secreting inflammatory mediators. It aligns with the broader senescence field's insight that a small fraction of senescent cells can dominate tissue microenvironments through SASP amplification loops. CCL7—a chemokine better known in cancer and inflammatory bowel disease contexts—emerges as a tractable therapeutic target. The logical next step is senolytics like navitoclax or dasatinib/quercetin combinations tested in animal GFS models, then human trials. Limitations are real: the causal chain from SASP to surgical failure remains correlational, cohort sizes aren't disclosed, and in vitro senolytic clearance must translate to intact ocular tissue. Still, this is a mechanistically novel, potentially paradigm-shifting reinterpretation of MMC biology with direct translational implications for improving bleb survival.
