Extracellular matrix-associated molecules of senescent cells induce a senescence phenotype in proliferative cells via TGF-β signaling pathway.

Abstract

Senescent cells accumulate in various tissues as we age and are characterized by growth arrest and a senescence-associated secretory phenotype (SASP). This phenotype involves the release of various factors, such as pro-inflammatory molecules, reactive oxygen species (ROS) and extracellular vesicles (EVs), which can trigger senescence in neighboring cells. However, it remains unclear whether non-soluble factors produced by senescent cells, such as the extracellular matrix (ECM) or its associated molecules (collectively termed the matrisome), can induce paracrine senescence. In this study, vascular cells were used as an in vitro model system to investigate this hypothesis. These findings reveal that decellularized ECM from senescent vascular smooth muscle cells (S-ECM) or fibroblasts, but not from proliferating cells (P-ECM), robustly induces a senescence phenotype in human proliferative endothelial cells (ECs) over a two-week culture period, whereas ECM from proliferating cells (P-ECM) does not elicit this effect. This induction appears to be at least partially mediated by the transforming growth factor beta (TGF-β) signaling pathway. Notably, inhibiting TGF-β receptor 1 (TGFβR1) in proliferative ECs grown in S-ECM significantly attenuated the senescence phenotype. These results further show that one of the matrisome proteins able to mediate the pro-senescence effect of S-ECM is transforming growth factor beta 1 induced transcript 1 (TGFβ1|1). Importantly, when discs coated with S-ECM were implanted in young mice, an increase in senescence markers was observed compared to mice implanted with discs coated with P-ECM. Overall, this research demonstrates that senescent-derived ECM acts as a potent trigger of cellular senescence, both in vitro and in vivo, with the involvement of the TGF-β signaling pathway playing a crucial role.