Bystander senescence in human peritoneal mesothelium and fibroblasts is related to thrombospondin-1-dependent activation of transforming growth factor-β1

• Senescent HPMCs promote senescence in young HPMCs and HPFBs.
• Senescence bystander effect elicited by HPMCs depends on their SASP.
• TGF-β1 mediates senescence in young HPMCs and HPFBs.
• Latent TGF-β1 in culture media is activated by TSP-1.

Senescence bystander effect refers to a phenomenon in which senescent cells elicit the development of senescence phenotype in their nearby young counterparts. In this paper we examined the mechanism of senescence bystander effect triggered by senescent human peritoneal mesothelial cells (HPMCs) in proliferating HPMCs and peritoneal fibroblasts (HPFBs). The results showed that conditioned medium (CM) derived from senescent HPMCs elicited a senescence response (growth inhibition coupled with increased expression of senescence-associated β-galactosidase and accumulation of histone γ-H2A.X) in either early-passage HPMCs or HPFBs. Samples of CM from senescent HPMCs contained increased amounts of numerous soluble mediators of which only transforming growth factor-β1 (TGF-β1) was able to induce senescence phenotype in the both types of peritoneal cells, likely through an induction of reactive oxygen species (ROS) and p38 mitogen-activated protein kinase (MAPK). At the same time, senescent HPMCs released increased amounts of thrombospondin-1 (TSP-1), a major activator of TGF-β1. Significantly, TSP-1 itself was unable to induce senescence phenotype in HPMCs or in HPFBs. The experiments employing anti-TSP-1 antibodies and specific TSP-1 blocking peptide revealed that neutralization of TSP-1 in CM prevented TGF-β1-dependent development of senescence phenotype. Collectively, our findings indicate that senescent HPMCs exhibit senescence-promoting activity toward neighboring young cells (HPMCs and HPFBs), and this effect is, at least partly, related to TSP-1-dependent activation and further ROS- and p38 MAPK-related activity of TGF-β1.

Figure optionsDownload high-quality image (111 K)Download as PowerPoint slide