Molecular Mechanisms of Insulin-like Growth Factor Binding Protein-7 in Stem Cell Senescence: A Multi-Dimensional Regulator of Senescence-Associated Secretory Phenotype (SASP)

Background: Senescent cells exert their effects through the release of various factors, collectively referred to as the senescence-associated secretory phenotype (SASP) factors. These factors can further induce senescence in healthy stem cells, modulate immune system function, reshape the extracellular matrix, and facilitate cancer progression. The key SASP factors that regulate the state of stem cell senescence remain to be elucidated. Objectives: Considering the constant presence of IGFBP-7 in SASP components, the current study evaluates whether IGFBP-7 promotes paracrine senescence and contributes to the spread of cellular senescence from stress-affected cells to apparently healthy cells. Results: Higher level of IGFBP-7 was found in the secretome of H2O2-treated MSCs compared to its matched control. Further incubation of healthy MSCs with secretome of H2O2-treated MSCs induced paracrine senescence while secretome from control group of cells did not show paracrine senescence. Its immunodepletion with anti-IGFBP-7 neutralizing antibodies in the secretome of senescent cells failed to cause secondary senescence while treatment of healthy MSCs with recombinant IGFBP-7 protein alone induced cellular senescence. The senescence induced by IGFBP-7 appears to be mediated through three primary pathways. Primarily, IGFBP-7 can bind to insulin and inhibits anti-senescence and pro-growth effects of insulin. Secondly, IGFBP-7 may enhance pro-senescence signaling of IGFII by promoting its interaction with IGF2R while blocking IGF1R. These activities are dependent on ERK and AKT signaling pathways. Finally, IGFBP-7 and Activin A appear to regulate and inhibit each other though both separately can induce cellular senescence. This finding suggests a compensatory mechanism to prevent excessive senescence in the body. The preliminary data also indicates IGFBP-7 interacts with Activin receptors and arrest cell cycle via SMAD family signaling pathways. Conclusion: These findings highlight that IGFBP-7, along with other members of the IGFBP family, plays a fundamental role in senescence-related signaling pathways. Therefore, IGFBP-7 may serve as a potential target for anti-aging strategies aimed at reducing the burden of senescence in tissues and organs.