Senescent human hepatocytes express a unique secretory phenotype and promote macrophage migration

摘要: AIM: To develop a model of stress-induced senescence to study the hepatocyte associated secretory phenotype (SASP). METHODS: Hydrogen peroxide treatment was used induce in human HepG2 cell line. Senescence confirmed by cytochemical staining for panel markers including Ki67, p21, heterochromatin protein 1β, and senescence-associated-β-galactosidase activity. Senescent hepatocytes were characterised gene expression arrays quantitative polymerase chain reaction (qPCR), conditioned media proteomic analyses, chemokine array, migration assays characterise composition function SASP. RESULTS: induced classical (p21, activity); downregulated proliferation marker, Ki67. Hepatocyte 4.6-fold increase total secreted (P = 0.06) without major alterations profile. Senescence-induced genes identified microarray (Benjamini Hochberg-corrected P < 0.05); and, consistent with protein, ontology analysis revealed significant enrichment proteins among inducible genes. The SASP included characteristic factors such as interleukin (IL)-8 IL-6, well novel components SAA4, IL-32 Fibrinogen, which validated qPCR and/or array. hepatocyte-conditioned medium elicited inflammatory (granulocyte-macrophage colony stimulating factor, GM-CSF-derived), but not non-inflammatory (CSF-1-derived) macrophages 0.022), could contribute pro-inflammatory microenvironment vivo, or facilitate clearance senescent cells. CONCLUSION: Our provides insights into mechanisms may promote chronic liver disease pathogenesis.