title: Insulin-like growth factor binding proteins 4 and 7 released by senescent cells promote premature senescence in mesenchymal stem cells.
abstract: Cellular senescence is the permanent arrest of cell cycle, physiologically related to aging and aging-associated diseases. Senescence is also recognized as a mechanism for limiting the regenerative potential of stem cells and to protect cells from cancer development. The senescence program is realized through autocrine/paracrine pathways based on the activation of a peculiar senescence-associated secretory phenotype (SASP). We show here that conditioned media (CM) of senescent mesenchymal stem cells (MSCs) contain a set of secreted factors that are able to induce a full senescence response in young cells. To delineate a hallmark of stem cells SASP, we have characterized the factors secreted by senescent MSC identifying insulin-like growth factor binding proteins 4 and 7 (IGFBP4 and IGFBP7) as key components needed for triggering senescence in young MSC. The pro-senescent effects of IGFBP4 and IGFBP7 are reversed by single or simultaneous immunodepletion of either proteins from senescent-CM. The blocking of IGFBP4/7 also reduces apoptosis and promotes cell growth, suggesting that they may have a pleiotropic effect on MSC biology. Furthermore, the simultaneous addition of rIGFBP4/7 increased senescence and induced apoptosis in young MSC. Collectively, these results suggest the occurrence of novel-secreted factors regulating MSC cellular senescence of potential importance for regenerative medicine and cancer therapy.
authors.affiliation: 1] Department of Environmental, Biological and Pharmaceutical Sciences and Technologies, Second University of Naples, Caserta, Italy [2] Institute of Biostructures and Bioimaging-IBB, CNR, Napoli, Italy [3] Centro Interuniversitario di Ricerca sui Peptidi Bioattivi-CIRPEB, Napoli, Italy.
authors.forename: V
authors.initials: V
authors.lastname: Severino
authors.forename: N
authors.initials: N
authors.lastname: Alessio
authors.forename: A
authors.initials: A
authors.lastname: Farina
authors.forename: A
authors.initials: A
authors.lastname: Sandomenico
authors.forename: M
authors.initials: M
authors.lastname: Cipollaro
authors.forename: G
authors.initials: G
authors.lastname: Peluso
authors.forename: U
authors.initials: U
authors.lastname: Galderisi
authors.forename: A
authors.initials: A
authors.lastname: Chambery
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D002454:Cell Differentiation / Q000187:drug effects / Q000235:genetics; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D016922:Cellular Senescence / Q000187:drug effects / Q000235:genetics; D002853:Chromatography, Liquid; D019295:Computational Biology; D017077:Culture Media, Conditioned / Q000494:pharmacology; D006801:Humans; D007150:Immunohistochemistry; D018974:Insulin-Like Growth Factor Binding Protein 4 / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D018969:Insulin-Like Growth Factor Binding Proteins / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D053719:Tandem Mass Spectrometry
chemical_list: D017077:Culture Media, Conditioned; D018974:Insulin-Like Growth Factor Binding Protein 4; D018969:Insulin-Like Growth Factor Binding Proteins; C102529:insulin-like growth factor binding protein-related protein 1