A Human-Like Senescence-Associated Secretory Phenotype Is Conserved in Mouse Cells Dependent on Physiological Oxygen

Abstract

Cellular senescence irreversibly arrests cell proliferation in response to oncogenic stimuli. Human cells develop a senescence-associated secretory phenotype (SASP), which increases the secretion of cytokines and other factors that alter the behavior of neighboring cells. We show here that “senescent” mouse fibroblasts, which arrested growth after repeated passage under standard culture conditions (20% oxygen), do not express a human-like SASP, and differ from similarly cultured human cells in other respects. However, when cultured in physiological (3%) oxygen and induced to senesce by radiation, mouse cells more closely resemble human cells, including expression of a robust SASP. We describe two new aspects of the human and mouse SASPs. First, cells from both species upregulated the expression and secretion of several matrix metalloproteinases, which comprise a conserved genomic cluster. Second, for both species, the ability to promote the growth of premalignant epithelial cells was due primarily to the conserved SASP factor CXCL-1/KC/GRO-α. Further, mouse fibroblasts made senescent in 3%, but not 20%, oxygen promoted epithelial tumorigenesis in mouse xenographs. Our findings underscore critical mouse-human differences in oxygen sensitivity, identify conditions to use mouse cells to model human cellular senescence, and reveal novel conserved features of the SASP.

Tau protein aggregation is associated with cellular senescence in the brain

“…Senescent cells exert chronic tissue degeneration through secretion of toxic SASP (Coppe et al, 2010). Consistent with the transcriptomic profile in human NFT‐bearing neurons and mouse brain tissue (Figure 1a‐c), SASP genes were found to be upregulated in tau NFT brains, that is, Il1b was four‐ and twofold higher than CTL and tau WT , respectively; and Cxcl1 was fourfold higher than both control genotypes; Tnfa was 13‐ and eightfold higher than CTL and tau WT , respectively; Tlr4 was threefold higher than both control genotypes (Figure 2a‐d).…”

Human CD8+EMRA T cells display a senescence‐associated secretory phenotype regulated by p38 MAPK

“…Consequently, senescent cells can alter the tissue microenvironment and affect neighbouring cells through paracrine signalling. The SASP is highly conserved between species (Coppe et al ., 2010) and occurs in a variety of cells types (Erusalimsky & Kurz, 2005; Salminen et al ., 2011) that may be specifically adapted to control different biological processes (Akbar et al ., 2016). …”

“…Furthermore, siRNA interference of p38 MAPK was shown to significantly reduce the secreted levels of most SASP factors (Freund et al ., 2011). To date, the SASP has predominantly been characterized in fibroblast cell culture models or aged mice (Coppe et al ., 2008, 2010; Aoshiba et al ., 2013), with very few reports of a SASP being found in the human immune system with either age or differentiation (Frasca et al ., 2017). …”

Senescence associated secretory phenotype profile from primary lung mice fibroblasts depends on the senescence induction stimuli

“…This secretion is one of the most interesting characteristics of senescent cells and is called senescence associated secretory phenotype (SASP). Factors that are secreted by senescent cells include interleukins 6, 7, and 8 (IL-6, IL-7, IL-8); Monocyte Chemoattractant Protein 2 (MCP-2); Macrophage Inflammatory Protein 3α (MIP-3α); Growth Regulated Oncogene alpha (GROα); Hepatocyte Growth Factor (HGF); Insulin-like Growth Factor Binding Protein (IGFBP); and others (Coppé et al 2008;Coppé et al 2010;Laberge et al 2015). Certain cytokines and chemokines included in SASP can attract and activate cells of the immune system in order to promote its clearance (Krizhanovsky et al 2008).…”