Life Sciences Division, Lawrence Berkeley National Laboratory, Berkeley, California, United States of America.
PLoS One. 2010 Feb 12;5(2):e9188. doi: 10.1371/journal.pone.0009188.
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-alpha. 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.
细胞衰老会在应对致癌刺激时不可逆地抑制细胞增殖。人类细胞会产生衰老相关分泌表型（SASP），这会增加细胞因子和其他因子的分泌，从而改变邻近细胞的行为。我们在此表明，在标准培养条件（20%氧气）下反复传代后停止生长的“衰老”小鼠成纤维细胞不会表达类似人类的 SASP，并且在其他方面与类似培养的人类细胞不同。然而，当在生理（3%）氧气中培养并通过辐射诱导衰老时，小鼠细胞更类似于人类细胞，包括强烈表达 SASP。我们描述了人类和小鼠 SASP 的两个新方面。首先，两种物种的细胞都上调了几种基质金属蛋白酶的表达和分泌，这些蛋白酶构成了一个保守的基因组簇。其次，对于两种物种，促进良性上皮细胞生长的能力主要归因于保守的 SASP 因子 CXCL-1/KC/GRO-alpha。此外，在 3%氧气而非 20%氧气中使成纤维细胞衰老，会促进小鼠异种移植物中的上皮肿瘤发生。我们的研究结果强调了氧气敏感性方面的关键的小鼠-人类差异，确定了使用小鼠细胞来模拟人类细胞衰老的条件，并揭示了 SASP 的新的保守特征。
