Vassilieva Irina O, Reshetnikova Galina F, Shatrova Alla N, Tsupkina Nataliya V, Kharchenko Marianna V, Alekseenko Larisa L, Nikolsky Nikolay N, Burova Elena B
Institute of Cytology RAS, Tikhoretsky Ave 4, St. Petersburg, 194064, Russia.
Biochem Biophys Res Commun. 2018 Feb 19;496(4):1162-1168. doi: 10.1016/j.bbrc.2018.01.163. Epub 2018 Jan 31.
Accumulating evidence suggests that the senescence-messaging secretome (SMS) factors released by senescent cells play a key role in cellular senescence and physiological aging. Phenomenon of the senescence induction in human endometrium-derived mesenchymal stem cells (MESCs) in response to SMS factors has not yet been described. In present study, we examine a hypothesis whether the conditioned medium from senescent cells (CM-old) may promote premature senescence of young MESCs. In this case, we assume that SMS factors, containing in CM-old are capable to trigger senescence mechanism in a paracrine manner. A long-term cultivation MESCs in the presence of CM-old caused deceleration of cell proliferation along with emerging senescence phenotype, including increase in both the cell size and SA-β-Gal activity. The phosphorylation of p53 and MAPKAPK-2, a direct target of p38MAPK, as well as the expression of p21Cip1 and p16Ink4a were increased in CM-old treated cells with senescence developing whereas the Rb phosphorylation was diminished. The senescence progression was accompanied by both enhanced ROS generation and persistent activation of DNA damage response, comprising protein kinase ATM, histone H2A.X, and adapter protein 53BP1. Thus, we suggest that a senescence inducing signal is transmitted through p16/MAPKAPK-2/Rb and DDR-mediated p53/p21/Rb signaling pathways. This study is the first to demonstrate that the SMS factors secreted in conditioned medium of senescent MESCs trigger a paracrine mechanism of premature senescence in young cells.
越来越多的证据表明，衰老细胞释放的衰老信息分泌组（SMS）因子在细胞衰老和生理老化中起关键作用。人类子宫内膜来源的间充质干细胞（MESCs）对SMS因子的衰老诱导现象尚未见报道。在本研究中，我们检验了一个假设，即衰老细胞的条件培养基（CM-old）是否会促进年轻MESCs的过早衰老。在这种情况下，我们假设CM-old中含有的SMS因子能够以旁分泌方式触发衰老机制。在CM-old存在的情况下对MESCs进行长期培养，导致细胞增殖减速并出现衰老表型，包括细胞大小和SA-β-Gal活性增加。在衰老的CM-old处理细胞中，p53和p38MAPK的直接靶点MAPKAPK-2的磷酸化以及p21Cip1和p16Ink4a的表达增加，而Rb磷酸化减少。衰老进程伴随着ROS生成的增强和DNA损伤反应的持续激活，包括蛋白激酶ATM、组蛋白H2A.X和衔接蛋白53BP1。因此，我们认为衰老诱导信号通过p16/MAPKAPK-2/Rb和DDR介导的p53/p21/Rb信号通路传递。本研究首次证明，衰老MESCs条件培养基中分泌的SMS因子触发了年轻细胞过早衰老的旁分泌机制。
