Green Linden A, Njoku Victor, Mund Julie, Case Jaime, Yoder Mervin, Murphy Michael P, Clauss Matthias
From the Department of Cellular and Integrative Physiology, RLR VA Medical Center, and Indiana Center for Vascular Biology and Medicine (L.A.G., M.P.M., M.C.), Department of Pediatrics (M.Y.), Department of Surgery (V.N., M.P.M.), and Department of Pediatrics, Herman B Wells Center for Pediatric Research, and Indiana University Simon Cancer Center (J.M., J.C.), Indiana University School of Medicine, Indianapolis; and Biomedical Sciences, University of Ulster, Coleraine, United Kingdom (M.C.).
Circ Res. 2016 May 13;118(10):1512-24. doi: 10.1161/CIRCRESAHA.116.308332. Epub 2016 Apr 13.
Transmembrane tumor necrosis factor-α (tmTNF-α) is the prime ligand for TNF receptor 2, which has been shown to mediate angiogenic and blood vessel repair activities in mice. We have previously reported that the angiogenic potential of highly proliferative endothelial colony-forming cells (ECFCs) can be explained by the absence of senescent cells, which in mature endothelial cells occupy >30% of the population, and that exposure to a chronic inflammatory environment induced premature, telomere-independent senescence in ECFCs.
The goal of this study was to determine the role of tmTNF-α in the proliferation of ECFCs.
Here, we show that tmTNF-α expression on ECFCs selects for higher proliferative potential and when removed from the cell surface promotes ECFC senescence. Moreover, the induction of premature senescence by chronic inflammatory conditions is blocked by inhibition of tmTNF-α cleavage. Indeed, the mechanism of chronic inflammation-induced premature senescence involves an abrogation of tmTNF/TNF receptor 2 signaling. This process is mediated by activation of the tmTNF cleavage metalloprotease TNF-α-converting enzyme via p38 MAP kinase activation and its concurrent export to the cell surface by means of increased iRhom2 expression.
Thus, we conclude that tmTNF-α on the surface of highly proliferative ECFCs plays an important role in the regulation of their proliferative capacity.
跨膜肿瘤坏死因子-α（tmTNF-α）是肿瘤坏死因子受体2的主要配体，已证明其在小鼠中介导血管生成和血管修复活动。我们之前报道过，高增殖性内皮集落形成细胞（ECFCs）的血管生成潜力可归因于其缺乏衰老细胞，而在成熟内皮细胞中衰老细胞占比超过30%，并且暴露于慢性炎症环境会诱导ECFCs发生过早的、不依赖端粒的衰老。
本研究的目的是确定tmTNF-α在ECFCs增殖中的作用。
在此，我们表明ECFCs上的tmTNF-α表达选择了更高的增殖潜力，而当从细胞表面去除时会促进ECFCs衰老。此外，慢性炎症条件诱导的过早衰老可通过抑制tmTNF-α裂解来阻断。实际上，慢性炎症诱导过早衰老的机制涉及tmTNF/肿瘤坏死因子受体2信号传导的废除。这个过程是由tmTNF裂解金属蛋白酶肿瘤坏死因子-α转换酶通过p38丝裂原活化蛋白激酶激活并通过增加iRhom2表达将其同时转运到细胞表面介导的。
因此，我们得出结论，高增殖性ECFCs表面的tmTNF-α在调节其增殖能力中起重要作用。
