Reed Daniel M, Foldes Gabor, Gatheral Timothy, Paschalaki Koralia E, Lendvai Zsuzsanna, Bagyura Zsolt, Nemeth Tamas, Skopal Judit, Merkely Bela, Telcian Aurica G, Gogsadze Leila, Edwards Michael R, Gough Peter J, Bertin John, Johnston Sebastian L, Harding Sian E, Mitchell Jane A
Department of Cardiothoracic Pharmacology, National Heart and Lung Institute, Imperial College London, London, United Kingdom.
Department of Cardiac Pharmacology, National Heart and Lung Institute, Imperial Centre for Translational and Experimental Medicine, Imperial College London, London, United Kingdom; Heart and Vascular Center, Semmelweis University, Budapest, Hungary.
PLoS One. 2014 Apr 1;9(4):e91119. doi: 10.1371/journal.pone.0091119. eCollection 2014.
Human embryonic stem cell-derived endothelial cells (hESC-EC), as well as other stem cell derived endothelial cells, have a range of applications in cardiovascular research and disease treatment. Endothelial cells sense Gram-negative bacteria via the pattern recognition receptors (PRR) Toll-like receptor (TLR)-4 and nucleotide-binding oligomerisation domain-containing protein (NOD)-1. These pathways are important in terms of sensing infection, but TLR4 is also associated with vascular inflammation and atherosclerosis. Here, we have compared TLR4 and NOD1 responses in hESC-EC with those of endothelial cells derived from other stem cells and with human umbilical vein endothelial cells (HUVEC). HUVEC, endothelial cells derived from blood progenitors (blood outgrowth endothelial cells; BOEC), and from induced pluripotent stem cells all displayed both a TLR4 and NOD1 response. However, hESC-EC had no TLR4 function, but did have functional NOD1 receptors. In vivo conditioning in nude rats did not confer TLR4 expression in hESC-EC. Despite having no TLR4 function, hESC-EC sensed Gram-negative bacteria, a response that was found to be mediated by NOD1 and the associated RIP2 signalling pathways. Thus, hESC-EC are TLR4 deficient but respond to bacteria via NOD1. This data suggests that hESC-EC may be protected from unwanted TLR4-mediated vascular inflammation, thus offering a potential therapeutic advantage.
人胚胎干细胞来源的内皮细胞（hESC-EC）以及其他干细胞来源的内皮细胞在心血管研究和疾病治疗中有一系列应用。内皮细胞通过模式识别受体（PRR）Toll样受体（TLR）-4和含核苷酸结合寡聚化结构域蛋白（NOD）-1感知革兰氏阴性菌。这些通路在感知感染方面很重要，但TLR4也与血管炎症和动脉粥样硬化有关。在此，我们比较了hESC-EC中TLR4和NOD1的反应与其他干细胞来源的内皮细胞以及人脐静脉内皮细胞（HUVEC）的反应。HUVEC、血液祖细胞来源的内皮细胞（血液来源的内皮细胞；BOEC）以及诱导多能干细胞来源的内皮细胞均显示出TLR4和NOD1反应。然而，hESC-EC没有TLR4功能，但确实具有功能性NOD1受体。在裸鼠体内预处理并未使hESC-EC表达TLR4。尽管没有TLR4功能，hESC-EC仍能感知革兰氏阴性菌，发现该反应由NOD1和相关的RIP2信号通路介导。因此，hESC-EC缺乏TLR4，但通过NOD1对细菌作出反应。该数据表明hESC-EC可能免受不必要的TLR4介导的血管炎症影响，从而提供潜在的治疗优势。
