Abstract
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.
Highlights
Endothelial cells line the luminal surface of blood vessels and provide a physical and metabolic barrier between the vessel and the circulation, and are essential for cardiovascular homeostasis
We have previously shown that endothelial cells derived from human embryonic stem cells express an immature immune phenotype, with no discernible TLR4 function [11]
We have previously shown that, whilst Human embryonic stem cell-derived endothelial cells (hESC-EC) do not respond to Toll-like receptor (TLR) agonists [11], they do express all of the necessary intracellular signalling to mount an immune/ inflammatory response, and respond avidly to IL-1b [11]
Summary
Endothelial cells line the luminal surface of blood vessels and provide a physical and metabolic barrier between the vessel and the circulation, and are essential for cardiovascular homeostasis. Endothelial cells are a key cell type in innate immunity, and express pattern recognition receptors (PRRs), including Toll like receptors (TLRs) and nucleotidebinding oligomerization domain-containing protein (NOD) receptors [2,3,4]. Activation of endothelial cells by pathogens is an early event in innate immunity, resulting in the expression of adhesion receptors and the release of chemokines [5,6]. This allows for immune cells to be recruited to an area of infection, and for subsequent pathogen killing, removal and resolution. PRRs on endothelial cells, including TLR4 and TLR2, have been associated with vascular inflammation and cardiovascular disease, such as atherosclerosis [7,8,9]
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