Pathogen sensing pathways in human embryonic stem cell derived-endothelial cells: Role of NOD1 receptors

Daniel M. Reed, Gabor Foldes, Timothy Gatheral, Koralia E. Paschalaki, Zsuzsanna Lendvai, Zsolt Bagyura, Tamas Nemeth, Judit Skopal, Bela Merkely, Aurica G. Telcian, Leila Gogsadze, Michael R. Edwards, Peter J. Gough, John Bertin, Sebastian L. Johnston, Sian E. Harding, Jane A. Mitchell

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13 Citations (Scopus)

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.

Original languageEnglish
Article numbere91119
JournalPloS one
Volume9
Issue number4
DOIs
Publication statusPublished - Apr 1 2014

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)
  • General

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    Reed, D. M., Foldes, G., Gatheral, T., Paschalaki, K. E., Lendvai, Z., Bagyura, Z., Nemeth, T., Skopal, J., Merkely, B., Telcian, A. G., Gogsadze, L., Edwards, M. R., Gough, P. J., Bertin, J., Johnston, S. L., Harding, S. E., & Mitchell, J. A. (2014). Pathogen sensing pathways in human embryonic stem cell derived-endothelial cells: Role of NOD1 receptors. PloS one, 9(4), [e91119]. https://doi.org/10.1371/journal.pone.0091119