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Angiogenesis

, Volume 21, Issue 3, pp 571–580 | Cite as

Extracellular vesicle-carried Jagged-1 inhibits HUVEC sprouting in a 3D microenvironment

  • Evan Tan
  • Harry H. Asada
  • Ruowen Ge
Original Paper

Abstract

NOTCH signalling is an evolutionarily conserved juxtacrine signalling pathway that is essential in development. Jagged1 (JAG1) and Delta-like ligand 4 (DLL4) are transmembrane NOTCH ligands that regulate angiogenesis by controlling endothelial cell (EC) differentiation, vascular development and maturation. In addition, DLL4 could bypass its canonical cell–cell contact-dependent signalling to influence NOTCH signalling and angiogenesis at a distance when it is packaged into extracellular vesicles (EVs). However, it is not clear whether JAG1 could also be packaged into EVs to influence NOTCH signalling and angiogenesis. In this work, we demonstrate that JAG1 is also packaged into EVs. We present evidence that JAG1-EVs inhibit NOTCH signalling and regulate EC behaviour and function. JAG1-EVs inhibited VEGF-induced HUVEC proliferation and migration in 2D culture condition and suppressed sprouting in a 3D microfluidic microenvironment. JAG1-EV treatment of HUVECs leads to a reduction of Notch1 intracellular domain (N1-ICD), and the proteasome and the intracellular domain of JAG1 (JAG1-ICD) are both required for this reduction to occur. These findings reveal a novel mechanism of JAG1 function in NOTCH signalling and ECs through EVs.

Keywords

Extracellular vesicles NOTCH signalling Jagged-1 

Supplementary material

10456_2018_9609_MOESM1_ESM.docx (14 kb)
Supplementary material 1 (DOCX 13 kb)
10456_2018_9609_MOESM2_ESM.docx (9.4 mb)
Supplementary material 2 (DOCX 9616 kb)

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Copyright information

© Springer Science+Business Media B.V., part of Springer Nature 2018

Authors and Affiliations

  1. 1.Department of Biological SciencesNational University of SingaporeSingaporeSingapore
  2. 2.Singapore-MIT Alliance for Research and TechnologyBioSystems and Micromechanics Inter-Disciplinary Research GroupSingaporeSingapore
  3. 3.d’Arbeloff Laboratory for Information Systems and TechnologyMassachusetts Institute of TechnologyCambridgeUSA

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