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

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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.

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Authors and Affiliations

  1. Department of Biological Sciences, National University of Singapore, Singapore, 117543, Singapore

    Evan Tan & Ruowen Ge

  2. Singapore-MIT Alliance for Research and Technology, BioSystems and Micromechanics Inter-Disciplinary Research Group, Singapore, 138602, Singapore

    Evan Tan & Harry H. Asada

  3. d’Arbeloff Laboratory for Information Systems and Technology, Massachusetts Institute of Technology, Cambridge, MA, 02139-4307, USA

    Harry H. Asada

Authors
  1. Evan Tan
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Correspondence to Ruowen Ge.

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Tan, E., Asada, H.H. & Ge, R. Extracellular vesicle-carried Jagged-1 inhibits HUVEC sprouting in a 3D microenvironment. Angiogenesis 21, 571–580 (2018). https://doi.org/10.1007/s10456-018-9609-6

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  • DOI: https://doi.org/10.1007/s10456-018-9609-6

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