Extracellular vesicle-carried Jagged-1 inhibits HUVEC sprouting in a 3D microenvironment
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10456_2018_9609_ReferencePDF.pdf
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Author(s)
Tan, Evan
Asada, Harry H
Ge, Ruowen
Date Issued
March 14, 2018
Publisher
Springer Netherlands
Version
Author's final manuscript
Abstract
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.
MIT Department
Singapore-MIT Alliance in Research and Technology (SMART)
d'Arbeloff Lab for Information Sytems and Technology (Massachusetts Institute of Technology)
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DOI of Published Version
https://doi.org/10.1007/s10456-018-9609-6
