Engineered patterns of Notch ligands Jag1 and Dll4 elicit differential spatial control of endothelial sprouting

Abstract

<p>Spatial regulation of angiogenesis is important for the generation of functional<br>engineered vasculature in regenerative medicine. The Notch ligands Jag1 and<br>Dll4 show distinct expression patterns in endothelial cells and, respectively, pro-<br>mote and inhibit endothelial sprouting. Therefore, patterns of Notch ligands may<br>be utilized to spatially control sprouting, but their potential and the underlying<br>mechanisms of action are unclear. Here, we coupled in vitro and in silico models<br>to analyze the ability of micropatterned Jag1 and Dll4 ligands to spatially control<br>endothelial sprouting. Dll4 patterns, but not Jag1 patterns, elicited spatial con-<br>trol. Computational simulations of the underlying signaling dynamics suggest<br>that different timing of Notch activation by Jag1 and Dll4 underlie their distinct<br>ability to spatially control sprouting. Hence, Dll4 patterns efficiently direct the<br>sprouts, whereas longer exposure to Jag1 patterns is required to achieve spatial<br>control. These insights in sprouting regulation offer therapeutic handles for<br>spatial regulation of angiogenesis.</p>