RESUMO
Spatial regulation of angiogenesis is important for the generation of functional engineered vasculature in regenerative medicine. The Notch ligands Jag1 and Dll4 show distinct expression patterns in endothelial cells and, respectively, promote and inhibit endothelial sprouting. Therefore, patterns of Notch ligands may be utilized to spatially control sprouting, but their potential and the underlying mechanisms of action are unclear. Here, we coupled in vitro and in silico models to analyze the ability of micropatterned Jag1 and Dll4 ligands to spatially control endothelial sprouting. Dll4 patterns, but not Jag1 patterns, elicited spatial control. Computational simulations of the underlying signaling dynamics suggest that different timing of Notch activation by Jag1 and Dll4 underlie their distinct ability to spatially control sprouting. Hence, Dll4 patterns efficiently direct the sprouts, whereas longer exposure to Jag1 patterns is required to achieve spatial control. These insights in sprouting regulation offer therapeutic handles for spatial regulation of angiogenesis.
RESUMO
Recreating functional tissues through bioengineering strategies requires steering of complex cell fate decisions. Notch, a juxtacrine signaling pathway, regulates cell fate and controls cellular organization with local precision. The engineering-friendly characteristics of the Notch pathway provide handles for engineering tissue patterning and morphogenesis. We discuss the physiological significance and mechanisms of Notch signaling with an emphasis on its potential use for engineering complex tissues. We highlight the current state of the art of Notch activation and provide a view on the design aspects, opportunities, and challenges in modulating Notch for tissue-engineering strategies. We propose that finely tuned control of Notch contributes to the generation of tissues with accurate form and functionality.