Engineered patterns of Notch ligands Jag1 and Dll4 elicit differential spatial control of endothelial sprouting
Laura A. Tiemeijer,
Tommaso Ristori,
Oscar M.J. A. Stassen,
Jaakko J. Ahlberg,
Jonne J.J. de Bijl,
Christopher S. Chen,
Katie Bentley,
Carlijn V.C. Bouten,
Cecilia M. Sahlgren
Affiliations
Laura A. Tiemeijer
Faculty for Science and Engineering, Biosciences, Åbo Akademi University, Turku, 20500, Finland; Department of Biomedical Engineering, Eindhoven University of Technology, Eindhoven, 5612 AZ, the Netherlands; Institute for Complex Molecular Systems (ICMS), Eindhoven University of Technology, Eindhoven, 5612 AZ, the Netherlands; Corresponding author
Tommaso Ristori
Department of Biomedical Engineering, Eindhoven University of Technology, Eindhoven, 5612 AZ, the Netherlands; Institute for Complex Molecular Systems (ICMS), Eindhoven University of Technology, Eindhoven, 5612 AZ, the Netherlands; The Biological Design Center and Department of Biomedical Engineering, Boston University, Boston, MA 02215, USA; Corresponding author
Oscar M.J. A. Stassen
Faculty for Science and Engineering, Biosciences, Åbo Akademi University, Turku, 20500, Finland; Department of Biomedical Engineering, Eindhoven University of Technology, Eindhoven, 5612 AZ, the Netherlands; Turku Bioscience Centre, Åbo Akademi University and University of Turku, Turku, 20500, Finland
Jaakko J. Ahlberg
Faculty for Science and Engineering, Biosciences, Åbo Akademi University, Turku, 20500, Finland
Jonne J.J. de Bijl
Department of Biomedical Engineering, Eindhoven University of Technology, Eindhoven, 5612 AZ, the Netherlands
Christopher S. Chen
The Biological Design Center and Department of Biomedical Engineering, Boston University, Boston, MA 02215, USA; The Wyss Institute for Biologically Inspired Engineering, Harvard University, Boston, MA 02115, USA
Katie Bentley
The Biological Design Center and Department of Biomedical Engineering, Boston University, Boston, MA 02215, USA; The Francis Crick Institute, London, NW1 1AT, UK; Department of Informatics, King’s College London, London, WC2B 4BG, UK
Carlijn V.C. Bouten
Department of Biomedical Engineering, Eindhoven University of Technology, Eindhoven, 5612 AZ, the Netherlands; Institute for Complex Molecular Systems (ICMS), Eindhoven University of Technology, Eindhoven, 5612 AZ, the Netherlands
Cecilia M. Sahlgren
Faculty for Science and Engineering, Biosciences, Åbo Akademi University, Turku, 20500, Finland; Department of Biomedical Engineering, Eindhoven University of Technology, Eindhoven, 5612 AZ, the Netherlands; Institute for Complex Molecular Systems (ICMS), Eindhoven University of Technology, Eindhoven, 5612 AZ, the Netherlands; Turku Bioscience Centre, Åbo Akademi University and University of Turku, Turku, 20500, Finland; Corresponding author
Summary: 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.
