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

Laura A. Tiemeijer (Corresponding author), Tommaso Ristori (Corresponding author), 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 (Corresponding author)

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Abstract

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.

Original languageEnglish
Article number104306
Number of pages20
JournaliScience
Volume25
Issue number5
DOIs
Publication statusPublished - 20 May 2022

Funding

Funding: this study was supported by the Academy of Finland , grant numbers 307133 , 316882 , and 330411 (LAT, OMJAS, CMS); the Marie Sklodowska-Curie Global Fellowship , grant number 846617 (to TR); ERC ForceMorph , grant number 771168 (OMJAS, CMS). LAT was supported by the Turku Doctoral Network in Molecular Biosciences at Åbo Akademi University . CSC was supported by NIH ( EB00262 and HL147585 ). KB was supported by the Francis Crick Institute , which receives its core funding from Cancer Research UK ( FC001751 ), the UK Medical Research Council ( FC001751 ), and the Wellcome Trust ( FC001751 ). We gratefully acknowledge the Gravitation Program “Materials Driven Regeneration”, funded by the Netherlands Organisation for Scientific Research ( 024.003.013 ) (CVB), the InFLAMES Flagship Program of the Academy of Finland ( 337531 ) (LAT, CMS), and the Åbo Akademi University Foundation’s Center of Excellence in Cellular Mechanostasis (CellMech) (CMS). Funding: this study was supported by the Academy of Finland, grant numbers 307133, 316882, and 330411 (LAT, OMJAS, CMS); the Marie Sklodowska-Curie Global Fellowship, grant number 846617 (to TR); ERC ForceMorph, grant number 771168 (OMJAS, CMS). LAT was supported by the Turku Doctoral Network in Molecular Biosciences at Åbo Akademi University. CSC was supported by NIH (EB00262 and HL147585). KB was supported by the Francis Crick Institute, which receives its core funding from Cancer Research UK (FC001751), the UK Medical Research Council (FC001751), and the Wellcome Trust (FC001751). We gratefully acknowledge the Gravitation Program “Materials Driven Regeneration”, funded by the Netherlands Organisation for Scientific Research (024.003.013) (CVB), the InFLAMES Flagship Program of the Academy of Finland (337531) (LAT, CMS), and the Åbo Akademi University Foundation's Center of Excellence in Cellular Mechanostasis (CellMech) (CMS). Conceptualization: LAT, TR, CMS. Formal Analyses: LAT, TR, OMJAS. Funding Acquisition: TR, KB, CS, CVCB, CMS. Investigation: LAT, TR, JJJB, JJA, OMJAS. Methodology: LAT, TR, CMS. Project Administration: LAT, TR, CMS. Resources: CSC, CVCB, CMS. Software: TR, JJJB. Supervision: CSC, KB, CVCB, CMS. Validation: LAT, TR, CMS. Visualization: LAT, TR. Writing—Original Draft: LAT, TR. Writing—Review and Editing: LAT, TR, OMJAS, CSC, KB, CVCB, CMS. Authors declare that they have no competing interests.

FundersFunder number
Åbo Akademi University
National Institutes of HealthHL147585, EB00262
Wellcome Trust
Francis Crick Institute
European Union's Horizon 2020 - Research and Innovation Framework Programme771168
Marie Skłodowska‐Curie846617
Cancer Research UKFC001751
H2020 European Research Council
Academy of Finland307133, 330411, 316882
Nederlandse Organisatie voor Wetenschappelijk Onderzoek337531, 024.003.013
China Scholarship Council

    Keywords

    • Bioengineering
    • Biological sciences
    • Developmental biology
    • Tissue engineering

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