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

doi:10.1016/j.isci.2022.104306

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

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

10 Citations (Scopus)

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 language	English
Article number	104306
Journal	iScience
Volume	25
Issue number	5
DOIs	https://doi.org/10.1016/j.isci.2022.104306
Publication status	Published - 20 May 2022

Keywords

Bioengineering
Biological sciences
Developmental biology
Tissue engineering

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10.1016/j.isci.2022.104306

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@article{55c9473a85a548e4bdaef8abec041544,

title = "Engineered patterns of Notch ligands Jag1 and Dll4 elicit differential spatial control of endothelial sprouting",

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.",

keywords = "Bioengineering, Biological sciences, Developmental biology, Tissue engineering",

author = "Tiemeijer, {Laura A.} and Tommaso Ristori and Stassen, {Oscar M.J.A.} and Ahlberg, {Jaakko J.} and {de Bijl}, {Jonne J.J.} and Chen, {Christopher S.} and Katie Bentley and Bouten, {Carlijn V.C.} and Sahlgren, {Cecilia M.}",

note = "Funding Information: 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 {\AA}bo 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 {\AA}bo Akademi University Foundation{\textquoteright}s Center of Excellence in Cellular Mechanostasis (CellMech) (CMS). Funding Information: 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 {\AA}bo 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 {\AA}bo 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. Publisher Copyright: {\textcopyright} 2022 The Author(s)",

year = "2022",

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doi = "10.1016/j.isci.2022.104306",

language = "English",

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T1 - Engineered patterns of Notch ligands Jag1 and Dll4 elicit differential spatial control of endothelial sprouting

AU - Tiemeijer, Laura A.

AU - Ristori, Tommaso

AU - Stassen, Oscar M.J.A.

AU - Ahlberg, Jaakko J.

AU - de Bijl, Jonne J.J.

AU - Chen, Christopher S.

AU - Bentley, Katie

AU - Bouten, Carlijn V.C.

AU - Sahlgren, Cecilia M.

N1 - Funding Information: 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 Information: 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. Publisher Copyright: © 2022 The Author(s)

PY - 2022/5/20

Y1 - 2022/5/20

N2 - 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.

AB - 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.

KW - Bioengineering

KW - Biological sciences

KW - Developmental biology

KW - Tissue engineering

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U2 - 10.1016/j.isci.2022.104306

DO - 10.1016/j.isci.2022.104306

M3 - Article

AN - SCOPUS:85129970334

SN - 2589-0042

VL - 25

JO - iScience

JF - iScience

IS - 5

M1 - 104306

ER -

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

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