Speaker
Description
To form new sprouts during angiogenesis, endothelial cells must coordinate their migration through biophysical and biomechanical signaling between each other and the micro-environment. A relatively simple model of angiogenesis is intersegmental vessel (ISV) formation in zebrafish. While various molecular, cellular, and mechanical factors coordinate ISV pathfinding between the somites, the specific contributions of ECM components remain incompletely understood. Here we hypothesize that guidance through ECM molecules laid down in the intersomitic space steers a process of self-organized pattern formation to reproducibly form blood vessels at stereotypic locations. We combine theoretical and experimental approaches in the zebrafish to investigate this hypothesis. Firstly, we developed a hybrid mathematical model to study the effect of ECM mechanics on a self-organized mechanism of endothelial network formation. We combined a previous, experimentally validated [1] model of endothelial network formation based upon the Cellular Potts Model (CPM) with a molecular dynamics-based bead-spring model of the intersegmental ECM [2,3] and gradients of signaling molecules secreted by the somites. While in absence of the ECM, our model predicts that the endothelial cells form network-like patterns as they do in vitro [1], in presence of the ECM, the model predicts the formation of intersomitic sprouts, consisting of endothelial cells that migrate along high concentrations of the ECM [4]. The model predicts that if the concentration of ECM were reduced in the intersomitic space, the endothelial cells should again organize into network-like structures. To investigate the contributions of the ECM to ISV formation in the zebrafish, we employed morpholino-mediated gene knockdown of ECM components in endothelial cell- and ECM-tagged zebrafish lines, coupled with high-resolution laser scanning confocal microscopy [4]. Although knock-down of Fibronectin-a and b or Laminin-a1 and a4 delays ISV sprouting during the first six hours, simultaneous knockdown of both ECM proteins resulted in aberrant vessel pathfinding, leading to disorganized, incomplete ISV development, resembling endothelial network patterns formed through self-organization by endothelial cells in silico and in vitro. Furthermore, we observed that endothelial cells interact with and migrate along laminin- and fibronectin-rich pathways, as revealed by zebrafish reporter lines, further underscoring the role of these ECM components in guiding vessel formation. Our simulations suggest that ECM stiffness may significantly influence endothelial cell migration, with cells potentially traveling further along VEGF gradients on stiff ECM compared to soft ECM under moderate VEGF sensitivity, providing a potential explanation for the observation in ECM component knockdowns. Our results highlight that ECM-regulated tip cell migration could be a key determinant of ISV growth speed and patterning. More generally, our study suggests an integrated, ‘mathematics-driven’ experimental approach, in which a digital twin is developed hand in hand with each next insight into the experimental system.
Bibliography
@article{vergroesen2025falsifying,
title={Falsifying computational models of endothelial cell network formation through quantitative comparison with in vitro models},
author={Vergroesen, Tessa M and Vermeulen, Vincent and Merks, Roeland MH},
journal={PLOS Computational Biology},
volume={21},
number={4},
pages={e1012965},
year={2025},
publisher={Public Library of Science San Francisco, CA USA}
}
@article{tsingos2023hybrid,
title={Hybrid cellular Potts and bead-spring modeling of cells in fibrous extracellular matrix},
author={Tsingos, Erika and Bakker, Bente Hilde and Keijzer, Koen AE and Hupkes, Hermen Jan and Merks, Roeland MH},
journal={Biophysical Journal},
volume={122},
number={13},
pages={2609--2622},
year={2023},
publisher={Elsevier}
}
@article{keijzer2025cells,
title={How cells align to structured collagen fibrils: a hybrid cellular Potts and molecular dynamics model with dynamic mechanosensitive focal adhesions},
author={Keijzer, Koen AE and Tsingos, Erika and Merks, Roeland MH},
journal={Frontiers in Cell and Developmental Biology},
volume={12},
pages={1462277},
year={2025},
publisher={Frontiers Media SA}
}
@article{abugattas2026laminin,
title={Laminin and Fibronectin Cooperate to Guide Endothelial Self-Organization During Intersegmental Vessel Formation},
author={Abugattas-Nunez Del Prado, Joaquin and Keijzer, Koen AE and Tsingos, Erika and Merks, Roeland MH},
journal={bioRxiv},
pages={2026--03},
year={2026},
publisher={Cold Spring Harbor Laboratory}
}
