Tip cell overtaking occurs as a side effect of sprouting in computational models of angiogenesis

TL;DR

This study uses computational models to investigate whether tip cell overtaking during angiogenesis is a side effect of sprouting or a biological function, finding it likely occurs spontaneously due to stochastic cell motion.

Contribution

The paper demonstrates through cellular Potts models that tip cell overtaking can arise spontaneously from cell migration dynamics, influenced by VEGF-Dll4-Notch signaling, without requiring specific regulatory mechanisms.

Findings

Tip cell overtaking occurs as a side effect of stochastic cell migration.

VEGF-Dll4-Notch signaling influences the likelihood of cells occupying the tip position.

Tip cell overtaking and sprouting are interdependent processes.

Abstract

During angiogenesis, endothelial cells compete for the tip position during angiogenesis: a phenomenon named tip cell overtaking. It is still unclear to what extent tip cell overtaking is a side effect of sprouting or to what extent a biological function. To address this question, we studied tip cell overtaking in two existing cellular Potts models of angiogenic sprouting. In these models angiogenic sprouting-like behavior emerges from a small set of plausible cell behaviors and the endothelial cells spontaneously migrate forwards and backwards within sprouts, suggesting that tip cell overtaking might occur as a side effect of sprouting. In accordance with experimental observations, in our simulations the cells' tendency to occupy the tip position can be regulated when two cell lines with different levels of Vegfr2 expression are contributing to sprouting (mosaic sprouting assay), where cell behavior is regulated by a simple VEGF-Dll4-Notch signaling network. Our modeling results suggest that tip cell overtaking occurs spontaneously due to the stochastic motion of cells during sprouting. Thus, tip cell overtaking and sprouting dynamics may be interdependent and should be studied and interpreted in combination. VEGF-Dll4-Notch can regulate the ability of cells to occupy the tip cell position, but only when cells in the simulation strongly differ in their levels of Vegfr2. We propose that VEGF-Dll4-Notch signaling might not regulate which cell ends up at the tip, but assures that the cell that randomly ends up at the tip position acquires the tip cell phenotype.