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

Abstract

BackgroundDuring angiogenesis, the formation of new blood vessels from existing ones, endothelial cells differentiate into tip and stalk cells, after which one tip cell leads the sprout. More recently, this picture has changed. It has become clear that endothelial cells compete for the tip position during angiogenesis: a phenomenon named tip cell overtaking. The biological function of tip cell overtaking is not yet known. From experimental observations, it is unclear to what extent tip cell overtaking is a side effect of sprouting or to what extent it is regulated through a VEGF-Dll4-Notch signaling network and thus might have a biological function. To address this question, we studied tip cell overtaking in computational models of angiogenic sprouting in absence and in presence of VEGF-Dll4-Notch signaling.ResultsWe looked for tip cell overtaking in two existing Cellular Potts models of angiogenesis. In these simulation models angiogenic sprouting-like behavior emerges from a small set of plausible cell behaviors. In the first model, cells aggregate through contact-inhibited chemotaxis. In the second model the endothelial cells assume an elongated shape and aggregate through (non-inhibited) chemotaxis. In both these sprouting models 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 other 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.ConclusionsOur modeling results suggest that tip cell overtaking can occur 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 in our simulations. We propose that the function of VEGF-Dll4-Notch signaling might not be to regulate which cell ends up at the tip, but to assure that the cell that randomly ends up at the tip position acquires the tip cell phenotype.Electronic supplementary materialThe online version of this article (doi:10.1186/s12918-015-0230-7) contains supplementary material, which is available to authorized users.

The temporal basis of angiogenesis

“…This Notch regulated differential adhesion along the sprout was found to generate matching data to a wide range of experiments. In a later study using a different CPM-based model, Boas et al [58] compared their data with those of Arima et al [52] and discussed how cell mixing can be seen as an emergent property of the ‘sprouting system’ as a whole; thus both studies agreed that positional interchanges/jostling can spontaneously occur when cells have differential motion and adhesion, but Notch/VEGF signalling is required to regulate this in a way to match the precise dynamics seen in vitro by both experimental teams [58]. …”

Visualizing Morphogenesis with the Processing Programming Language

“…Branching morphogenetic processes that could be modeled encompass lung morphogenesis (Menshykau et al, 2014), establishment of blood vascular networks (Boas and Merks 2015), and branching of tumors (Miura 2015;Takaki 2005). Blender (www.blender.org), an open source 3D animation and graphics software, could also be used to model morphogenesis.…”

A multiscale model of complex endothelial cell dynamics in early angiogenesis

“…Several recent computational models have started to address these issues [3,37]. For example, Bentley et al [3] studied the mechanisms underlying cell rearrangement behaviour during angiogenic sprouting.…”