Computational Screening of Tip and Stalk Cell Behavior Proposes a Role for Apelin Signaling in Sprout Progression

TL;DR

This study uses a computational model to explore tip and stalk cell behaviors in angiogenesis, identifying Apelin signaling as a key factor in sprout progression and validating this through in vitro experiments.

Contribution

The paper introduces a novel computational model predicting tip cell behavior based on chemoattractant response differences, highlighting Apelin signaling's role in sprout extension.

Findings

Inhibition of Apelin reduces angiogenic sprouting.

Tip cells respond less effectively to chemoattractants than stalk cells.

Differential Apelin and APJ expression may create self-generated gradients.

Abstract

Angiogenesis involves the formation of new blood vessels by sprouting or splitting of existing blood vessels. During sprouting, a highly motile type of endothelial cell, called the tip cell, migrates from the blood vessels followed by stalk cells, an endothelial cell type that forms the body of the sprout. To get more insight into how tip cells contribute to angiogenesis, we extended an existing computational model of vascular network formation based on the cellular Potts model with tip and stalk differentiation, without making a priori assumptions about the differences between tip cells and stalk cells. To predict potential differences, we looked for parameter values that make tip cells (a) move to the sprout tip, and (b) change the morphology of the angiogenic networks. The screening predicted that if tip cells respond less effectively to an endothelial chemoattractant than stalk cells, they move to the tips of the sprouts, which impacts the morphology of the networks. A comparison of this model prediction with genes expressed differentially in tip and stalk cells revealed that the endothelial chemoattractant Apelin and its receptor APJ may match the model prediction. To test the model prediction we inhibited Apelin signaling in our model and in an \emph{in vitro} model of angiogenic sprouting, and found that in both cases inhibition of Apelin or of its receptor APJ reduces sprouting. Based on the prediction of the computational model, we propose that the differential expression of Apelin and APJ yields a "self-generated" gradient mechanisms that accelerates the extension of the sprout.