Regulation of endothelial sheet morphogenesis: contrasting collective versus autonomous cell behaviors


Endothelial cell sheets lie at the interface of all blood and lymph vasculature in the human body. At this interface endothelial cells serve a range of functions, including providing a ready surface for exchange of nutrients and waste, relaying information about adjacent tissues, and providing a pathway for immune surveillance. Endothelial cell sheets are highly dynamic, they must remodel extensively during development and growth, to establish and extend to support for new tissues, and during homeostasis, to expand and retract with cardiovascular function and as physiological needs of the tissue and organism change. Endothelial cell sheets also play a major role in human disease where its morphogenesis is frequently co-opted during disease, for example, expansion of vascular and lymphatic networks enable growth and spread of cancer or result in fibrosis and permanent tissue damage after injury.

Given the critical nature of endothelial biology in health and disease there has been considerable progress identifying biophysical and molecular regulators of cell motility, cell protrusion, cell adhesion, and cell-matrix interactions. These major advances have begun to inform development of in silico methods for analyzing epithelial cell movements and morphogenesis. However, in silico models have been used primarily as plausibility tests for specific hypotheses, for instance, "can we generate observed patterns of cell movements from a set of hypothesized rules?" Almost invariably the answer is "yes" but models have only rarely been integrated with experiment design or to make testable predictions. With these advances we propose advancing in silico methods to couple experimental studies of endothelial cell sheet morphogenesis with computer simulations of endothelial cells where biophysical features of motility and adhesion can be directly modeled and outcomes can be directly compared to experiment.

Recent studies have started to challenge that ability of endothelial sheets to move within confined spaces or over complex patterned substrates (Yang, Y., et al., 2016. Scientific Reports 6, 22707) but it is unclear biological or biophysical principles are being tested or exposed. With the emergence of rapid microfabrication and advanced 3D printing tools we propose there is an urgent need to increase integration of computational simulation with experimental design to identify the most powerful route to advance future studies.

So far there are few tools that can directly integrate biophysical simulations that incorporate detailed cell biology with experimental studies of endothelial morphogenesis. Simulation tools such as the Tissue Simulation Toolkit and VirtualLeaf, both developed by Dr. Merks and recently modified to analyze animal epithelial morphogenesis provide robust a open-source foundation to integrate cell biology and cell mechanics modeling with image analysis tools such as TissueMiner (Etournay, et al., 2016, eLife 5, e14334.) or CellEct (Delibaltov, et al., 2016, BMC bioinformatics 17, 88).

The work plan for the sabbatical leave at Leiden University is to develop computational models of endothelial cell migration that can recapitulate collective behaviors observed in different subtypes of endothelial cells exposed to microenvironmental cues.





Prof. dr. R.M.H. Merks

Verbonden aan

Universiteit Leiden, Faculteit der Wiskunde en Natuurwetenschappen, Institute of Biology Leiden - IBL


01/02/2019 tot 31/05/2019