Chalmers Conferences, 9th European Conference on Mathematical and Theoretical Biology

Synergy of vacuolation and cell-cell repulsion in lumen formation
Sonja Boas, Roeland Merks

Last modified: 2014-06-09


New blood vessels form during physiological and pathological conditions including wound  healing and tumor growth. The new vessels subsequently hollow to allow blood perfusion, a process called lumen formation. The mechanisms of lumen formation are a topic of ongoing debate. We present a mechanistic, multi-scale, agent-based (Cellular Potts Model) model to address this debate.

The debate on lumen formation revolves around two alternative, proposed mechanisms: vacuolation and cell-cell repulsion. In the vacuolation mechanism, large intracellular vacuoles coalesce into an intracellular lumen. The alternative cell-cell repulsion mechanism suggests that no intracellular vacuoles form, but that lumens form extracellularly by electrostatic repulsion of adjacent cells. Our model can reproduce lumen formation for both mechanisms by dynamically representing the underlying molecular processes, such as cell surface polarization, pinocytosis, and vacuole formation, coalescence and secretion

We have validated the model by mimicking experimental perturbations in parameter studies that varied the effectivity of the molecular processes. The model produces lumens most effectively when both mechanisms are operational, suggesting that the underlying molecular mechanisms function synergistically. Interestingly, when both mechanisms are active in the model, the hollowing process visually resembles the vacuolation mechanism when simulated in thin vessels, as lumens form intracellulary. In thicker vessels the same mechanisms produces lumens between cells, visually resembling the cell-cell repulsion mechanism. The model thus provides a possible explanation for the contradictory experimental observations that sparked the scientific debate on lumen formation.


Acknowledgments: We thank the Indiana University and the Biocomplexity Institute for providing the CC3D modeling environment and SARA for providing access to the National Compute Cluster LISA.


S.E.M. Boas, R.M.H. Merks. (2014) Synergy of Cell-Cell Repulsion and Vacuolation in a Computational Model of Lumen Formation. J. R. Soc. Interface 11: 20131049