Optimal mechanical interactions direct multicellular network formation on elastic substrates

TL;DR

This study demonstrates that substrate deformation-mediated mechanical interactions can drive the self-organization of cells into functional, branched networks, with optimal formation at intermediate substrate stiffness, combining modeling and experimental validation.

Contribution

It introduces a combined agent-based model and experimental approach to show how mechanical interactions via substrate deformation guide multicellular network formation, highlighting the importance of substrate properties.

Findings

Network formation depends on substrate stiffness, optimal at intermediate levels.

Mechanical interactions lead to more robust network self-organization than local interactions alone.

Predicted network metrics like percolation and fractal dimension vary with cell and substrate parameters.

Abstract

Cells self-organize into functional, ordered structures during tissue morphogenesis, a process that is evocative of colloidal self-assembly into engineered soft materials. Understanding how inter-cellular mechanical interactions may drive the formation of ordered and functional multicellular structures is important in developmental biology and tissue engineering. Here, by combining an agent-based model for contractile cells on elastic substrates with endothelial cell culture experiments, we show that substrate deformation-mediated mechanical interactions between cells can cluster and align them into branched networks. Motivated by the structure and function of vasculogenic networks, we predict how measures of network connectivity like percolation and fractal dimension, as well as local morphological features including junctions, branches, and rings depend on cell contractility and density, and on substrate elastic properties including stiffness and compressibility. We predict and confirm with experiments that cell network formation is substrate stiffness-dependent, being optimal at intermediate stiffness. Overall, we show that long-range, mechanical interactions provide an optimal and general strategy for multi-cellular self-organization, leading to more robust and efficient realization of space-spanning networks than through just local inter-cellular interactions.