Coupling differential adhesion to cell signaling avoids kinetic traps to yield robust multicellular self-organization

Abstract

Differential adhesion, where cells physically reorganize based on their heterogeneous adhesion preferences, is one of the major models for self-organization in development and tissue formation. However, accumulating evidence suggests that differential adhesion is many times insufficient for robust convergence to a target minimal energy multicellular structure. Here we use computational simulations and engineered synthetic cell circuits to systematically explore alternative mechanisms for programming formation of a simple two-cell type core-shell morphology. Starting with two pre-differentiated cell types with constitutively high differential adhesion leads to kinetic trapping in variable, multi-core structures. In contrast, hybrid mechanisms that gradually induce differential adhesion upon cell-cell contact signaling consistently converge to the target single-core structure, in a manner robust to variation in cell numbers, interaction energy, and noise. This work delineates intrinsic limitations of self-organizing systems based solely on differential adhesion, and shows how inducible systems provide a way to invoke the strong adhesion required to maintain a multicellular structure, while avoiding the pitfall of kinetic traps. This study illustrates how joint computational and experimental exploration of synthetic circuits can be used to probe key developmental principles and tradeoffs and inform the design of synthetic development and self-organization.