Agent-Based Model of Multicellular Spheroid Pattern Formation Driven by Synthetic Cell Adhesion Signaling Circuits

Dynamically activated differential adhesion within cell populations enables the emergence of unique patterns in heterogeneous multicellular systems. This process has previously been explored using synthetically engineered heterogenous multicell spheroid systems in which cell subpopulations engage in bidirectional intercellular signaling to regulate the expression of different cadherins. While engineered cell systems provide excellent experimental tools to observe pattern formation in cell populations, computational models may be leveraged to explore the key parameters that drive the emergence of different patterns more systematically. Here, we developed and validated two- and three-dimensional agent-based models (ABMs) of spheroid patterning for cells engineered with a bidirectional signaling circuit regulating N- and P-cadherin expression. The model was used to predict how varying initial cell seeding, cadherin induction probabilities, or homotypic adhesion strengths between cells leads to different spheroid patterns, and unsupervised machine learning techniques were used to map system parameters to unique spheroid patterns. The model was also used as a tool to design new synthetic cell signaling circuits based on a desired final multicell pattern.