A computational modeling approach for predicting multicell spheroid patterns based on signaling-induced differential adhesion

• Published in: PLoS computational biology 2022-11, Vol.18 (11), p.e1010701-e1010701
• Main Authors: Sivakumar, Nikita, Warner, Helen V, Peirce, Shayn M, Lazzara, Matthew J
• Format: Article
• Language: English
• Subjects: Adhesion; Adhesives; Agent based models; Analysis; Biology and Life Sciences; Cadherins; Cadherins - metabolism; Cell adhesion; Cell Adhesion - physiology; Cell Communication; Cell culture; Cell signaling; Circuit design; Clustering; Computer applications; Computer Simulation; Embryogenesis; Embryonic Development; Embryonic growth stage; Engineering and Technology; Experiments; Genotype & phenotype; Hypotheses; Ligands; Mathematical models; Medicine and Health Sciences; Methods; Parameters; Pattern formation; Patterning; Physical Sciences; Probability; Protein expression; Proteins; Research and Analysis Methods; Signal Transduction; Signaling; Sphere; Spheroids; Subpopulations; Synthetic biology; Three dimensional models; Tumorigenesis
• ISSN: 1553-7358; 1553-734X; 1553-7358
• DOI: 10.1371/journal.pcbi.1010701

Physiological and pathological processes including embryogenesis and tumorigenesis rely on the ability of individual cells to work collectively to form multicell patterns. In these heterogeneous multicell systems, cell-cell signaling induces differential adhesion between cells that leads to tissue-level patterning. However, the sensitivity of pattern formation to changes in the strengths of signaling or cell adhesion processes is not well understood. Prior work has explored these issues using synthetically engineered heterogeneous 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 of these systems may be leveraged to explore more systematically how specific combinations of signaling and adhesion parameters can drive the emergence of unique patterns. We developed and validated two- and three-dimensional agent-based models (ABMs) of spheroid patterning for previously described cells engineered with a bidirectional signaling circuit that regulates N- and P-cadherin expression. Systematic exploration of model predictions, some of which were experimentally validated, revealed how cell seeding parameters, the order of signaling events, probabilities of induced cadherin expression, and homotypic adhesion strengths affect pattern formation. Unsupervised clustering was also used to map combinations of signaling and adhesion parameters to these unique spheroid patterns predicted by the ABM. Finally, we demonstrated how the model may be deployed to design new synthetic cell signaling circuits based on a desired final multicell pattern.