Multi-cell ECM compaction is predictable via superposition of nonlinear cell dynamics linearized in augmented state space

Cells interacting through an extracellular matrix (ECM) exhibit emergent behaviors resulting from collective intercellular interaction. In wound healing and tissue development, characteristic compaction of ECM gel is induced by multiple cells that generate tensions in the ECM fibers and coordinate their actions with other cells. Computational prediction of collective cell-ECM interaction based on first principles is highly complex especially as the number of cells increase. Here, we introduce a computationally-efficient method for predicting nonlinear behaviors of multiple cells interacting mechanically through a 3-D ECM fiber network. The key enabling technique is superposition of single cell computational models to predict multicellular behaviors. While cell-ECM interactions are highly nonlinear, they can be linearized accurately with a unique method, termed Dual-Faceted Linearization. This method recasts the original nonlinear dynamics in an augmented space where the system behaves more linearly. The independent state variables are augmented by combining auxiliary variables that inform nonlinear elements involved in the system. This computational method involves a) expressing the original nonlinear state equations with two sets of linear dynamic equations b) reducing the order of the augmented linear system via principal component analysis and c) superposing individual single cell-ECM dynamics to predict collective behaviors of multiple cells. The method is computationally efficient compared to original nonlinear dynamic simulation and accurate compared to traditional Taylor expansion linearization. Furthermore, we reproduce reported experimental results of multi-cell induced ECM compaction.Author summary: Collective behaviors of multiple cells interacting through an ECM are prohibitively complex to predict with a mechanistic computational model due to its highly nonlinear dynamics and high dimensional space. We introduce a methodology where nonlinear dynamics of single cells are superposed to predict collective multi-cellular behaviors through a developed linearization method. We represent nonlinear single cell dynamics with linear state equations by augmenting the independent state variables with a set of auxiliary variables. We then transform the linear augmented state equations to a low-dimensional latent model and superpose the linear latent models of individual cells to predict collective behaviors that emerge from multi-cellular interactions. The method successfully reproduced experimental results of cell-induced ECM compaction.