A model of multicellular communication mediated through extracellular matrix microstructure

AbstractExtracellular matrix (ECM) is a key part of the cellular microenvironment and critical in multiple disease and developmental processes. Representing ECM and cell-ECM interactions is a challenging multiscale problem. While several computational frameworks exist for ECM modeling, they typically focus on very detailed modeling of individual ECM fibers or represent only a single aspect of the ECM. Using the PhysiCell agent-based modeling platform, we developed a new framework of intermediate detail that addresses direct cell-ECM interactions. We represent a small region of ECM, an ECM element, with 3 variables: anisotropy, density, and orientation. We then place many ECM elements throughout a space to form an ECM. Cells have a mechanical response to the ECM element variables and remodel ECM elements based on their velocity. We demonstrate aspects of this framework with a model of cell invasion where a cell’s motility is driven by the ECM microstructure patterned by prior cells’ movements. Investigating the limit of high-speed communication and with stepwise introduction of the framework features, we generate a range of cellular dynamics and ECM configurations – from recapitulating a homeostatic tissue, to indirect communication of paths (stigmergy), to collective migration. When we relax the high-speed communication assumption, we find that the behaviors persist but can be lost as rate of signal generation declines. This result suggests that cell-cell communication mediated via the ECM can constitute an important mechanism for collective cell behavior and multicellular pattern formation, with implications for tissue morphogenesis, developmental biology, microbial ecosystems, and cancer invasion.