Cell-Extracellular Matrix Feedback Results in Spontaneous Cell Polarization and Heterogeneous Remodeling in 3D Isotropic and Aligned Discrete-Fiber Models of Cell-Mediated Remodeling.

Purpose: The extracellular matrix (ECM) is a dynamic fiber environment containing structural information that significantly impacts cell behavior. Recent experimental work has demonstrated that cells also have significant capacity to remodel their microenvironment, often resulting in ECM heterogeneity. We present an open-source molecular dynamics platform that simulates cell-mediated remodeling wherein cells plasticly remodel their microenvironment and respond to induced structural heterogeneity over multiple retraction cycles. Methods: The model applies a coarse-grained discrete fiber approach to cell-mediated remodeling. The ECM, represented by a bead-spring polymer, allows proximity-mediated fiber-fiber interactions, representing fiber crosslinking and entanglement. A simulated cell interprets the heterogeneity of its local microenvironment with variable sensitivity and exhibits anisotropic behavior informed by its microenvironment. The cells generate tractors, representing pseudopods, that bind to the ECM and retract towards the cell surface, causing ECM displacement. The cell detaches from the ECM by deleting tractors and allowing the ECM to relax before re-interpreting its surroundings and repeating this process. Metrics of ECM remodeling (fiber densification, orientation, bond strain) and cell morphology were recorded throughout the simulation. The model was extended to a cell remodeling fiber networks with different levels of pre-existing alignment. Results: The addition of plasticity in the model enables measurable remodeling: increasing fiber density close to the cell, reorienting fibers radially, and increasing residual fiber bond strain over time. These patterns of remodeling were consistent with previously published experimental results. In initially unaligned fiber networks, cell remodeling resulted in ECM heterogeneity that depended on distance from the cell surface and alignment with the cell's primary axis. In aligned networks, pre-alignment and sensitivity synergized to increase the heterogeneity of the remodeled networks at further distances from the cell surface. Conclusions: These findings suggest that cell-ECM feedback mechanisms contribute to heterogeneous remodeling patterns and illustrate that pre-existing alignment impacts remodeling patterns far from the cell. Further, the model presented herein provides a novel modular platform for further investigations into cell-ECM sensing and ECM remodeling heterogeneity. Supplementary Information: The online version contains supplementary material available at 10.1007/s12195-026-00922-0.