Collective Cell Fluidity Controls Active Prestress Transmission in Cell-Extracellular-Matrix Tissues

Abstract

Tissues are active composites in which multicellular collectives and extracellular matrices mechanically reorganize one another. We develop a three-dimensional micromechanical model that couples deformable, rearranging cell clusters to a disordered network of semiflexible fibers through a dynamic, force-generating interface. Cell clusters are represented as solid-like or fluid-like vertex-model spheroids and coupled to the matrix by passive or contractile linkers renewed as the cluster boundary reorganizes. Matched intact, voided, and passive-linker controls separate cavity formation, interfacial tethering, and active loading. At small strain, passive tethering provides modest reinforcement, whereas active contraction prestresses and strongly stiffens the matrix. Solid-like clusters preserve coherent force transmission and exhibit an excess modulus scaling approximately as $|σ|^{1.4}$ across changes in activity, cluster size, and cluster number. Fluid-like clusters undergo greater interfacial renewal, producing weaker and nonmonotonic coupling between prestress and stiffness. Increasing cluster number produces collective stiffening when prestressed regions become connected through sufficiently persistent interfaces. At large strain, both solid-like and fluid-like systems approach the corresponding voided-network response as the residual fiber backbone becomes mechanically dominant. Thus, cell-generated prestress controls macroscopic stiffness only together with the organization and persistence of its transmission across the cell-matrix interface.