Grouped cells often leave large cell colonies in the form of narrow multicellular streams. However, it remains unknown how collective cell streaming exploits specific matrix properties, like stiffness and fiber length. It is also unclear how cellular forces, cell-cell adhesion and velocities are coordinated within streams. To independently tune stiffness and collagen fiber length, we developed new hydrogels and discovered invasion-like streaming of normal epithelial cells on soft substrates coated with long collagen fibers. Here, streams arise owing to a surge in cell velocities, forces, YAP activity and expression of mesenchymal marker proteins in regions of high-stress anisotropy. Coordinated velocities and symmetric distribution of tensile and compressive stresses support persistent stream growth. Stiff matrices diminish cell-cell adhesions, disrupt front-rear velocity coordination and do not promote sustained fiber-dependent streaming. Rac inhibition reduces cell elongation and cell-cell cooperation, resulting in a complete loss of streaming in all matrix conditions. Our results reveal a stiffness-modulated effect of collagen fiber length on collective cell streaming and unveil a biophysical mechanism of streaming governed by a delicate balance of enhanced forces, monolayer cohesion and cell-cell cooperation.
Cell collectives use aligned extracellular matrix fibers for directed migration in development, regeneration, and cancer metastasis. Previously, stiffer matrices and aligned matrix topographies have been shown to independently enhance and polarize cellular forces, which in turn speed up cell migration. However, it remains unknown whether fibers serve as active conduits for spatial propagation of cellular mechanotransduction and directed collective cell migration independently of stiffness cues. In this work, we developed soft hydrogels coated with magnetically aligned collagen fibers and studied migration of defined epithelial clusters. We report that epithelial (MCF10A) cell clusters adhered to soft substrates with aligned collagen fibers (AF) migrate faster with much lesser traction forces, compared to those on uniform fibers (UF). Fiber alignment causes motility and force transmission deeper into the monolayer, leading to polarized cell flocking, compared to migration on UF where cellular jamming occurs. Using a motor-clutch model, we explain that force-effective fast migration phenotype occurs due to faster stabilization of cellular contractile forces enabled by aligned ligand connectivity. As a result, cells migrate faster with lesser effort, thereby revealing that aligned matrix topographies may help conserve energy for cell migration in fundamental biological processes such as wound repair and tumor invasion.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.