Force-exerting perpendicular lateral protrusions in fibroblastic cell contraction

Aligned extracellular matrix fibers enable fibroblasts to undergo myofibroblastic activation and achieve elongated shapes. Activated fibroblasts are able to contract, perpetuating the alignment of these fibers. This poorly understood feedback process is critical in chronic fibrosis conditions, including cancer. Here, using fiber networks that serve as force sensors, we identify 3D perpendicular lateral protrusions (3D-PLPs) that evolve from lateral cell extensions named twines. Twines originate from stratification of cyclic-actin waves traversing the cell and swing freely in 3D to engage neighboring fibers. Once engaged, a lamellum forms and extends multiple secondary twines, which fill in to form a sheet-like PLP, in a force-entailing process that transitions focal adhesions to activated (i.e., pathological) 3D-adhesions. The specific morphology of PLPs enables cells to increase contractility and force on parallel fibers. Controlling geometry of extracellular networks confirms that anisotropic fibrous environments support 3D-PLP formation and function, suggesting an explanation for cancer-associated desmoplastic expansion. Padhi et al. employ nanofibers with controlled structure and alignment as an extra-cellular matrix model, on which they study the exertion of forces from adherent fibroblasts. Identifying force exerting 3D perpendicular lateral protrusions, authors describe a mechanism which leads to the contraction of parallel, neighbouring fibers, and the forces needed to move and align the neighbouring fibers. These findings have relevance in understanding cancer-associated desmoplastic expansion.