Tension anisotropy drives fibroblast phenotypic transition by self-reinforcing cell-extracellular matrix mechanical feedback.

Mechanical factors such as stress in the extracellular environment affect the phenotypic commitment of cells. Stress fields experienced by cells in tissues are multiaxial, but how cells integrate such information is largely unknown. Here we report that the anisotropy of stress fields is a critical factor triggering a phenotypic transition in fibroblast cells, outweighing the role of stress amplitude, a factor previously described to modulate such a transition. Combining experimental and computational approaches, we identified a self-reinforcing mechanism in which cellular protrusions interact with collagen fibres to establish tension anisotropy. This anisotropy, in turn, stabilizes the protrusions and enhances their contractile forces. Disruption of this self-reinforcing process, either by reducing tension anisotropy or by inhibiting contractile protrusions, prevents the phenotypic conversion of fibroblasts to contractile myofibroblasts. Overall, our findings support stress anisotropy as a factor modulating cellular responses, expanding our understanding of the role of mechanical forces in biological processes.