The mechanobiology of fibroblast activation

Abstract

Mechanical factors are well known to affect cell fate. However, this understanding has been largely limited to the effects of uniaxial tension. While studying how fibroblasts cells change phenotype to become wound-healing myofibroblasts, we observed that the multiaxial nature of the stress field can dominate over previously known effects of tension magnitude, with the surprising result that stresses applied in two directions can have less of an effect than the same stress applied in only one direction. We explain this through the mechanobiology of cellular protrusions and collagen fibers, which undergo a two-way, self-reinforcing feedback mechanism in which cell protrusions align and stiffen collagen fibers anisotropically, while the anisotropic stress field induced by collagen fiber alignment in turn stabilizes the protrusions and aligns cells. Using integrated predictive mathematical models and experiments, we identified how to control the phenotypic transformation from fibroblast to myofibroblast. We will discuss implications for the role of mechanical factors in promoting wound healing in skin grafting and for preventing pathologies such as fibrosis.