A New Lock-step Mechanism of Matrix Remodelling Based on Subcellular Contractile Events

Myofibroblasts promote tissue contractures during fibrotic diseases. To understand how spontaneous changes in the intracellular calcium concentration, Ca2+, contribute to myofibroblast contraction, we analysed both Ca2+ and subcellular contractions. Contractile events were assessed by tracking stress-fibre-linked microbeads and measured by atomic force microscopy. Myofibroblasts exhibit periodic (similar to 100 seconds) Ca2+ oscillations that control small (similar to 400 nm) and weak (similar to 100 pN) contractions. Whereas depletion of Ca2+ reduces these microcontractions, cell isometric tension is unaffected, as shown by growing cells on deformable substrates. Inhibition of Rho-and ROCK-mediated Ca2+-independent contraction has no effect on microcontractions, but abolishes cell tension. On the basis of this two-level regulation of myofibroblast contraction, we propose a single-cell lock-step model. Rho- and ROCK-dependent isometric tension generates slack in extracellular matrix fibrils, which are then accessible for the low-amplitude and high-frequency contractions mediated by Ca2+. The joint action of both contraction modes can result in macroscopic tissue contractures of similar to 1 cm per month.