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Myofibroblasts promote tissue contractures during fibrotic diseases. To understand how spontaneous changes in the intracellular calcium concentration, Ca(2+)(i), contribute to myofibroblast contraction, we analysed both Ca(2+)(i) and subcellular contractions. Contractile events were assessed by tracking stress-fibre-linked microbeads and measured by atomic force microscopy. Myofibroblasts exhibit periodic (approximately 100 seconds) Ca(2+)(i) oscillations that control small (approximately 400 nm) and weak (approximately 100 pN) contractions. Whereas depletion of Ca(2+)(i) reduces these microcontractions, cell isometric tension is unaffected, as shown by growing cells on deformable substrates. Inhibition of Rho- and ROCK-mediated Ca(2+)-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 Ca(2+)(i). The joint action of both contraction modes can result in macroscopic tissue contractures of approximately 1 cm per month.
Castella et al. (Thu,) studied this question.