A new lock-step mechanism of matrix remodelling based on subcellular contractile events

Abstract

Myofibroblasts promote tissue contractures during fibrotic diseases. To understand how spontaneous changes in the intracellular calcium concentration, [Ca2+]i, contribute to myofibroblast contraction, we analysed both [Ca2+]i and subcellular contractions. Contractile events were assessed by tracking stress-fibre-linked microbeads and measured by atomic force microscopy. Myofibroblasts exhibit periodic (~100 seconds) [Ca2+]i oscillations that control small (~400 nm) and weak (~100 pN) contractions. Whereas depletion of [Ca2+]i 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+]i. The joint action of both contraction modes can result in macroscopic tissue contractures of ~1 cm per month.