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

Abstract

SummaryMyofibroblasts 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 (~100 seconds) [Ca 2+ ] i oscillations that control small (~400 nm) and weak (~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 ROCKdependent isometric tension generates slack in extracellular matrix fibrils, which are then accessible for the low-amplitude and highfrequency contractions mediated by [Ca 2+ ] i . The joint action of both contraction modes can result in macroscopic tissue contractures of ~1 cm per month.

Actin stress fibers – assembly, dynamics and biological roles

“…Indeed, it is possible that, under many conditions, stress fibers instead inhibit cell motility because the reorganization of stable actin bundles and focal adhesions can be a relatively slow process. The physiological significance of stress fibers in cell migration might thus be linked to their role in constricting the ECM and deforming the substrate through the generation of tension (Castella et al, 2010). This could be important in wound healing processes and in cell migration on stiff matrices.…”

Matrix Remodeling in Pulmonary Fibrosis and Emphysema

“…In addition to enhanced synthetic and invasive capacity, activated myofibroblasts exert isometric contractile activity. This activity is maintained by a single-cell lock-step model via the combined actions of intracellular calcium and Rho/Rho kinase (Rho/ROCK)-mediated calcium-independent contraction (46). The contractile activity of myofibroblasts results in macroscopic tissue contracture (28), which likely contributes to alveolar collapse and the observed reduction in total lung capacity in IPF.…”

Transient mechanical strain promotes the maturation of invadopodia and enhances cancer cell invasion in vitro

“…During the remodeling process, a tugging force is generated on the surrounding collagen fibers as they are bundled and arranged (Castella et al, 2010;Goffin et al, 2006;Murrell et al, 2015;Oudin et al, 2016). The presence of the myofibroblasts and the forces they generate have been linked to increased cancer cell invasion and motility (De Wever et al, 2008;Elkabets et al, 2011;Fuyuhiro et al, 2012).…”