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, [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
Lysianne Follonier
LF
Laboratory of Cell Biophysics, Ecole Polytechnique Fédérale de Lausanne, CH-1015 Lausanne, Switzerland.
Buscemi
Lara
L
Godbout
Charles
C
Meister
Jean-Jacques
JJ
Hinz
Boris
B
D000199:Actins / Q000378:metabolism; D000818:Animals; D020013:Calcium Signaling; D002454:Cell Differentiation; D002478:Cells, Cultured; D005109:Extracellular Matrix / Q000378:metabolism*; D005347:Fibroblasts / Q000502:physiology*; D005355:Fibrosis / Q000503:physiopathology*; D022001:Focal Adhesions / Q000378:metabolism; D008954:Models, Biological; D032342:Muscle Cells / Q000502:physiology*; D009200:Myocardial Contraction; D051381:Rats; D022502:Stress Fibers / Q000378:metabolism*; D054460:rho-Associated Kinases / Q000378:metabolism
C541116:ACTA2 protein, human; D000199:Actins; D054460:rho-Associated Kinases