Journal
JOURNAL OF CELL SCIENCE
Volume 123, Issue 10, Pages 1751-1760Publisher
COMPANY OF BIOLOGISTS LTD
DOI: 10.1242/jcs.066795
Keywords
Myofibroblast; Fibrosis; Calcium oscillations; Rho kinase; Stress fibre; Collagen
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Funding
- Swiss National Science Foundation [3100A0-113733/1]
- GEBERT RUF STIFTUNG
- Novartis Science Foundation
- Connaught Funding Program
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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 (similar to 100 seconds) [Ca2+](i) oscillations that control small (similar to 400 nm) and weak (similar to 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 similar to 1 cm per month.
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