Calmodulin‐myosin light chain kinase inhibition changes fibroblast‐populated collagen lattice contraction, cell migration, focal adhesion formation, and wound contraction

Levinson, Howard; Moyer, Kurtis E.; Saggers, Gregory C.; Ehrlich, H. Paul

doi:10.1111/j.1067-1927.2004.012502.x

Cited by 37 publications

(29 citation statements)

References 38 publications

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“…This would be similar to the regulation of fibroblast contraction (Katoh et al, 2001b;Tomasek et al, 2002). Other reports have maintained that myofibroblast contraction is regulated by changes in intracellular Ca 2+ concentration ([Ca 2+ ] i ) and MLC kinase (MLCK) (Follonier et al, 2008;Furuya et al, 2005;Goto et al, 1998;Levinson et al, 2004;Raizman et al, 2007), which is well described for phenotyperelated smooth muscle cells (SMCs) (Kamm and Stull, 1989).…”

Section: Introductionmentioning

confidence: 53%

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

Castella

Buscemi

Godbout

et al. 2010

Journal of Cell Science

114

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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.

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Section: Introductionmentioning

confidence: 53%

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

Castella

Buscemi

Godbout

et al. 2010

Journal of Cell Science

114

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“…8 In contrast, in rat studies, wound contraction is inhibited by an MLCK inhibitor, which supports rapid myosin ATPase activity in wound contraction. 9 Alizadeh and coworkers 6 reported that retarded wound contraction was related to inhibited conversion of wound fibroblasts into myofibroblasts. However, other studies showed that wound contraction proceeds in the absence of myofibroblast populations.…”

Section: Experimental Models Animal Studiesmentioning

confidence: 99%

Collagen Organization Critical Role in Wound Contraction

Ehrlich

Hunt

2012

Advances in Wound Care

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Background: Open wound closure by wound contraction produces a healed defect made up mostly of dermis. Generating thicker collagen fibers condenses granulation tissue, which pulls surrounding skin into the defect. The Problem: What is the mechanism for open wound contraction? Is it through the generation of contractile force using sustained myosin ATPase, thus causing cell contraction or by rapid myosin ATPase that condenses collagen fibrils into fibers? Basic/Clinical Science Addressed: The mechanism for wound contraction is not often debated after the discovery of the myofibroblast. Myofibroblasts are the major cell phenotype in maturing granulation tissue. It is concluded, not quite accurately, that myofibroblasts are responsible for wound contraction. As wound contraction progresses, polarized light microscopy reveals birefringence patterns associated with ever-increasing thickening of collagen fibers. Collagen fibers thicken by eliminating water between fibrils. Wound contraction requires collagen synthesis and granulation tissue compaction. Both myofibroblasts and fibroblasts synthesize collagen, but fibroblasts, not myofibroblasts, compact collagen. Free-floating fibroblast-populated collagen lattices (FPCL) contract by rapid myosin ATPase, thus resulting in thicker collagen fibers by elongated fibroblasts. The release of an attached FPCL, using sustained myosin ATPase, produces rapid lattice contraction, now populated with contracted myofibroblasts in the absence of thick collagen fibers. Discussion: In vivo and in vitro studies show that rapid myosin ATPase is the motor for wound contraction. Myofibroblasts maintain steady mechanotension through sustained myosin ATPase, which generates cell contraction forces that fail to produce thicker collagen fibers. The hypothesis is that cytoplasmic microfilaments pull collagen fibrils over the fibroblast's plasma membrane surface, bringing collagen fibrils in closer contact with one another. The self-assembly nature of collagen fixes collagen fibrils in regular arrays generating thicker collagen fibers. Conclusion: Wound contraction progresses through fibroblasts generating thicker collagen fibers, using tractional forces; rather than by myofibroblasts utilizing cell contraction forces. BACKGROUNDWound contraction, literally a shrinkage of open skin wounds, leaves a remarkably small scar as the surrounding normal skin moves centripetally to close the wound. It has aroused the curiosity of students

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“…[i] concentration was shown to activate myosin light chain kinase via Ca 2+ /calmodulin, leading to short-lived contraction similar to that in smooth muscle (Ehrlich et al, 1991;Katoh et al, 2001;Levinson et al, 2004). It is conceivable that contractions following Ca…”

Section: +mentioning

confidence: 99%

Myofibroblast communication is controlled by intercellular mechanical coupling

Follonier

Schaub

Meister

et al. 2008

Journal of Cell Science

110

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Neoformation of intercellular adherens junctions accompanies the differentiation of fibroblasts into contractile myofibroblasts, a key event during development of fibrosis and in wound healing. We have previously shown that intercellular mechanical coupling of stress fibres via adherens junctions improves contraction of collagen gels by myofibroblasts. By assessing spontaneous intracellular Ca2+ oscillations, we here test whether adherens junctions mechanically coordinate myofibroblast activities. Periodic Ca2+ oscillations are synchronised between physically contacting myofibroblasts and become desynchronised upon dissociation of adherens junctions with function-blocking peptides. Similar uncoupling is obtained by inhibiting myofibroblast contraction using myosin inhibitors and by blocking mechanosensitive ion channels using Gd3+ and GSMTx4. By contrast, gap junction uncouplers do not affect myofibroblast coordination. We propose the following model of mechanical coupling for myofibroblasts: individual cell contraction is transmitted via adherens junctions and leads to the opening of mechanosensitive ion channels in adjacent cells. The resulting Ca2+ influx induces a contraction that can feed back on the first cell and/or stimulate other contacting cells. This mechanism could improve the remodelling of cell-dense tissue by coordinating the activity of myofibroblasts.

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Calmodulin‐myosin light chain kinase inhibition changes fibroblast‐populated collagen lattice contraction, cell migration, focal adhesion formation, and wound contraction

Cited by 37 publications

References 38 publications

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

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

Collagen Organization Critical Role in Wound Contraction

Myofibroblast communication is controlled by intercellular mechanical coupling

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