Myofibroblast communication is controlled by intercellular mechanical coupling

Abstract

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.

Ion channels contribute to the regulation of cell sheet forces during Drosophila dorsal closure

“…We hypothesize that GsMTx4 affects MGC activity by modifying the thickness or curvature of the lipid bilayer in which these channels are embedded, consistent with known mechanisms of GsMTx4 action (Nishizawa, 2011). Studies in cell culture demonstrate that loss of MGC function by pharmacological inhibitors or targeted mutations in channel subunits leads to defects in actomyosin contractile behaviors (Guilak et al, 1999;Follonier et al, 2008;Wei et al, 2009). Nevertheless, we cannot rule out that possible indirect effects of MGC inhibition obscure specific and direct long-term effects of MGC inhibition (e.g.…”

“…Based on our observations, we hypothesize that MGCs function in a mechanical circuit(s) to coordinate forces across the embryo. Similar feedback loops are proposed for the oscillatory behavior of other mechanically coupled, contractile cells (Follonier et al, 2008;Kruse and Riveline, 2011;Schillers et al, 2010). Given that morphogenesis throughout Drosophila development requires the assembly and regulation of forceproducing structures (Butler et al, 2009;Martin et al, 2010), it will be interesting to determine how other morphogenetic processes are affected by channel inhibition.…”

Myofibroblasts in interstitial lung diseases show diverse electron microscopic and invasive features

“…24 The finding that adherens-type junctions are present in myofibroblasts is in line with the results of previous studies. 14,25 Although the existence of adherens junctions in each case of our study was variable, no statistically significant difference was observed between different diseases. On the other hand, there was a more frequent occurrence of adherens junctions in BALcultured diseased cells than in cells derived from normal lung.…”

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

“…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).…”