Cellular Dewetting: Opening of Macroapertures in Endothelial Cells

Abstract

Pathogenic bacteria can cross from blood vessels to host tissues by opening transendothelial cell macroapertures (TEMs). To induce TEM opening, bacteria intoxicate endothelial cells with proteins that disrupt the contractile cytoskeletal network. Cell membrane tension is no longer resisted by contractile fibers, leading to the opening of TEMs. Here we model the opening of TEMs as a new form of dewetting. While liquid dewetting is irreversible, we show that cellular dewetting is transient. Our model predicts the minimum radius for hole nucleation, the maximum TEM size, and the dynamics of TEM opening, in good agreement with experimental data. The physical model is then coupled with biological experimental data to reveal that the protein missing in metastasis (MIM) controls the line tension at the rim of the TEM and opposes its opening.

Transcellular tunnel dynamics: Control of cellular dewetting by actomyosin contractility and I‐BAR proteins

“…Two recent studies have revealed that TEM tunnel opening can be described as a cellular form of dewetting, that is, the physical processes governing TEM are analogous to those governing the opening of dry patches in liquid films (Box 1 and see Maddugoda et al, 2011;Gonzalez-Rodriguez et al, 2012 for biological and physical details). Liquid dewetting is a very common phenomenon that occurs for instance when water is forced to spread on a hydrophobic substrate or when oil is heated on a non-adhering pan.…”

“…Excessive contraction or disruption of the actin cytoskeleton cortex leads to the local detachment of the membrane associated with induction of membrane blebs (Sheetz et al, 2006;Ridley, 2011;Spangler et al, 2011;Salbreux et al, 2012). In contrast, a reduction of actomyosin cable contractility produces large tunnels across thin endothelial cells, referred to as transendothelial cell macroaperture tunnels (TEMs) (Boyer et al, 2006;Maddugoda et al, 2011;Gonzalez-Rodriguez et al, 2012). Internal cellular regulation usually inhibits the spontaneous formation of such TEMs, but some bacterial toxins or leucocytes have the capability to induce TEMs to cross the endothelial barrier .…”

“…Tunnels open up to a maximum diameter of about 10-20 μm within 1-2 min, depending on the type of cell intoxication ( Figure 1). Next, membrane waves rich in actin filaments (F-actin) extend around the edge of the TEM driving aperture closure in about 3-5 min ( Figure 1) (Boyer et al, 2006;Maddugoda et al, 2011; Gonzalez-Rodriguez et al, 2012). As discussed in the following section from liquid dewetting to cellular dewetting, recent physical modelling of TEM dynamics suggests a new framework to help decipher the relationship between actomyosin contractility and membrane tension, and how this interplay affects cell shape organisation (Gonzalez-Rodriguez et al, 2012).…”

“…While cell blebs have been extensively studied from biological and physical perspectives, much remains to be learned on TEM dynamic. Recently, studies conducted on a group of bacterial toxins, now referred to as tunnel-forming toxins (TFTs), have shed light on the molecular and biophysical aspects of the dynamic of TEM formation (Maddugoda et al, 2011;Gonzalez-Rodriguez et al, 2012). These toxins reduce actomyosin contractility and allow for the spontaneous opening of large apertures (macroapertures) across endothelial cells (Boyer et al, 2006;Maddugoda et al, 2011).…”

Critical density for the stability of a 2D magnet array

“…Many periodic systems can relax towards equilibrium when a large enough disturbance appears, such as supercooled liquids [2], dewetting cells [3], snow avalanches [4] and nucleating bubbles in liquids [5]. Of particular note are instabilities driven by a competition between weight and magnetic forces created by permanent magnets.…”