by Keyword: tension

Pérez-González, Carlos, Ceada, Gerardo, Matejcic, Marija, Trepat, Xavier, (2022). Digesting the mechanobiology of the intestinal epithelium Current Opinion In Genetics & Development 72, 82-90

The dizzying life of the homeostatic intestinal epithelium is governed by a complex interplay between fate, form, force and function. This interplay is beginning to be elucidated thanks to advances in intravital and ex vivo imaging, organoid culture, and biomechanical measurements. Recent discoveries have untangled the intricate organization of the forces that fold the monolayer into crypts and villi, compartmentalize cell types, direct cell migration, and regulate cell identity, proliferation and death. These findings revealed that the dynamic equilibrium of the healthy intestinal epithelium relies on its ability to precisely coordinate tractions and tensions in space and time. In this review, we discuss recent findings in intestinal mechanobiology, and highlight some of the many fascinating questions that remain to be addressed in this emerging field.Copyright © 2021 The Author(s). Published by Elsevier Ltd.. All rights reserved.

JTD Keywords: crypt fission, designer matrices, differentiation, growth, gut, migration, model, scaffold, tissue mechanics, Cell migration, Cell proliferation, Ex vivo study, Human tissue, Intestine epithelium, Monolayer culture, Organoid, Review, Stem-cell, Tension, Traction therapy

Nyga, Agata, Muñoz, Jose J., Dercksen, Suze, Fornabaio, Giulia, Uroz, Marina, Trepat, Xavier, Baum, Buzz, Matthews, Helen K., Conte, Vito, (2021). Oncogenic RAS instructs morphological transformation of human epithelia via differential tissue mechanics Science Advances 7, eabg6467

Pérez-González C, Ceada G, Greco F, Matejcic M, Gómez-González M, Castro N, Menendez A, Kale S, Krndija D, Clark AG, Gannavarapu VR, Álvarez-Varela A, Roca-Cusachs P, Batlle E, Vignjevic DM, Arroyo M, Trepat X, (2021). Mechanical compartmentalization of the intestinal organoid enables crypt folding and collective cell migration Nature Cell Biology 23, 745-757

Intestinal organoids capture essential features of the intestinal epithelium such as crypt folding, cellular compartmentalization and collective movements. Each of these processes and their coordination require patterned forces that are at present unknown. Here we map three-dimensional cellular forces in mouse intestinal organoids grown on soft hydrogels. We show that these organoids exhibit a non-monotonic stress distribution that defines mechanical and functional compartments. The stem cell compartment pushes the extracellular matrix and folds through apical constriction, whereas the transit amplifying zone pulls the extracellular matrix and elongates through basal constriction. The size of the stem cell compartment depends on the extracellular-matrix stiffness and endogenous cellular forces. Computational modelling reveals that crypt shape and force distribution rely on cell surface tensions following cortical actomyosin density. Finally, cells are pulled out of the crypt along a gradient of increasing tension. Our study unveils how patterned forces enable compartmentalization, folding and collective migration in the intestinal epithelium. Perez-Gonzalez et al. explore the mechanical properties of intestinal organoids, and report the existence of distinct mechanical domains and that cells are pulled out of the central crypt along a gradient of increasing tension.

JTD Keywords: Forces, Growth, Gut, Monolayers, Morphogenesis, Reveal, Stem-cells, Tension

Pieper CC, Feißt A, Meyer C, Luetkens J, Praktiknjo M, Trebicka J, Attenberger U, Jansen C, (2021). Impact of transjugular intrahepatic portosystemic shunt creation on the central lymphatic system in liver cirrhosis Scientific Reports 11, 7065

The puropse of this study was to evaluate associations of cisterna chyli (CCh) diameter with portal hemodynamics and the influence of TIPS-creation in cirrhotic patients. 93 cirrhotic patients (57 male, mean age 59 years) received CT prior to TIPS-creation. 38/93 additionally underwent post-interventional CT. CCh-diameter was measured. After categorization into patients with and without large venous collaterals (i.e. > 6 mm), data were analyzed regarding associations between CCh-diameter, clinical and portal-hemodynamic parameters and diameter-changes after TIPS-creation. Patient survival post-TIPS was analyzed. Median portosystemic pressure-gradient decreased from 20 to 9 mmHg after TIPS-creation. Large venous collaterals were observed in 59 patients. In 69/93 patients (74.2%) the CCh was detectable. Mean pre-interventional diameter was 9.4 ± 2.7 mm (large collaterals: 8.7 ± 2.0 mm, no large collaterals: 10.7 ± 3.2 mm, p = 0.003). CCh-diameter correlated strongly with pre-TIPS portal-pressure (Rs = 0.685, p = 0.0001), moderately with portosystemic-gradient (Rs = 0.524, p = 0.006), liver shear-wave-elastography (Rs = 0.597, p = 0.004) and spleen size (Rs = 0.501, p = 0.01) in patients without large collaterals, but not in patients with large collaterals. Post-TIPS CCh-diameter decreased significantly from 10.2 ± 2.8 mm to 8.3 ± 3.0 mm (p < 0.001). Patients without a detectable CCh on CT survived significantly shorter. The diameter of the CCh is associated with portal-pressure and decreases after TIPS-creation in cirrhotic patients, reflecting a portal decompression mechanism via the lymphatic system. Lack of larger central lymphatics detectable on CT may be associated with shorter survival.

JTD Keywords: circulation, cisterna chyli, fluid, hepatic cirrhosis, shear-wave elastography, thoracic-duct, vessels, Significant portal-hypertension

Raote, Ishier, Chabanon, Morgan, Walani, Nikhil, Arroyo, Marino, Garcia-Parajo, Maria F., Malhotra, Vivek, Campelo, Felix, (2020). A physical mechanism of TANGO1-mediated bulky cargo export eLife 9, e59426

The endoplasmic reticulum (ER)-resident protein TANGO1 assembles into a ring around ER exit sites (ERES), and links procollagens in the ER lumen to COPII machinery, tethers, and ER-Golgi intermediate compartment (ERGIC) in the cytoplasm (Raote et al., 2018). Here, we present a theoretical approach to investigate the physical mechanisms of TANGO1 ring assembly and how COPII polymerization, membrane tension, and force facilitate the formation of a transport intermediate for procollagen export. Our results indicate that a TANGO1 ring, by acting as a linactant, stabilizes the open neck of a nascent COPII bud. Elongation of such a bud into a transport intermediate commensurate with bulky procollagens is then facilitated by two complementary mechanisms: (i) by relieving membrane tension, possibly by TANGO1-mediated fusion of retrograde ERGIC membranes and (ii) by force application. Altogether, our theoretical approach identifies key biophysical events in TANGO1-driven procollagen export.

JTD Keywords: Membrane tension, Procollagen export, Secretory pathway, Membrane curvature, Membrane dynamics, Budding

Torner, M., Mangal, A., Scharnagl, H., Jansen, C., Praktiknjo, M., Queck, A., Gu, W., Schierwagen, R., Lehmann, J., Uschner, F. E., Graf, C., Strassburg, C. P., Fernandez, J., Stojakovic, T., Woitas, R., Trebicka, J., (2020). Sex specificity of kidney markers to assess prognosis in cirrhotic patients with TIPS Liver International 40, (1), 186-193

Background & Aims: Renal function assessed by creatinine is a key prognostic factor in cirrhotic patients. However, creatinine is influenced by several factors, rendering interpretation difficult in some situations. This is especially important in early stages of renal dysfunction where renal impairment might not be accompanied by an increase in creatinine. Other parameters, such as cystatin C (CysC) and beta‐trace protein (BTP), have been evaluated to fill this gap. However, none of these studies have considered the role of the patient's sex. The present study analysed CysC and BTP to evaluate their prognostic value and differentiate them according to sex. Patients and methods: CysC and BTP were measured in 173 transjugular intrahepatic portosystemic shunt (TIPS)-patients from the NEPTUN-STUDY(NCT03628807) and analysed their relationship with mortality and sex. Propensity score for age, MELD, etiology and TIPS indication was used. Results: Cystatin C and BTP showed excellent correlations with creatinine values at baseline and follow-up. CysC was an independent predictor of overall mortality (HR = 1.66(1.33-2.06)) with an AUC of 0.75 and identified a cut-off of 1.55 mg/L in the whole cohort. Interestingly, CysC was significantly lower in females, also after propensity score matching. In males, the only independent predictor was the creatinine level (HR = 1.54(1.25-1.58)), while in females CysC levels independently predicted mortality (HR = 3.17(1.34-7.52)). Conclusion: This study demonstrates for the first time that in TIPS-patients creatinine predicts mortality in males better than in females, whereas CysC is a better predictor of mortality in females. These results may influence future clinical decisions on therapeutic options for example, allocation for liver transplantation in TIPS-patients.

JTD Keywords: Beta-trace protein, Cirrhosis, Cystatin C, Portal hypertension, Renal function

Cremonese, C., Schierwagen, R., Uschner, F. E., Torres, S., Tyc, O., Ortiz, C., Schulz, M., Queck, A., Kristiansen, G., Bader, M., Sauerbruch, T., Weiskirchen, R., Walther, T., Trebicka, J., Klein, S., (2020). Short-term western diet aggravates non-alcoholic fatty liver disease (NAFLD) with portal hypertension in TGR(mREN2)27 rats International Journal of Molecular Sciences 21, (9), 3308

Non-alcoholic fatty liver disease (NAFLD) is gaining in importance and is linked to obesity. Especially, the development of fibrosis and portal hypertension in NAFLD patients requires treatment. Transgenic TGR(mREN2)27 rats overexpressing mouse renin spontaneously develop NAFLD with portal hypertension but without obesity. This study investigated the additional role of obesity in this model on the development of portal hypertension and fibrosis. Obesity was induced in twelve-week old TGR(mREN2)27 rats after receiving Western diet (WD) for two or four weeks. Liver fibrosis was assessed using standard techniques. Hepatic expression of transforming growth factor-β1 (TGF-β1), collagen type Iα1, α-smooth muscle actin, and the macrophage markers Emr1, as well as the chemoattractant Ccl2, interleukin-1β (IL1β) and tumor necrosis factor-α (TNFα) were analyzed. Assessment of portal and systemic hemodynamics was performed using the colored microsphere technique. As expected, WD induced obesity and liver fibrosis as confirmed by Sirius Red and Oil Red O staining. The expression of the monocyte-macrophage markers, Emr1, Ccl2, IL1β and TNFα were increased during feeding of WD, indicating infiltration of macrophages into the liver, even though this increase was statistically not significant for the EGF module-containing mucin-like receptor (Emr1) mRNA expression levels. Of note, portal pressure increased with the duration of WD compared to animals that received a normal chow. Besides obesity, WD feeding increased systemic vascular resistance reflecting systemic endothelial and splanchnic vascular dysfunction. We conclude that transgenic TGR(mREN2)27 rats are a suitable model to investigate NAFLD development with liver fibrosis and portal hypertension. Tendency towards elevated expression of Emr1 is associated with macrophage activity point to a significant role of macrophages in NAFLD pathogenesis, probably due to a shift of the renin–angiotensin system towards a higher activation of the classical pathway. The hepatic injury induced by WD in TGR(mREN2)27 rats is suitable to evaluate different stages of fibrosis and portal hypertension in NAFLD with obesity.

JTD Keywords: ADGRE1, EMR1, F4/80, Immunity, Liver fibrosis, Macrophage, NAFLD, Portal hypertension, TGR(mREN2)27, Western diet

Praktiknjo, M., Simón-Talero, M., Römer, J., Roccarina, D., Martínez, J., Lampichler, K., Baiges, A., Low, G., Llop, E., Maurer, M. H., Zipprich, A., Triolo, M., Maleux, G., Fialla, A. D., Dam, C., Vidal-González, J., Majumdar, A., Picón, C., Toth, D., Darnell, A., Abraldes, J. G., López, M., Jansen, C., Chang, J., Schierwagen, R., Uschner, F., Kukuk, G., Meyer, C., Thomas, D., Wolter, K., Strassburg, C. P., Laleman, W., La Mura, V., Ripoll, C., Berzigotti, A., Calleja, J. L., Tandon, P., Hernandez-Gea, V., Reiberger, T., Albillos, A., Tsochatzis, E. A., Krag, A., Genescà , J., Trebicka, J., (2020). Total area of spontaneous portosystemic shunts independently predicts hepatic encephalopathy and mortality in liver cirrhosis Journal of Hepatology 72, (6), 1140-1150

Background & Aims: Spontaneous portosystemic shunts (SPSS) frequently develop in liver cirrhosis. Recent data suggested that the presence of a single large SPSS is associated with complications, especially overt hepatic encephalopathy (oHE). However, the presence of >1 SPSS is common. This study evaluates the impact of total cross-sectional SPSS area (TSA) on outcomes in patients with liver cirrhosis. Methods: In this retrospective international multicentric study, CT scans of 908 cirrhotic patients with SPSS were evaluated for TSA. Clinical and laboratory data were recorded. Each detected SPSS radius was measured and TSA calculated. One-year survival was the primary endpoint and acute decompensation (oHE, variceal bleeding, ascites) was the secondary endpoint. Results: A total of 301 patients (169 male) were included in the training cohort. Thirty percent of all patients presented with >1 SPSS. A TSA cut-off of 83 mm2 was used to classify patients with small or large TSA (S-/L-TSA). Patients with L-TSA presented with higher model for end-stage liver disease score (11 vs. 14) and more commonly had a history of oHE (12% vs. 21%, p <0.05). During follow-up, patients with L-TSA experienced more oHE episodes (33% vs. 47%, p <0.05) and had lower 1-year survival than those with S-TSA (84% vs. 69%, p <0.001). Multivariate analysis identified L-TSA (hazard ratio 1.66; 95% CI 1.02–2.70, p <0.05) as an independent predictor of mortality. An independent multicentric validation cohort of 607 patients confirmed that patients with L-TSA had lower 1-year survival (77% vs. 64%, p <0.001) and more oHE development (35% vs. 49%, p <0.001) than those with S-TSA. Conclusion: This study suggests that TSA >83 mm2 increases the risk for oHE and mortality in patients with cirrhosis. Our results support the clinical use of TSA/SPSS for risk stratification and decision-making in the management of patients with cirrhosis. Lay summary: The prevalence of spontaneous portosystemic shunts (SPSS) is higher in patients with more advanced chronic liver disease. The presence of more than 1 SPSS is common in advanced chronic liver disease and is associated with the development of hepatic encephalopathy. This study shows that total cross-sectional SPSS area (rather than diameter of the single largest SPSS) predicts survival in patients with advanced chronic liver disease. Our results support the clinical use of total cross-sectional SPSS area for risk stratification and decision-making in the management of SPSS.

JTD Keywords: ACLF, Acute decompensation, Acute-on-chronic liver failure, Ascites, Cirrhosis, Computed tomography, Hepatic encephalopathy, Liver, Portal hypertension, Spontaneous portosystemic shunt, SPSS, TIPS

Trebicka, J., Bastgen, D., Byrtus, J., Praktiknjo, M., Terstiegen, S., Meyer, C., Thomas, D., Fimmers, R., Treitl, M., Euringer, W., Sauerbruch, T., Rössle, M., (2019). Smaller-diameter covered transjugular intrahepatic portosystemic shunt stents are associated with increased survival Clinical Gastroenterology and Hepatology 17, (13), 2793-2799.e1

Background & Aims: We studied the effects of diameter of covered, self-expandable, nitinol stents on survival times of patients with a transjugular intrahepatic portosystemic shunt (TIPS). Methods: We collected data from 185 patients (median age, 55 y; 30% female) who received a covered nitinol stent, from February 2006 through September 2010, using the online multicenter German TIPS registry. TIPS were given to 107 patients for refractory ascites and to 78 patients for variceal bleeding. Patients at risk of hepatic encephalopathy (owing to advanced age, prior episodes) or liver failure (bilirubin level, >3 mg/dL), and bleeding patients receiving variceal embolization at TIPS, received 8-mm stents (n = 53). The remaining patients received 10-mm stents (n = 132). Eighty-one of the 10-mm stents were underdilated using 8-mm dilation balloons. Clinical and biochemical data were collected after TIPS placement at 1 month, 3 months, 6 months, 9 months, 1 year, and thereafter every 3 to 6 months. Groups were compared using propensity score analysis. Results: Patients who received 8-mm stents survived significantly longer (34 ± 26 mo) than patients who received 10-mm stents (18 ± 19 mo), regardless of whether they were fully dilated or underdilated. When we compared 10-mm stents with or without underdilation, we found that a significantly higher proportion of patients who received underdilated stents survived for 1 month after TIPS placement (95% vs 84%; P = .03), but not for 3 months (P = .10). In multivariate analysis, 1-year mortality correlated with full dilation of the stent to 10 mm (hazard ratio [HR], 2.0; 95% CI, 1.1–3.5) and with serum creatinine concentration at baseline (HR, 1.5; 95% CI, 1.0–1.7). Five-year mortality was associated with use of the 10-mm stents (HR, 1.8; 95% CI, 1.4–2.7) and baseline concentration of creatinine (HR, 1.3; 95% CI, 1.1–1.6). Conclusions: A smaller stent (nominal diameter of 8 mm, but not underdilation of a 10-mm stent) is associated with a prolonged survival compared with 10-mm stents, independent of liver-specific prognostic criteria.

JTD Keywords: Cirrhosis, Comparison, Covered, Portal Hypertension

Roux, Anabel-Lise Lee, Quiroga, Xarxa, Walani, Nikhil, Arroyo, Marino, Roca-Cusachs, Pere, (2019). The plasma membrane as a mechanochemical transducer Philosophical Transactions of the Royal Society B: Biological Sciences 374, (1779), 20180221

Cells are constantly submitted to external mechanical stresses, which they must withstand and respond to. By forming a physical boundary between cells and their environment that is also a biochemical platform, the plasma membrane (PM) is a key interface mediating both cellular response to mechanical stimuli, and subsequent biochemical responses. Here, we review the role of the PM as a mechanosensing structure. We first analyse how the PM responds to mechanical stresses, and then discuss how this mechanical response triggers downstream biochemical responses. The molecular players involved in PM mechanochemical transduction include sensors of membrane unfolding, membrane tension, membrane curvature or membrane domain rearrangement. These sensors trigger signalling cascades fundamental both in healthy scenarios and in diseases such as cancer, which cells harness to maintain integrity, keep or restore homeostasis and adapt to their external environment.

JTD Keywords: Plasma membrane, Mechanotransduction, Membrane tension, Mechanosensor

Lehmann, J., Praktiknjo, M., Nielsen, M. J., Schierwagen, R., Meyer, C., Thomas, D., Violi, F., Strassburg, C. P., Bendtsen, F., Moller, S., Krag, A., Karsdal, M. A., Leeming, D. J., Trebicka, J., (2019). Collagen type IV remodelling gender-specifically predicts mortality in decompensated cirrhosis Liver International 39, (5), 885-893

Background & Aims: Remodelling of extracellular matrix is crucial in progressive liver fibrosis. Collagen type III desposition has been shown in acute decompensation. Extratracellular matrix is compiled of deposition of various components. The role of basement membrane collagen type IV in advanced cirrhosis and acute decompensation is unclear and investigated in this study. Methods: Patients with decompensated cirrhosis from the prospective NEPTUN cohort ( Identifier: NCT03628807), who underwent transjugular intrahepatic portosystemic shunt procedure were included. Clinical and laboratory parameters, PRO-C4 and C4M levels were measured in blood samples from portal and hepatic veins just before transjugular intrahepatic portosystemic shunt placement. Results: Levels of C4M and PRO-C4 are significantly lower in patients with massive ascites and impaired renal sodium excretion. C4M and PRO-C4 show gender-specific profiles with significantly lower levels in females compared to males. Females with higher C4M levels show higher mortality. By contrast, males with higher C4M levels show lower mortality. In multivariate Cox regression analysis, C4M is an independent predictor of survival in female patients. Conclusion: This study shows that markers of collagen type IV remodelling do not accumulate in severe renal dysfunction. Although collagen type IV degradation markers derive from the liver, portal venous C4M levels are relevant for survival. Moreover, it demonstrates that circulating C4M shows gender-specific profiles, which can independently predict survival in female patients with decompensated cirrhosis.

JTD Keywords: ACLF, Acute decompensation, Acute-on-chronic liver failure, Cirrhosis, Collagen type IV, Extracellular matrix remodelling, Gender, Liver, Portal hypertension, Transjugular intrahepatic portosystemic shunt

Marsal, Maria, Jorba, Ignasi, Rebollo, Elena, Luque, Tomas, Navajas, Daniel, Martín-Blanco, Enrique, (2017). AFM and microrheology in the zebrafish embryo yolk cell Journal of Visualized Experiments Developmental Biology, (129), e56224

Elucidating the factors that direct the spatio-temporal organization of evolving tissues is one of the primary purposes in the study of development. Various propositions claim to have been important contributions to the understanding of the mechanical properties of cells and tissues in their spatiotemporal organization in different developmental and morphogenetic processes. However, due to the lack of reliable and accessible tools to measure material properties and tensional parameters in vivo, validating these hypotheses has been difficult. Here we present methods employing atomic force microscopy (AFM) and particle tracking with the aim of quantifying the mechanical properties of the intact zebrafish embryo yolk cell during epiboly. Epiboly is an early conserved developmental process whose study is facilitated by the transparency of the embryo. These methods are simple to implement, reliable, and widely applicable since they overcome intrusive interventions that could affect tissue mechanics. A simple strategy was applied for the mounting of specimens, AFM recording, and nanoparticle injections and tracking. This approach makes these methods easily adaptable to other developmental times or organisms.

JTD Keywords: Developmental Biology, Zebrafish, Yolk, Atomic Force Microscopy, Cortical Tension, Microrheology, Nanoparticle tracking

Klein, S., Schierwagen, R., Uschner, F. E., Trebicka, J., (2017). Mouse and rat models of induction of hepatic fibrosis and assessment of portal hypertension Fibrosis (Methods in Molecular Biology) (ed. Rittié, L.), Humana Press (New York, USA) 1627, 91-116

Portal hypertension either develops due to progressive liver fibrosis or is the consequence of vascular liver diseases such as portal vein thrombosis or non-cirrhotic portal hypertension. This chapter focuses on different rodent models of liver fibrosis with portal hypertension and also in few non-cirrhotic portal hypertension models. Importantly, after the development of portal hypertension, the proper assessment of drug effects in the portal and systemic circulation should be discussed. The last part of the chapter is dedicated in these techniques to assess the in vivo hemodynamics and the ex vivo techniques of the isolated liver perfusion and vascular contractility.

JTD Keywords: Aortic ring contraction, Bile duct ligation, Carbon tetrachloride, Colored microsphere technique, High-fat diet, Isolated in situ liver perfusion, Methionine-choline-deficient diet, Partial portal vein ligation, Portal hypertension

Dalmases, M., Torres, M., Márquez-Kisinousky, L., Almendros, I., Planas, A. M., Embid, C., Martínez-Garcia, M. A., Navajas, D., Farré, R., Montserrat, J. M., (2014). Brain tissue hypoxia and oxidative stress induced by obstructive apneas is different in young and aged rats Sleep , 37, (7), 1249-1256

Study Objectives: To test the hypotheses that brain oxygen partial pressure (PtO2) in response to obstructive apneas changes with age and that it might lead to different levels of cerebral tissue oxidative stress. Design: Prospective controlled animal study. Setting: University laboratory. Participants: Sixty-four male Wistar rats: 32 young (3 mo old) and 32 aged (18 mo). Interventions: Protocol 1: Twenty-four animals were subjected to obstructive apneas (50 apneas/h, lasting 15 sec each) or to sham procedure for 50 min. Protocol 2: Forty rats were subjected to obstructive apneas or sham procedure for 4 h. Measurements and Results: Protocol 1: Real-time PtO2 measurements were performed using a fast-response oxygen microelectrode. During successive apneas cerebral cortex PtO2 presented a different pattern in the two age groups; there was a fast increase in young rats, whereas it remained without significant changes between the beginning and the end of the protocol in the aged group. Protocol 2: Brain oxidative stress assessed by lipid peroxidation increased after apneas in young rats (1.34 ± 0.17 nmol/mg of protein) compared to old ones (0.63 ± 0.03 nmol/mg), where a higher expression of antioxidant enzymes was observed. Conclusions: The results suggest that brain oxidative stress in aged rats is lower than in young rats in response to recurrent apneas, mimicking obstructive sleep apnea. This could be due to the different PtO2 response observed between age groups and the increased antioxidant expression in aged rats.

JTD Keywords: Aging, Animal model, Obstructive apnea, Oxidative stress, Tissue oxygenation, antioxidant, glutathione disulfide, aged, animal experiment, animal model, animal tissue, apnea, arterial oxygen saturation, article, brain cortex, brain oxygen tension, brain tissue, controlled study, groups by age, hypoxia, lipid peroxidation, male, nonhuman, oxidative stress, pressure, priority journal, rat

Gauthier, Nils C., Fardin, Marc Antoine, Roca-Cusachs, Pere, Sheetz, Michael P., (2011). Temporary increase in plasma membrane tension coordinates the activation of exocytosis and contraction during cell spreading Proceedings of the National Academy of Sciences of the United States of America 108, (35), 14467-14472

Cell migration and spreading involve the coordination of membrane trafficking, actomyosin contraction, and modifications to plasma membrane tension and area. The biochemical or biophysical basis for this coordination is however unknown. In this study, we show that during cell spreading, lamellipodia protrusion flattens plasma membrane folds and blebs and, once the plasma membrane area is depleted, there is a temporary increase in membrane tension by over twofold that is followed by activation of exocytosis and myosin contraction. Further, an artificial increase in plasma membrane tension stopped lamellipodia protrusion and activated an exocytotic burst. Subsequent decrease in tension restored spreading with activation of contraction. Conversely, blebbistatin inhibition of actomyosin contraction resulted in an even greater increase in plasma membrane tension and exocytosis activation. This spatio-temporal synchronization indicates that membrane tension is the signal that coordinates membrane trafficking, actomyosin contraction, and plasma membrane area change. We suggest that cells use plasma membrane tension as a global physical parameter to control cell motility.

JTD Keywords: Surface-area regulation, Cytoskeleton adhesion, Erythrocyte-membrane, Extensional flow, Elastic tether, Force