54 results found
Lachowski D, Cortes E, Robinson B, et al., 2016, SAT-402 - Elucidating the Biomechanical Response of Human Hepatic Stellate Cells on Substrates Mimicking Healthy and Fibrotic Matrix Rigidity, EASL International Liver Congress, Publisher: Elsevier, Pages: S706-S706, ISSN: 0168-8278
Chronopoulos A, Robinson B, Sarper M, et al., 2016, ATRA mechanically reprograms pancreatic stellatecells to suppress matrix remodelling and inhibitcancer cell invasion, Nature Communications, Vol: 7, ISSN: 2041-1723
Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive malignancy with a dismalsurvival rate. Persistent activation of pancreatic stellate cells (PSCs) can perturb thebiomechanical homoeostasis of the tumour microenvironment to favour cancer cell invasion.Here we report that ATRA, an active metabolite of vitamin A, restores mechanical quiescencein PSCs via a mechanism involving a retinoic acid receptor beta (RAR-b)-dependentdownregulation of actomyosin (MLC-2) contractility. We show that ATRA reduces the abilityof PSCs to generate high traction forces and adapt to extracellular mechanical cues(mechanosensing), as well as suppresses force-mediated extracellular matrix remodelling toinhibit local cancer cell invasion in 3D organotypic models. Our findings implicate aRAR-b/MLC-2 pathway in peritumoural stromal remodelling and mechanosensory-drivenactivation of PSCs, and further suggest that mechanical reprogramming of PSCs with retinoicacid derivatives might be a viable alternative to stromal ablation strategies for the treatmentof PDAC.
Robinson B, Rice A, Cortes E, et al., Assessment of extracellular matrix remodeling using 3D Matrigel/collagen matrices and second harmonic generation microscopy, Jove-Journal of Visualized Experiments, ISSN: 1940-087X
Sarper M, Lieberthal T, Del Rio Hernandez AE, Elucidating the Effect of Extracellular Matrix Remodeling by Stromal Cells on Pancreatic Cancer Cell Invasion in 3D Organotypic Systems, Jove-Journal of Visualized Experiments, ISSN: 1940-087X
Kis Z, Rodin T, Zafar A, et al., 2016, Development of a synthetic gene network to module gene expression by mechanical forces, Scientific Reports, Vol: 6, ISSN: 2045-2322
The majority of (mammalian) cells in our body are sensitive to mechanical forces, but little work hasbeen done to develop assays to monitor mechanosensor activity. Furthermore, it is currently impossibleto use mechanosensor activity to drive gene expression. To address these needs, we developed thefrst mammalian mechanosensitive synthetic gene network to monitor endothelial cell shear stresslevels and directly modulate expression of an atheroprotective transcription factor by shear stress. Thetechnique is highly modular, easily scalable and allows graded control of gene expression by mechanicalstimuli in hard-to-transfect mammalian cells. We call this new approach mechanosyngenetics. To insertthe gene network into a high proportion of cells, a hybrid transfection procedure was developed thatinvolves electroporation, plasmids replication in mammalian cells, mammalian antibiotic selection,a second electroporation and gene network activation. This procedure takes 1 week and yielded over60% of cells with a functional gene network. To test gene network functionality, we developed a fowsetup that exposes cells to linearly increasing shear stress along the length of the fow channel foor.Activation of the gene network varied logarithmically as a function of shear stress magnitude.
Haining AW, von Essen M, Attwood SJ, et al., 2016, All Subdomains of the Talin Rod Are Mechanically Vulnerable and May Contribute to Cellular Mechanosensing, ACS Nano, Vol: 10, Pages: 6648-6658, ISSN: 1936-086X
Although the relevance of mechanotransduction in cell signalling is currently appreciated, themechanisms that drive this process remain largely unknown. Mechanical unfolding of proteins maytrigger distinct downstream signals in cells, providing a mechanism for cellular mechanotransduction.Force-induced unfolding of talin, a prominent focal adhesion protein, has been demonstrated previouslyfor a small portion of its rod domain. Here, using single-molecule atomic force microscopy (smAFM), weshow that the entire talin rod can be unfolded by mechanical extension, over a physiological range offorces between 10 – 40 pN. We also demonstrate, through a combination of smAFM and steeredmolecular dynamics (SMD), that the different bundles within the talin rod exhibit a distinct hierarchy ofmechanical stability. These results provide a mechanism by which different force conditions within thecell control a graduated unfolding of the talin rod. Mechanical unfolding of the rod subdomains, and thesubsequent effect on talin’s binding interactions, would allow for a finely-tuned cellular response tointernally or externally applied forces.
Sarper M, Cortes E, Lieberthal T, et al., 2016, ATRA modulates mechanical activation of TGF-β by pancreatic stellate cells, Scientific Reports, Vol: 6, ISSN: 2045-2322
The hallmark of pancreatic ductal adenocarcinoma (PDAC) is abundant desmoplasia, which is orchestrated by pancreatic stellate cells (PSCs) and accounts for the majority of the stroma surrounding the tumour. Healthy PSCs are quiescent, but upon activation during disease progression, they adopt a myofibroblast-contractile phenotype and secrete and concomitantly reorganise the stiff extracellular matrix (ECM). Transforming growth factor β (TGF-β) is a potent activator of PSCs, and its activation requires spatiotemporal organisation of cellular and extracellular cues to liberate it from an inactive complex with latent TGF-β binding protein (LTBP). Here we study the mechanical activation of TGF-β by PSCs in vitro by investigating LTBP-1 organisation with fibrillar fibronectin and show that all trans-retinoic acid (ATRA), which induces PSC quiescence, down-regulates the ability of PSCs to mechanically organise LTBP-1 and activate TGF-β through a mechanism involving myosin II dependent contractility. Therefore, ATRA inhibits the ability of PSCs to mechanically release active TGF-β, which might otherwise act in an autocrine manner to sustain PSCs in an active state and a tumour-favouring stiff microenvironment.
Robinson BK, Cortes E, Rice AJ, et al., 2016, Quantitative analysis of 3D extracellular matrix remodelling bypancreatic stellate cells, Biology Open, Vol: 5, Pages: 875-882, ISSN: 2046-6390
Extracellular matrix (ECM) remodelling is integral to numerousphysiological and pathological processes in biology, such asembryogenesis, wound healing, fibrosis and cancer. Until recently,most cellular studies have been conducted on 2D environmentswhere mechanical cues significantly differ from physiologicallyrelevant 3D environments, impacting cellular behaviour andmasking the interpretation of cellular function in health and disease.We present an integrated methodology where cell-ECM interactionscan be investigated in 3D environments via ECM remodelling.Monitoring and quantification of collagen-I structure in remodelledmatrices, through designated algorithms, show that 3D matrices canbe used to correlate remodelling with increased ECM stiffnessobserved in fibrosis. Pancreatic stellate cells (PSCs) are the keyeffectors of the stromal fibrosis associated to pancreatic cancer. Weuse PSCs to implement our methodology and demonstrate that PSCmatrix remodelling capabilities depend on their contractile machineryand β1 integrin-mediated cell-ECM attachment.
Haining AWM, Lieberthal TJ, del Rio Hernandez A, 2016, Talin: a mechanosensitive molecule in healthand disease, The FASEB Journal, ISSN: 0892-6638
Talin is a ubiquitous, large focal adhesion protein that links intracellular networks with the extracellularmatrix (ECM)via its connection with the actin cytoskeleton andmembrane integrins. It is one of a handfulmoleculesthat can expose new recognition sites when undergoing force-induced mechanical unfolding, and it can bind andrecruit cytoskeletal proteins that are involved in mechanotransduction. Talin has attracted great interest in the fieldof mechanobiology because of its plasticity in undergoing conformational changes under force stimulation as wellas its cellular localization that bridges the cytoskeleton with the ECM. In addition to these roles in healthy cells, thedysregulation of talin activators can lead to disease states in which aberrant integrin activation and mechanotransductionprecipitate changes in cell spreading, migration, and survival. New data have implicated a role for talinin diseases that are highly regulated by mechanical cues. In this review, we present the current understanding of talinstructure, its relationship to binding partners, and its role in disease states.—Haining, A.W.M., Lieberthal,T. J., del R´ıoHernandez, A. Talin: a mechanosensitive mol ´ ecule in health and disease.
Roca-Cusachs P, del Rio A, Puklin-Faucher E, et al., 2013, Integrin-dependent force transmission to the extracellular matrix by alpha-actinin triggers adhesion maturation, PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, Vol: 110, Pages: E1361-E1370, ISSN: 0027-8424
Roca-Cusachs P, Gauthier NC, del Rio A, et al., 2009, Clustering of alpha(5)beta(1) integrins determines adhesion strength whereas alpha(v)beta(3) and talin enable mechanotransduction, PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, Vol: 106, Pages: 16245-16250, ISSN: 0027-8424
del Rio A, Perez-Jimenez R, Liu R, et al., 2009, Stretching Single Talin Rod Molecules Activates Vinculin Binding, SCIENCE, Vol: 323, Pages: 638-641, ISSN: 0036-8075
Del Rio A, Dutta K, Chavez J, et al., 2007, Solution structure and dynamics of the N-terminal cytosolic domain of rhomboid intramembrane protease from Pseudomonas aeruginosa: Insights into a functional role in intramembrane proteolysis, JOURNAL OF MOLECULAR BIOLOGY, Vol: 365, Pages: 109-122, ISSN: 0022-2836
Del Rio A, Anand A, Ghose R, 2006, Detection of correlated dynamics on multiple timescales by measurement of the differential relaxation of zero- and double-quantum coherences involving sidechain methyl groups in proteins, JOURNAL OF MAGNETIC RESONANCE, Vol: 180, Pages: 1-17, ISSN: 1090-7807
del Rio A, Coto B, Renuncio JAR, et al., 2004, Vapor-liquid equilibria for the binary system 2,2-dimethylbutane plus 1,1-dimethylpropyl methyl ether (TAME) at 298.15, 318.15, and 338.15 K, FLUID PHASE EQUILIBRIA, Vol: 221, Pages: 1-6, ISSN: 0378-3812
de Llano JJ, Segade L, Jimenez E, et al., 2003, Vapor-liquid equilibria for the binary system hexan-1-ol plus tert-butyl methyl ether (MTBE) at 298.15, 318.15, and 338.15 K, FLUID PHASE EQUILIBRIA, Vol: 208, Pages: 115-121, ISSN: 0378-3812
Spuhl O, Arlt W, Hernandez AD, 2003, Prediction of thermodynamic material properties with the COSMO-RS continuum model, Meeting of the GVC Specialized committee on Thermal Dismantling of Gas, Publisher: WILEY-V C H VERLAG GMBH, Pages: 58-62, ISSN: 0009-286X
Segade L, de Llano JJ, Jimenez E, et al., 2003, Vapor-liquid equilibria of propan-1-ol+1,1-dimethylethyl methyl ether (MTBE) mixtures. Experimental results and modeling, PHYSICAL CHEMISTRY CHEMICAL PHYSICS, Vol: 5, Pages: 2858-2861, ISSN: 1463-9076
del Rio A, Coto B, Pando C, et al., 2002, Vapor-liquid equilibria and excess properties of octane+1,1-dimethylpropyl methyl ether (TAME) mixtures, FLUID PHASE EQUILIBRIA, Vol: 200, Pages: 41-51, ISSN: 0378-3812
del Rio A, Coto B, Pando C, et al., 2002, Vapor-liquid equilibria for the binary system hexane+1,1-dimethylpropyl methyl ether at 298.15, 308.15, 318.15, and 328.15 K, INDUSTRIAL & ENGINEERING CHEMISTRY RESEARCH, Vol: 41, Pages: 1364-1369, ISSN: 0888-5885
del Rio A, Coto B, Pando C, et al., 2001, Vapor-liquid equilibria for the binary systems decane+1, 1-dimethylethyl methyl ether (MTBE) and decane+1, 1-dimethylpropyl methyl ether (TAME) at 308.15, 318.15 and 328.15 K, FLUID PHASE EQUILIBRIA, Vol: 187, Pages: 299-310, ISSN: 0378-3812
del Rio A, Coto B, Pando C, et al., 2001, Vapor-liquid equilibria and excess properties of cyclohexane-1,1-dimethylpropyl methyl ether (TAME) mixtures, INDUSTRIAL & ENGINEERING CHEMISTRY RESEARCH, Vol: 40, Pages: 689-695, ISSN: 0888-5885
del Rio A, Horstmann S, Renuncio JAR, et al., 2001, Isothermal Vapor-Liquid Equilibrium and Excess Enthalpy Data for the Binary Systems Methyl tert-Butyl Ether + Cyclohexane and Ethyl tert-Butyl Ether + Cyclohexane, n-Hexane, and n-Heptane in a Temperature Range from 298.15 to 393.15 K., Journal of Chemical Engineering Data, Vol: 46, Pages: 1181-1187
Isothermal vapor−liquid equilibrium (VLE) and excess enthalpy (HE) data are reported for binary systems containing branched ethers and hydrocarbons. The vapor−liquid equilibrium data for methyl tert-butyl ether (MTBE) + cyclohexane at 308.15 K, for ethyl tert-butyl ether (ETBE) + cyclohexane, n-hexane + ethyl tert-butyl ether, and ethyl tert-butyl ether + n-heptane from 298.15 to 363.15 K were measured by means of a computer-controlled static apparatus. An isothermal flow calorimeter was used to obtain excess enthalpy data for the systems containing ethyl tert-butyl ether at 313.15 and 393.15 K. The experimental VLE and HE data were compared with the data of other authors and have been used simultaneously for the correlation of temperature-dependent UNIQUAC parameters.
del Rio A, Coto R, Pando C, et al., 1999, Vapour-liquid equilibria for the binary system cyclohexane-1,1-dimethylethyl methyl ether (MTBE) at 298.15, 308.15 and 318.15 K, PHYSICAL CHEMISTRY CHEMICAL PHYSICS, Vol: 1, Pages: 4995-4998, ISSN: 1463-9076
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