A phenomenological model of cell-cell adhesion mediated by cadherins

International audienceWe present a phenomenological model intended to describe at the protein population level the formation of cell-cell junctions by the local recruitment of homophilic cadherin adhesion receptors. This modeling may have a much wider implication in biological processes since many adhesion receptors, channel proteins and other membrane-born proteins associate in clusters or oligomers at the cell surface. Mathematically, it consists in a degenerate reaction-diffusion system of two partial differential equations modeling the time-space evolution of two cadherin populations over a surface: the first one represents the diffusing cadherins and the second one concerns the fixed ones. After discussing the stability of the solutions of the model, we perform numerical simulations and show relevant analogies with experimental results. In particular, we show patterns or aggregates formation for a certain set of parameters. Moreover, perturbing the stationary solution, both density populations converge in large times to some saturation level. Finally, an exponential rate of convergence is numerically obtained and is shown to be in agreement, for a suitable set of parameters, with the one obtained in some in vitro experiments

Cx43-Associated Secretome and Interactome Reveal Synergistic Mechanisms for Glioma Migration and MMP3 Activation

Extracellular matrix (ECM) remodeling, degradation and glioma cell motility are critical aspects of glioblastoma multiforme (GBM). Despite being a rich source of potential biomarkers and targets for therapeutic advance, the dynamic changes occurring within the extracellular environment that are specific to GBM motility have yet to be fully resolved. The gap junction protein connexin43 (Cx43) increases glioma migration and invasion in a variety of in vitro and in vivo models. In this study, the upregulation of Cx43 in C6 glioma cells induced morphological changes and the secretion of proteins associated with cell motility. Demonstrating the selective engagement of ECM remodeling networks, secretome analysis revealed the near-binary increase of osteopontin and matrix metalloproteinase-3 (MMP3), with gelatinase and NFF-3 assays confirming the proteolytic activities. Informatic analysis of interactome and secretome downstream of Cx43 identifies networks of glioma motility that appear to be synergistically engaged. The data presented here implicate ECM remodeling and matrikine signals downstream of Cx43/MMP3/osteopontin and ARK1B10 inhibition as possible avenues to inhibit GBM

Microfabrication: Tailoring Common Hydrogels into 3D Cell Culture Templates (Adv. Healthcare Mater. 18/2020)

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Effet de l'inhibition de l'expression de la Cx43 sur les capacités prolifératives et invasives des cellules U251 de glioblastome

Pour tenter d'élucider quelles sont les caractéristiques phénotypiques des cellules de glioblastome que contrôle la Cx43, nous avons inhibé son expression dans les cellules U251. Cette approche nous a permis de confirmer que la Cx43 est impliquée dans divers processus associés au développement des gliomes. En effet, si son absence favorise la croissance cellulaire, elle favorise l'angiogénèse tout en diminuant l'adhérence aux protéines matricielles, l'invasion en chambre de Boyden et l'invasion tissulaire ex vivo. Les capacités invasives des cellules de glioblastome étant responsables de la récurrence de ces tumeurs, nous avons tenté d'appréhender l'implication de la Cx43 dans ce phénomène. Tout d'abord, une analyse protéomique par spectrométrie de masse du sécrétome de cellules C6 de gliome de rat suggère que l'effet pro-migratoire induit par l'expression de la Cx43 est contrôlé, au moins en partie, par une composition différente du pool de protéines secrétées [les cytokines (MCP-1, TGF-b binding protein 1, galectine-1), les enzymes protéolytiques (MMP3, cathepsines B et L1), les composants de la matrice extracellulaire (fibronectine, SPARC et collagène a-1) qont notamment sursecrétés par les cellules C6 de gliome de rat exprimant la Cx43]. Par ailleurs, notre étude démontre l'importance des radeaux liquides dans le phénomène d'invasion cellulaire contrôlé par la Cx43. En effet, la désorganisation chimique de ces microdomaines conduit à une diminution drastique des capacités invasives associée à une inhibition des capacités de communication entre les cellules U251 et entre les cellules U251 et les astrocytes en culture primaire. En conclusion, nos résultats suggèrent que la Cx43 joue un rôle complexe voire contradictoire dans le contrôle du phénotype des cellules de glioblastome. En effet, alors que la Cx43 inhibe la prolifération, elle favorise l'invasion, phénomène nécessitant une correcte organisation des radeaux lipidiques.In order to elucidate what are the phenotypic characteristics controlled by Cx43 in glioblastoma cells, we inhibited its expression, by using the shRNA strategy, in human glioblastoma U251 cells. This approach confirmed that Cx43 is involved in various processes associated to glioma development. Indeed, if its sbsence favors cell proliferation under some conditions (growth in soft agar), it increase angiogenesis while decreasing the adhesion to extracellular matrix proteins, the invasion capacity in Boyden chamber and ex vivo tissue invasion. Moreover, since the invasive capacities of glioblastoma cells are responsible for the tumor recurrence, we were interested to see how Cx43 regulates such capacities. First, a proteomic analysis by mass spectrometry of the secretome of rat glioma cells permitted to consider that such a capacity which is induced by the expression of Cx43 is at least partly mediated by a different pool of secreted proteins [citokines (MCP-1, TGF-b binding protein 1, galectin-1), proteases (MMP3, cathepsins B and L1) and extracellular matrix compounds (fibronectin, SPARC, collagen- a-1) are notably oversecreted by rat C6 glioma cells expressing Cx43]. Second, our study demonstrates that lipid rafts are involved in the invasion process controlled by Cx43. Indeed, the chemically-induced disorganization of these membrane microdomains leads to a drastic decrease of the invasive capacities of U251 cells associated with the inhibition of communication capacities between themselves (homocellular communication) or between them and the astrocytes in primary cultures (heterocellular communication). In conclusion, our results suggest that Cx43 play a complex and even contradictory role in the control of the phenotype of glioblastoma cells. Indeed, while Cx43 inhibits the proliferation of U251 cells, it favors their invasive capacities in association with the presence of lipid rafts.POITIERS-BU Sciences (861942102) / SudocSudocFranceF

Lymphocytes perform reverse adhesive haptotaxis mediated by LFA-1 integrins

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Down-regulation of connexin43 expression reveals the involvement of caveolin-1 containing lipid rafts in human U251 glioblastoma cell invasion

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Effect of endothelin-1 on osteoblastic differentiation is modified by the level of connexin43: comparative study on calvarial osteoblastic cells isolated from Cx43+/−and Cx43+/+ mice

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Correction: The formation of ordered nanoclusters controls cadherin anchoring to actin and cell-cell contact fluidity

https://hal-univ-rennes1.archives-ouvertes.fr/hal-01196599International audienceIn Figure 5 A, the authors noticed the inadvertent duplication of one kymograph in the wt Ecad and cis Ecad panels. The HTML and PDF versions of this article have been corrected. The error remains only in the print version

How cells respond to environmental cues - insights from bio-functionalized substrates

Biomimetic materials have long been the (he)art of bioengineering. They usually aim at mimicking in vivo conditions to allow in vitro culture, differentiation and expansion of cells. The past decade has witnessed a considerable amount of progress in soft lithography, bio-inspired micro-fabrication and biochemistry, allowing the design of sophisticated and physiologically relevant micro- and nano-environments. These systems now provide an exquisite toolbox with which we can control a large set of physicochemical environmental parameters that determine cell behavior. Bio-functionalized surfaces have evolved from simple protein-coated solid surfaces or cellular extracts into nano-textured 3D surfaces with controlled rheological and topographical properties. The mechanobiological molecular processes by which cells interact and sense their environment can now be unambiguously understood down to the single-molecule level. This Commentary highlights recent successful examples where bio-functionalized substrates have contributed in raising and answering new questions in the area of extracellular matrix sensing by cells, cell-cell adhesion and cell migration. The use, the availability, the impact and the challenges of such approaches in the field of biology are discussed