The Experts below are selected from a list of 17178 Experts worldwide ranked by ideXlab platform
Bela Suki - One of the best experts on this subject based on the ideXlab platform.
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lung Tissue Mechanics as an emergent phenomenon
Journal of Applied Physiology, 2011Co-Authors: Bela Suki, Jason H T BatesAbstract:The mechanical properties of lung parenchymal Tissue are both elastic and dissipative, as well as being highly nonlinear. These properties cannot be fully understood, however, in terms of the individual constituents of the Tissue. Rather, the mechanical behavior of lung Tissue emerges as a macroscopic phenomenon from the interactions of its microscopic components in a way that is neither intuitive nor easily understood. In this review, we first consider the quasi-static mechanical behavior of lung Tissue and discuss computational models that show how smooth nonlinear stress-strain behavior can arise through a percolation-like process in which the sequential recruitment of collagen fibers with increasing strain causes them to progressively take over the load-bearing role from elastin. We also show how the concept of percolation can be used to link the pathologic progression of parenchymal disease at the micro scale to physiological symptoms at the macro scale. We then examine the dynamic mechanical behavior of lung Tissue, which invokes the notion of Tissue resistance. Although usually modeled phenomenologically in terms of collections of springs and dashpots, lung Tissue viscoelasticity again can be seen to reflect various types of complex dynamic interactions at the molecular level. Finally, we discuss the inevitability of why lung Tissue Mechanics need to be complex.
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lung Tissue Mechanics as an emergent phenomenon
Journal of Applied Physiology, 2011Co-Authors: Bela Suki, Jason H T BatesAbstract:The mechanical properties of lung parenchymal Tissue are both elastic and dissipative, as well as being highly nonlinear. These properties cannot be fully understood, however, in terms of the indiv...
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heterogeneous airway versus Tissue Mechanics and their relation to gas exchange function during mechanical ventilation
Annals of Biomedical Engineering, 2005Co-Authors: Carissa Bellardine, Bela Suki, Edward P Ingenito, A M Hoffman, Francisco J Lopez, W Sanborn, Kenneth R LutchenAbstract:We have advanced a commercially available ventilator (NPB840, Puritan Bennett/Tyco Healthcare, Pleasanton, CA) to deliver an Enhanced Ventilation Waveform (EVW). This EVW delivers a broadband waveform that contains discrete frequencies blended to provide a tidal breath, followed by passive exhalation. The EVW allows breath-by-breath estimates of frequency dependence of lung and total respiratory resistance (R) and elastance (E) from 0.2 to 8 Hz. We hypothesized that the EVW approach could provide continuous ventilation simultaneously with an advanced evaluation of mechanical heterogeneities under heterogeneous airway and Tissue disease conditions. We applied the EVW in five sheep before and after a bronchial challenge and an oleic acid (OA) acute lung injury model. In all sheep, the EVW maintained gas exchange during and after bronchoconstriction, as well as during OA injury. Data revealed a range of disease conditions from mild to severe with heterogeneities and airway closures. Correlations were found between the arterial partial pressure of oxygen (PaO2) and the levels and frequency-dependent features of R and E that are indicative of mechanical heterogeneity and Tissue disease. Lumped parameter models provided additional insight on heterogeneous airway and Tissue disease. In summary, information obtained from EVW analysis can provide enhanced guidance on the efficiency of ventilator settings and on patient status during mechanical ventilation.
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airway inhomogeneities contribute to apparent lung Tissue Mechanics during constriction
Journal of Applied Physiology, 1996Co-Authors: Kenneth R Lutchen, Zoltán Hantos, Ferenc Petak, A Adamicza, Bela SukiAbstract:Recent studies have suggested that part of the measured increase in lung Tissue resistance after bronchoconstriction is an artifact due to increased airway inhomogeneities. To resolve this issue, we measured lung impedance (ZL) in seven open-chest rats with the lungs equilibrated on room air and then on a mixture of neon and oxygen (NeOx). The rats were placed in a body box with the tracheal tube leading through the box wall. A broadband flow signal was delivered to the box. The signal contained seven oscillation frequencies in the 0.234- to 12.07-Hz range, which were combined to produce tidal ventilation. The ZL was measured before and after bronchoconstriction caused by infusion of methacholine (MCh). Partitioning of airway and Tissue properties was achieved by fitting ZL with a model including airway resistance (Raw), airway inertance, Tissue damping (G), and Tissue elastance (H). We hypothesized that if the inhomogeneities were not significant, the apparent Tissue properties would be independent of th...
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airway inhomogeneities contribute to apparent lung Tissue Mechanics during constriction
Journal of Applied Physiology, 1996Co-Authors: Kenneth R Lutchen, Zoltán Hantos, Ferenc Petak, A Adamicza, Bela SukiAbstract:Recent studies have suggested that part of the measured increase in lung Tissue resistance after bronchoconstriction is an artifact due to increased airway inhomogeneities. To resolve this issue, w...
Valerie M Weaver - One of the best experts on this subject based on the ideXlab platform.
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Tissue Mechanics in stem cell fate development and cancer
Developmental Cell, 2021Co-Authors: Marykate Hayward, Jonathon M Muncie, Valerie M WeaverAbstract:Cells in Tissues experience a plethora of forces that regulate their fate and modulate development and homeostasis. Cells sense mechanical cues through localized mechanoreceptors or by influencing cytoskeletal or plasma membrane organization. Cells translate force and modulate their behavior through a process termed mechanotransduction. Cells tune their tension upon exposure to chronic force by engaging cellular machinery that modulates actin tension, which in turn stimulates matrix remodeling and stiffening and alters cell-cell adhesions until cells achieve a state of tensional homeostasis. Loss of tensional homeostasis can be induced through oncogene activity and/or Tissue fibrosis, accompanies tumor progression, and is associated with increased cancer risk. The mechanical stresses that develop in tumors can also foster the mesenchymal-like transdifferentiation of cells to induce a stem-like phenotype that contributes to their aggression, metastatic dissemination, and treatment resistance. Thus, strategies that ameliorate tumor Mechanics may comprise an effective strategy to prevent aggressive tumor behavior.
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proteoglycans as mediators of cancer Tissue Mechanics
Frontiers in Cell and Developmental Biology, 2020Co-Authors: Anna Barkovskaya, Alexander Buffone, Martin židek, Valerie M WeaverAbstract:Proteoglycans are a diverse group of molecules which are characterized by a central protein backbone that is decorated with a variety of linear sulfated glycosaminoglycan side chains. Proteoglycans contribute significantly to the biochemical and mechanical properties of the interstitial extracellular matrix where they modulate cellular behavior by engaging transmembrane receptors. Proteoglycans also comprise a major component of the cellular glycocalyx to influence transmembrane receptor structure/function and mechanosignaling. Through their ability to initiate biochemical and mechanosignaling in cells, proteoglycans elicit profound effects on proliferation, adhesion and migration. Pathologies including cancer and cardiovascular disease are characterized by perturbed expression of proteoglycans where they compromise cell and Tissue behavior by stiffening the extracellular matrix and increasing the bulkiness of the glycocalyx. Increasing evidence indicates that a bulky glycocalyx and proteoglycan-enriched extracellular matrix promote malignant transformation, increase cancer aggression and alter anti-tumor therapy response. In this review, we focus on the contribution of proteoglycans to mechanobiology in the context of normal and transformed Tissues. We discuss the significance of proteoglycans for therapy response, and the current experimental strategies that target proteoglycans to sensitize cancer cells to treatment.
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Tissue Mechanics an important regulator of development and disease
Philosophical Transactions of the Royal Society B, 2019Co-Authors: Shelly Kaushik, Nadia M E Ayad, Valerie M WeaverAbstract:A growing body of work describes how physical forces in and around cells affect their growth, proliferation, migration, function and differentiation into specialized types. How cells receive and re...
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abstract pr05 glycoprotein mediated Tissue Mechanics regulate glioblastoma aggression
Cancer Research, 2017Co-Authors: Matthew J Barnes, Elliot C Woods, Russell Bainer, Yekaterina A Miroshnikova, Gabriele Bergers, Carolyn R Bertozzi, Valerie M WeaverAbstract:Glioblastoma multiforme (GBM) is a malignant glioma whose progression is associated with rampant extracellular matrix (ECM) remodeling. We recently found that GBM ECM stiffness predicts reduced survival in human patients. Instead of collagen fibrosis, which is common in many solid tumors, we showed that GBM stiffening involves increased production of extracellular glycoproteins, glycosaminoglycans, and sugar-binding proteins. Using bioinformatics, we revealed that genes of the glycocalyx (transmembrane glycoproteins and their interacting partners) are disproportionately upregulated in GBM relative to lower grade gliomas. Further, these genes are overexpressed within GBM in the mesenchymal (MES) relative to the proneural (PRO) subtype, the former of which is associated with treatment resistance and relapse. Using mouse models of human GBM, we showed that MES tumors are more lethal than PRO, and present with elevated ECM stiffness and mechanical signaling. To test our hypothesis that mechanical signaling can drive the MES phenotype, we engineered PRO GBM cells with constitutively-elevated integrin signaling. Compared to control PRO cells, these undergo a robust MES-like transition, upregulate bulky glycoprotein expression, and result in stiffer and more lethal tumors. This phenotype was reversed by the inhibition of focal adhesion kinase in MES cells. To test whether an enhanced glycocalyx can directly elevate mechanical signaling, we decorated GBM cells with synthetic glycoprotein polymers. Indeed, this resulted in enhanced integrin-focal adhesion signaling and more aggressive tumor progression. The invasive properties and therapy resistance observed in mesenchymal tumor cells are often associated with elevated stem cell-like features. To investigate a link between the glycocalyx, Tissue Mechanics, and the mesenchymal-stem cell phenotype, we interfered with components of the gylcocalyx or mechanical signaling machinery and found a reduction in stem cell genes and surface proteins, as well as increased sensitivity to chemotherapy. These data support a model in which glycoprotein-mediated Tissue stiffening drives GBM aggression through promotion of a mesenchymal phenotype. This abstract is also being presented as Poster A39. Citation Format: J. Matthew Barnes, Elliot C. Woods, Russell O. Bainer, Yekaterina A. Miroshnikova, Kan Lu, Gabriele Bergers, Carolyn Bertozzi, Valerie M. Weaver. Glycoprotein-mediated Tissue Mechanics regulate glioblastoma aggression. [abstract]. In: Proceedings of the AACR Special Conference on Engineering and Physical Sciences in Oncology; 2016 Jun 25-28; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2017;77(2 Suppl):Abstract nr PR05.
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Tissue Mechanics regulate brain development homeostasis and disease
Journal of Cell Science, 2017Co-Authors: Matthew J Barnes, Laralynne Przybyla, Valerie M WeaverAbstract:All cells sense and integrate mechanical and biochemical cues from their environment to orchestrate organismal development and maintain Tissue homeostasis. Mechanotransduction is the evolutionarily conserved process whereby mechanical force is translated into biochemical signals that can influence cell differentiation, survival, proliferation and migration to change Tissue behavior. Not surprisingly, disease develops if these mechanical cues are abnormal or are misinterpreted by the cells - for example, when interstitial pressure or compression force aberrantly increases, or the extracellular matrix (ECM) abnormally stiffens. Disease might also develop if the ability of cells to regulate their contractility becomes corrupted. Consistently, disease states, such as cardiovascular disease, fibrosis and cancer, are characterized by dramatic changes in cell and Tissue Mechanics, and dysregulation of forces at the cell and Tissue level can activate mechanosignaling to compromise Tissue integrity and function, and promote disease progression. In this Commentary, we discuss the impact of cell and Tissue Mechanics on Tissue homeostasis and disease, focusing on their role in brain development, homeostasis and neural degeneration, as well as in brain cancer.
Yanlan Mao - One of the best experts on this subject based on the ideXlab platform.
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Tissue Mechanics regulate mitotic nuclear dynamics during epithelial development
Current Biology, 2020Co-Authors: Natalie J Kirkland, Alice C Yuen, Melda Tozluoglu, Nancy Hui, Ewa K Paluch, Yanlan MaoAbstract:Cell divisions are essential for Tissue growth. In pseudostratified epithelia, where nuclei are staggered across the Tissue, each nucleus migrates apically before undergoing mitosis. Successful apical nuclear migration is critical for planar-orientated cell divisions in densely packed epithelia. Most previous investigations have focused on the local cellular mechanisms controlling nuclear migration. Inter-species and inter-organ comparisons of different pseudostratified epithelia suggest global Tissue architecture may influence nuclear dynamics, but the underlying mechanisms remain elusive. Here, we use the developing Drosophila wing disc to systematically investigate, in a single epithelial type, how changes in Tissue architecture during growth influence mitotic nuclear migration. We observe distinct nuclear dynamics at discrete developmental stages, as epithelial morphology changes. We use genetic and physical perturbations to show a direct effect of cell density on mitotic nuclear positioning. We find Rho kinase and Diaphanous, which facilitate mitotic cell rounding in confined cell conditions, are essential for efficient apical nuclear movement. Perturbation of Diaphanous causes increasing defects in apical nuclear migration as the Tissue grows and cell density increases, and these defects can be reversed by acute physical reduction of cell density. Our findings reveal how the mechanical environment imposed on cells within a Tissue alters the molecular and cellular mechanisms adopted by single cells for mitosis.
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Tissue fluidity promotes epithelial wound healing
Nature Physics, 2019Co-Authors: Robert J Tetley, Yanlan Mao, Michael F Staddon, Davide Heller, Andreas Hoppe, Shiladitya BanerjeeAbstract:The collective behaviour of cells in epithelial Tissues is dependent on their mechanical properties. However, the contribution of Tissue Mechanics to wound healing in vivo remains poorly understood. Here we investigate the relationship between Tissue Mechanics and wound healing in live Drosophila wing imaginal discs and show that by tuning epithelial cell junctional tension, we can systematically alter the rate of wound healing. Coincident with the contraction of an actomyosin purse string, we observe cells flowing past each other at the wound edge by intercalating, reminiscent of molecules in a fluid, resulting in seamless wound closure. Using a cell-based physical model, we predict that a reduction in junctional tension fluidises the Tissue through an increase in intercalation rate and corresponding reduction in bulk viscosity, in the manner of an unjamming transition. The resultant fluidisation of the Tissue accelerates wound healing. Accordingly, when we experimentally reduce Tissue tension in wing discs, intercalation rate increases and wounds repair in less time.
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Tissue Mechanics regulate mitotic nuclear dynamics during epithelial development
bioRxiv, 2019Co-Authors: Natalie J Kirkland, Alice C Yuen, Melda Tozluoglu, Nancy Hui, Ewa K Paluch, Yanlan MaoAbstract:Cell divisions are essential for Tissue growth. In pseudostratified epithelia, where nuclei are staggered across the Tissue, each nucleus migrates apically before undergoing mitosis. Successful apical nuclear migration is critical to preserve Tissue integrity during cell division. Most previous investigations have focused on the local cellular mechanisms controlling nuclear migration. Yet, inter-species and inter-organ comparisons of different pseudostratified epithelia suggest global Tissue architecture may influence nuclear dynamics, but the underlying mechanisms remain elusive. Here, we use the developing Drosophila wing disc to systematically investigate, in a single epithelial type, how changes in Tissue architecture during growth influence mitotic nuclear migration. We observe distinct nuclear dynamics at discrete developmental stages, as epithelial morphology changes. We then use genetic and physical perturbations to show a direct effect of cell density on mitotic nuclear positioning. We also find Rho kinase and Diaphanous, which facilitate mitotic cell rounding in confined cell conditions, are essential for efficient apical nuclear movement. Strikingly, perturbation of Diaphanous causes increasing defects in apical nuclear migration as the Tissue grows, and these defects can be reversed by acute physical reduction of cell density. Our findings reveal how the mechanical environment imposed on cells within a Tissue alters the molecular and cellular mechanisms adopted by single cells for mitosis. We speculate that mechanical regulation of apical mitotic positioning could be a global mechanism for Tissue growth control.
Kenneth R Lutchen - One of the best experts on this subject based on the ideXlab platform.
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heterogeneous airway versus Tissue Mechanics and their relation to gas exchange function during mechanical ventilation
Annals of Biomedical Engineering, 2005Co-Authors: Carissa Bellardine, Bela Suki, Edward P Ingenito, A M Hoffman, Francisco J Lopez, W Sanborn, Kenneth R LutchenAbstract:We have advanced a commercially available ventilator (NPB840, Puritan Bennett/Tyco Healthcare, Pleasanton, CA) to deliver an Enhanced Ventilation Waveform (EVW). This EVW delivers a broadband waveform that contains discrete frequencies blended to provide a tidal breath, followed by passive exhalation. The EVW allows breath-by-breath estimates of frequency dependence of lung and total respiratory resistance (R) and elastance (E) from 0.2 to 8 Hz. We hypothesized that the EVW approach could provide continuous ventilation simultaneously with an advanced evaluation of mechanical heterogeneities under heterogeneous airway and Tissue disease conditions. We applied the EVW in five sheep before and after a bronchial challenge and an oleic acid (OA) acute lung injury model. In all sheep, the EVW maintained gas exchange during and after bronchoconstriction, as well as during OA injury. Data revealed a range of disease conditions from mild to severe with heterogeneities and airway closures. Correlations were found between the arterial partial pressure of oxygen (PaO2) and the levels and frequency-dependent features of R and E that are indicative of mechanical heterogeneity and Tissue disease. Lumped parameter models provided additional insight on heterogeneous airway and Tissue disease. In summary, information obtained from EVW analysis can provide enhanced guidance on the efficiency of ventilator settings and on patient status during mechanical ventilation.
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airway and lung Tissue Mechanics in asthma effects of albuterol
American Journal of Respiratory and Critical Care Medicine, 1999Co-Authors: David W Kaczka, Edward P Ingenito, Elliot Israel, Kenneth R LutchenAbstract:We examined the partitioning of total lung resistance (R L ) into airway resistance (Raw) and Tissue resistance (Rti) in patients with mild to moderate asthma (baseline FEV 1 , 54 to 91% of predicted) before and after albuterol inhalation. An optimal ventilator waveform was used to measure R L and lung elastance (E L ) in 21 asthmatics from approximately 0.1 to 8 Hz during tidal excursions. Analysis of the R L and E L provided separate estimates of airway and lung Tissue properties. Eleven subjects, classified as Type A asthmatics, displayed slightly elevated R L but normal E L . Their data were well described with a model consisting of homogeneous airways leading to viscoelastic Tissues before and after albuterol. The other 10 subjects, classified as Type B asthmatics, demonstrated highly elevated R L and an E L that became highly elevated at frequencies above 2 Hz. These subjects required the inclusion of an airway wall compliance in the model prealbuterol but not postalbuterol. This suggests that the Type B subjects were experiencing pronounced constriction in the periphery of the lung, resulting in shunting of flow into the airway walls. Spirometric data were consistent with higher constriction in Type B subjects. Both groups demonstrated significant (p , 0.05) decreases in Raw and Tissue damping after albuterol, but Tissue elastance decreased only in the Type B group. The percent contributions of Raw and Rti to R L were similar in both groups and did not change after albuterol. We conclude that in asthma, Raw comprises the majority ( . 70%) of R L at breathing frequencies. The relative contributions of Raw and Rti to R L appear to be independent of the degree of smooth muscle constriction. Kaczka DW, Ingenito EP, Israel E, Lutchen KR. Airway and lung Tissue Mechanics in asthma: effects of albuterol. AM J RESPIR CRIT CARE MED 1999;159:169‐178.
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airway inhomogeneities contribute to apparent lung Tissue Mechanics during constriction
Journal of Applied Physiology, 1996Co-Authors: Kenneth R Lutchen, Zoltán Hantos, Ferenc Petak, A Adamicza, Bela SukiAbstract:Recent studies have suggested that part of the measured increase in lung Tissue resistance after bronchoconstriction is an artifact due to increased airway inhomogeneities. To resolve this issue, we measured lung impedance (ZL) in seven open-chest rats with the lungs equilibrated on room air and then on a mixture of neon and oxygen (NeOx). The rats were placed in a body box with the tracheal tube leading through the box wall. A broadband flow signal was delivered to the box. The signal contained seven oscillation frequencies in the 0.234- to 12.07-Hz range, which were combined to produce tidal ventilation. The ZL was measured before and after bronchoconstriction caused by infusion of methacholine (MCh). Partitioning of airway and Tissue properties was achieved by fitting ZL with a model including airway resistance (Raw), airway inertance, Tissue damping (G), and Tissue elastance (H). We hypothesized that if the inhomogeneities were not significant, the apparent Tissue properties would be independent of th...
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airway inhomogeneities contribute to apparent lung Tissue Mechanics during constriction
Journal of Applied Physiology, 1996Co-Authors: Kenneth R Lutchen, Zoltán Hantos, Ferenc Petak, A Adamicza, Bela SukiAbstract:Recent studies have suggested that part of the measured increase in lung Tissue resistance after bronchoconstriction is an artifact due to increased airway inhomogeneities. To resolve this issue, w...
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airway and Tissue Mechanics during physiological breathing and bronchoconstriction in dogs
Journal of Applied Physiology, 1994Co-Authors: Kenneth R Lutchen, Bela Suki, Ferenc Petak, Qin Zhang, B Daroczy, Zoltán HantosAbstract:In five open-chest dogs and with four to five alveolar capsules we used an optimal ventilator waveform (OVW) to follow frequency and tidal volume (VT) dependence of lung, airway, and Tissue resistance (R) and elastance (E) before and during constant infusion of histamine (16 micrograms.kg-1.min-1). OVW contains sufficient flow energy between 0.234 and 4.7 Hz, avoids nonlinear harmonic interactions, and simultaneously ventilates with physiological VT. Each OVW breath permits a smooth estimate of frequency dependence of R and E for the whole lung. A constant-phase model analysis provided estimates of purely viscous resistance (Rvis), which represents the sum of airway resistance (Raw) and any purely newtonian component of Tissue resistance (Rti), and parameters G and H, which govern frequency dependence of Rti and Tissue elastance (Eti), respectively. Tissue structural damping (eta) is calculated as G/H. This model was applied to the whole lung and Tissue impedance as estimated from each capsule. We found a small but inconsequential purely newtonian component of Rti, even during constriction. Four dogs showed a peak response at approximately 4 min in lung Rvis coupled (in time) to initial increases in G, H, eta, and airway inhomogeneities. In two of these dogs the response was severe. Tissue properties estimated from whole lung impedance (G, H, and eta) were nearly identical to values estimated from unobstructed capsules throughout infusion. By using a technique independent of alveolar capsules, our results indicate that a major if not dominant response to a constrictive agonist occurs in lung Tissues, resulting in a large increase in Rti and Eti. With severe constriction, significant increases occur in Raw and airway inhomogeneities as well. Finally, separation of airway and Tissue properties using input impedance estimated from the frequency-rich OVW avoids use of alveolar capsules and may prove an effective tool for partitioning airway and Tissue properties in humans.
Elias H Barriga - One of the best experts on this subject based on the ideXlab platform.
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Tissue stiffening coordinates morphogenesis by triggering collective cell migration in vivo
Nature, 2018Co-Authors: Elias H Barriga, Kristian Franze, Guillaume Charras, Roberto MayorAbstract:Collective cell migration is essential for morphogenesis, Tissue remodelling and cancer invasion. In vivo, groups of cells move in an orchestrated way through Tissues. This movement involves mechanical as well as molecular interactions between cells and their environment. While the role of molecular signals in collective cell migration is comparatively well understood, how Tissue Mechanics influence collective cell migration in vivo remains unknown. Here we investigated the importance of mechanical cues in the collective migration of the Xenopus laevis neural crest cells, an embryonic cell population whose migratory behaviour has been likened to cancer invasion. We found that, during morphogenesis, the head mesoderm underlying the cephalic neural crest stiffens. This stiffening initiates an epithelial-to-mesenchymal transition in neural crest cells and triggers their collective migration. To detect changes in their mechanical environment, neural crest cells use mechanosensation mediated by the integrin-vinculin-talin complex. By performing mechanical and molecular manipulations, we show that mesoderm stiffening is necessary and sufficient to trigger neural crest migration. Finally, we demonstrate that convergent extension of the mesoderm, which starts during gastrulation, leads to increased mesoderm stiffness by increasing the cell density underneath the neural crest. These results show that convergent extension of the mesoderm has a role as a mechanical coordinator of morphogenesis, and reveal a link between two apparently unconnected processes-gastrulation and neural crest migration-via changes in Tissue Mechanics. Overall, we demonstrate that changes in substrate stiffness can trigger collective cell migration by promoting epithelial-to-mesenchymal transition in vivo. More broadly, our results raise the idea that Tissue Mechanics combines with molecular effectors to coordinate morphogenesis.
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Tissue stiffening coordinates morphogenesis by triggering collective cell migration in vivo
Nature, 2018Co-Authors: Elias H Barriga, Kristian Franze, Guillaume Charras, Roberto MayorAbstract:Stiffening of the mesoderm owing to an accumulation of cells triggers collective migration of neural crest cells during morphogenesis. Groups of cells from distinct germ layers move in an organized fashion to direct morphogenesis and Tissue remodelling during embryonic development. Roberto Mayor and colleagues examine the influence of Tissue Mechanics during the collective migration of neural crest cells in Xenopus laevis. Stiffening of the mesoderm that underlies the neural crest arises as a consequence of a convergent extension movement during gastrulation. Neural crest cells sense the resulting change in the extracellular matrix through integrin signalling, and undergo an epithelial-to-mesenchymal transition before starting their collective migration. This analysis reveals the importance of Tissue Mechanics in coordinating different events in morphogenesis. Collective cell migration is essential for morphogenesis, Tissue remodelling and cancer invasion1,2. In vivo, groups of cells move in an orchestrated way through Tissues. This movement involves mechanical as well as molecular interactions between cells and their environment. While the role of molecular signals in collective cell migration is comparatively well understood1,2, how Tissue Mechanics influence collective cell migration in vivo remains unknown. Here we investigated the importance of mechanical cues in the collective migration of the Xenopus laevis neural crest cells, an embryonic cell population whose migratory behaviour has been likened to cancer invasion3. We found that, during morphogenesis, the head mesoderm underlying the cephalic neural crest stiffens. This stiffening initiates an epithelial-to-mesenchymal transition in neural crest cells and triggers their collective migration. To detect changes in their mechanical environment, neural crest cells use mechanosensation mediated by the integrin–vinculin–talin complex. By performing mechanical and molecular manipulations, we show that mesoderm stiffening is necessary and sufficient to trigger neural crest migration. Finally, we demonstrate that convergent extension of the mesoderm, which starts during gastrulation, leads to increased mesoderm stiffness by increasing the cell density underneath the neural crest. These results show that convergent extension of the mesoderm has a role as a mechanical coordinator of morphogenesis, and reveal a link between two apparently unconnected processes—gastrulation and neural crest migration—via changes in Tissue Mechanics. Overall, we demonstrate that changes in substrate stiffness can trigger collective cell migration by promoting epithelial-to-mesenchymal transition in vivo. More broadly, our results raise the idea that Tissue Mechanics combines with molecular effectors to coordinate morphogenesis4.
