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Dissertationen zum Thema „Cell migration“
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1
Falk, Anna. "Stem cells : proliferation, differentiation, migration /." Stockholm, 2005. http://diss.kib.ki.se/2006/91-7140-497-X/.
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2
Sundström, Magnus. "Signal transduction in mast cell migration /." Uppsala : Acta Universitatis Upsaliensis : Univ.-bibl. [distributör], 2001. http://publications.uu.se/theses/91-554-5130-6/.
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3
SUN, Xue-Zhi, Sentaro TAKAHASHI, Chun GUI, Rui ZHANG, Kazuo KOGA, Minoru NOUYE, and Yoshiharu MURATA. "Neuronal Migration and Neuronal Migration Disorder in Cerebral Cortex." Research Institute of Environmental Medicine, Nagoya University, 2002. http://hdl.handle.net/2237/2773.
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4
Chometon-Luthe, Gretel. "Epithelial cell migration on laminins." [S.l. : s.n.], 2005. http://deposit.ddb.de/cgi-bin/dokserv?idn=975579185.
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5
Burthem, John. "Hairy cell adhesion and migration." Thesis, University of Liverpool, 1994. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.240394.
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6
Dawson, M. "Mast cell migration in allergy." Thesis, University College London (University of London), 2012. http://discovery.ucl.ac.uk/1357935/.
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The symptomology associated with allergic diseases are a direct consequence of the release of pro-inflammatory mediators from mast cells following bi- or multivalent antigen cross-linking with the high affinity immunoglobulin (Ig) E receptor, FcεR1. Chemokines, small 8-15 kDa polypeptides, control the activation and recruitment of immune cells during the allergic response. Previous studies have demonstrated that co-stimulation by the chemokine, macrophage inflammatory protein-1α (Mip-1α) and cross-linking by IgE with antigen result in four phenomenon 1) enhanced degranulation in ex vivo conjunctival mast cells and rat basophilic leukemia (RBL-2H3) cell line via its chemokine receptor (CCR) 1, cell line also referred to as RBL-CCR1; 2) arrested Mip-1α-induced chemotaxis of RBL-CCR1 cells; 3) enhanced production of proinflammatory mediators from RBL-CCR1 cells and 4) enhanced gene expression in RBL-CCR1 cells of regulatory molecules downstream of CCR1 and FcεR1 signaling pathways, Regulator of G-protein Signaling (RGS)-1 and Tribbles (TRB)- 3. It has therefore been proposed that co-engagement of CCR1 and FcεR1 affects other mast cell processes such as chemotaxis, and moreover these data indicate cross-talk between CCR1 and and FcεR1 signaling pathways. Chemotaxis of mast cells to sites of inflammation and the subsequent release of pro-inflammatory mediators are key to eliciting allergic response. Although there is a vast amount of information pertaining to the molecular mechanisms of chemotaxis in several cell types, there is very little evidence to understand mast cell chemotaxis at this level. Based on current knowledge, the main objective of this thesis was to investigate 1) the effect of CCR1 and FcεR1 co-engagement on mast cell motility and 2) the role of RGS1 and TRB3 on mast degranulation, mediator release and chemotaxis. The data obtained from this thesis is the first to demonstrate the role of WASP, CCR1 and actin polymerisation as mechanisms underlying Mip-1α induced RBLCCR1 chemotaxis, using real time microscopy. Moreover, CCR1 and FcεR1 engagement inhibits RBL-CCR1 actin cytoskeletal re-organisation and significantly increases other cell motility parameters such as directionality and Euclidean distances which are required for efficient Mip-1α-induced chemotaxis. Also, by using a murine model of allergic conjunctivitis, conjunctival mast cells accumulate in the forniceal area of an inflamed conjunctiva in comparison to non-diseased vi mice. In addition, by using siRNA the present study is also the first to show that RGS1 and TRB3 serve as negative regulators of RBL-CCR1 degranulation, mediator release and chemotaxis upon CCR1 and FcεR1 engagement. In conclusion, the data presented in this thesis could advance our understanding of the mechanisms responsible for mast cell migration and arrest during an allergic response, and hence provide new targets for anti-allergic drugs.
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Erlandsson, Anna. "Neural Stem Cell Differentiation and Migration." Doctoral thesis, Uppsala : Acta Universitatis Upsaliensis : Univ.-bibl.[distributör], 2003. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-3546.
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8
Belotti, Yuri. "Microfluidic methods for investigating cell migration and cell mechanics." Thesis, University of Dundee, 2016. https://discovery.dundee.ac.uk/en/studentTheses/fb5ac03d-a752-45a1-8b95-37c8180dc7d9.
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In this thesis I explore how migratory properties of the model organism Dictyostelium discoideum are influenced by dimensionality and topology of the environment that surrounds the cell. Additionally, I sought to develop a microfluidic device able to measure mechanical properties of single cells with a sufficient throughput to account for the inherent heterogeneity of biological samples. Throughout this thesis I made use of microfabrication methods such as photo-lithography and soft-lithography, to develop ad hoc microstructured substrates. These tools enabled me to tackle different biological and biomedical questions related to cell migration and cell mechanics. Confining cells into channels with low dimensionality appeared to regulate the velocity of cellular locomotion, as well as the migration strategy adopted by the cell. Spatial confinement induced an altered arrangement of the acto-myosin cytoskeleton and microtubules. Moreover, the spatial constraint resulted in a simplified, mono-dimensional migration, characterised by constant average speed. Additionally, some cellular processes tended to occur in a periodic fashion, upon confinement. Interestingly, if Dictyostelium cells migrated through asymmetric bifurcating micro- channels, they appeared to be able to undergo a ’decision-making’ process leading to a directional bias. Although the biophysical mechanism underlying this response is yet to be understood, the data shown in this thesis suggest that Dictyostelium cells respond to differences in local concentrations of chemoattractants. The speed of a cell that crawls in a channel also depends on the cell’s stiffness, that in turn represents a measure of the density and structure of its cytoskeleton. To date, only a few methods have been developed to investigate cell mechanics with sufficient throughput. This motivated my interest in developing a microfluidic-based device that, exploiting the recording capabilities of a modern high speed camera, enabled me to assess the cellular mechanical properties at a rate greater than 10,000 cells per second, without the need for cell labelling. In this thesis I presented an example of how this method can be employed to detect differences between healthy and cancerous prostate cells, as well as to differentiate between prostate and bladder cancer cells based on their mechanical response. In conclusion, the work presented in this thesis highlights the interdisciplinarity required to investigate complex biological and biomedical problems. Specifically, the use of quantitative approaches that span from microtechnology, live imaging, computer vision and computational modelling enabled me to investigate novel biological processes as well as to explore new diagnostic technologies that aim to promote the improvement of the future healthcare.
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RUNYAN, CHRISTOPHER MICHAEL. "The Role of Cell Death in Germ Cell Migration." University of Cincinnati / OhioLINK, 2008. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1210732680.
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10
Shuib, Anis Suhaila. "Investigation of blood cells migration in large stenosed artery." Thesis, University of Edinburgh, 2012. http://hdl.handle.net/1842/6265.
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Atherosclerosis is one of the main diseases responsible for the high global mortality rate involving heart and blood vessel disorders. The build-up of fatty materials in the inner wall of the human artery prevents sufficient oxygen and nutrients reaching the organs of the body. Atherosclerosis is a chronic, long term condition, which develops and progresses over time; however, the disease does not present any symptoms until an advanced stage is reached, which results in potential permanent debility and sometimes sudden death. This thesis is concerned with the progression of atherosclerosis in an artery with mild stenosis that has resulted in a 30% reduction in its diameter. To this end, data on the low wall shear stress has been correlated with the atherosclerotic prone region. In a stenosed artery, this region corresponds to the separation zone that is formed distal to the lumen reduction. Atherosclerosis is a complex phenomenon, and not only involves wall shear stress, but also cellular interactions. Previous research has shown that even in the absence of wall biological effects, the blood cell distribution is strongly influenced by the hydrodynamics of the fluid. The mechanisms of blood cell distribution and the dynamic behaviour of the blood flow were investigated by developing a physical model of the stenosed artery, and by using particles to represent the presence of the blood cells. Particle Image Velocimetry system was employed and the size of particles were the 10μm and 20μm. The flow field was characterised and the particle distribution was measured. The characteristics of steady flow in the stenosed artery at Reynolds numbers of 250 and 320 revealed the importance of fluid inertia and the shear gradient distal to stenosis. Unequal distribution of the particles modelling the blood cells was observed, as more particles occupied the recirculation zones than the high shear region and central jet. The particle migration was found to depend on the particle size, particle concentration and fluid flow rates. The results suggested that the presence of similar effects in the real human arterial system may be significant to the progression of atherosclerotic plaques. At lower Reynolds number of 130, a particle depleted layer was observed at the wall region. In physiological flow the cell free layer will prevent the transport of oxygen and nitrogen oxide (NO) to the muscle tissues. A numerical method was used to simulate the flow characteristics measured in the experiment. The numerical results revealed the importance of the hydrodynamic mechanism of particle migration. Drag and lift forces were found to affect the residence time of particles in the recirculation region. The findings of this work have suggested that for a complex geometry like a large stenosed artery at physiological flow rates, hydrodynamic forces are important in cell migration in the flow separation zone. Even without biological forces, the cells migrate to the low wall shear stress region. For computational dynamics studies, this study has demonstrated the need for higher-order modelling at the cellular level in order to establish the particle migration mechanisms.
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Kozyrska, Katarzyna. "The mechanisms underlying mechanical cell competition and leader cell migration in mammalian epithelia." Thesis, University of Cambridge, 2019. https://www.repository.cam.ac.uk/handle/1810/289434.
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Cell competition is a form of cell-cell signalling that results in the elimination of less fit cells from a tissue by their fitter counterparts. I take advantage of an established in vitro model of cell competition using Madin-Darby canine kidney (MDCK) cells to shed insight into the molecular basis of cell competition in epithelial cells. In this system, silencing of the tumour suppressor scribble (scribKD) results in a 'loser' phenotype whereby scribKD cells are specifically eliminated from the monolayer by surrounding wild-type cells. More specifically, scribKD cells are compacted into tight clones through activation of a directed, collective migration in the wild-type population: scribKD are 'mechanical losers' and delaminate and die due to an intrinsic hypersensitivity to high cell density. Remarkably, p53 activation is both necessary and sufficient for this mechanical loser cell status. I first investigate the role of E-, N-, and P-cadherin in the directed migration between scribKD and wild-type cells and in scribKD cell loser status. I show that differential expression of E-cadherin between scribKD losers and wild-type winners is required but not sufficient for directed migration and has no impact on loser cell status. I also show that elevation of neither E-cadherin nor N-cadherin is sufficient to induce directed migration or loser status, but that P-cadherin may play a role in both. I next focus on translating findings about the molecular details of competition from the scribKD set-up into a system where p53 differences alone drive the formation and elimination of mechanical losers. I show that the ROCK - P-p38 - p53 pathway activated in response to mechanical compaction in scribKD cells is conserved in p53-driven losers. In the latter part of my thesis, I characterise the directed migration observed during MDCK competition by drawing parallels to canonical leader-follower migration. Canonical leader cells emerge when epithelial sheets are wounded and, by becoming migratory, drive collective cell migration of follower cells, which results in wound closure. It was not known what confers the leader cell fate. I show that p53 and its effector p21 (and potentially other cyclin-dependent kinase inhibitors) are the key drivers of leader cell migration. I demonstrate that p53-induced leaders use the same molecular pathways that have been shown to drive leader cell migration during wound healing and, in fact, p53 and p21 are also elevated in leaders generated by wounding. Importantly, I establish that p53 activity drives efficient wound closure. Lastly, I show that leader cells are often eliminated by cell competition in the final stages of wound closure, as their elevated p53 mediates their hypersensitivity to density. The model incorporating these data proposes that cellular damage during wounding generates cells with elevated p53, which become leaders and drive wound healing, but these are then cleared once the wound is closed because their high p53 levels cause them to become mechanical losers.
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Sundström, Magnus. "Signal Transduction in Mast Cell Migration." Doctoral thesis, Uppsala University, Department of Genetics and Pathology, 2001. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-1474.
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<p>Mast cells are essential effector cells in the immune system as they release several inflammatory mediators. An accumulation of mast cells has been described in inflammatory conditions such as asthma and allergic rhinitis. Increased mast cell number, in the skin and other organs, is also a characteristic in mastocytosis, a disease without an effective treatment. One explanation for the increase in mast cell number is migration of mast cells in the tissue. In our studies we utilised mast cell lines, including HMC-1; cell lines transfected with the <i>c-kit</i> gene; and <i>in vitro</i> developed mast cells.</p><p>Our aim was to characterise, two variants of the HMC-1 cell line; the signalling pathways essential for mast cell migration towards TGF-β and SCF; and the mechanism regulating mast cell accumulation in mastocytosis.</p><p>Our results help to explain inconsistent findings regarding mast cell biology when HMC-1 cells have been used as a model system. The two variants, which we name HMC-1<sup>560</sup> and HMC-1<sup>560, 816</sup>, are used in different laboratories around the world. HMC-1<sup>560</sup> and HMC-1<sup>560, 816</sup> exhibited different characteristics regarding their karyotype, phenotype as well as their set of activating point mutations in the Kit receptor. Furthermore, divergent signalling pathways are of importance for mast cell migration towards TGF-β and SCF. The classical MAP kinase-signalling cascade was found to be of major relevance for TGF-β-induced migration. In contrast, this pathway had a modest impact on SCF-induced migration, which instead was highly dependent on p38 MAP kinase signalling. Finally, one mechanism for mast cell accumulation in mastocytosis appeared to be an activating point mutation in the gene for the Kit receptor. This mutation appeared to prone transfected cells and mast cell progenitors to a higher rate of migration towards SCF if compared with cells expressing wt Kit receptor.</p><p>In conclusion, our results show the importance of two different MAP kinase signalling pathways and mutations in the Kit receptor for mast cell migration induced by various types of stimuli. This knowledge helps us to understand the mechanism </p>
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Olsson, Niclas. "Mast Cell Migration in Inflammatory Diseases." Doctoral thesis, Uppsala University, Department of Genetics and Pathology, 2003. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-3615.
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<p>Mast cells (MCs) are forceful multifunctional effector cells of the immune system. MCs are normally distributed throughout connective and mucosal tissues, but in several pathological conditions accumulation of MCs occur. This accumulation is probable due to directed migration of MCs and they are subjects for migration at least two different occations: 1) when they are recruited as progenitor cells from the blood into the tissue; and 2) when they as mature MCs are recruited to sites of inflammation. The aim of this study was to investigate MC migration to chemoattractants released <i>in vivo</i> or <i>in vitro</i> (body fluids collected from patients with asthma or rheumatoid arthritis and T<sub>H</sub>1- and T<sub>H</sub>2-cytokines) and to recombinant cytokines (transforming growth factor -β (TGF-β) and CCL5/RANTES).</p><p>This thesis shows that bronchoalveolar lavage (BAL) fluid from asthmatic patients and synovial fluid from patients with rheumatiod arthritis contain MC chemoattractants, and that part of the chemotactic activity can be related to the presence of stem cell factor (SCF) and TGF-β. We also show that MC chemotactic activity during pollen season is significantly increased compared to before pollen season. Furthermore, we demonstrate that TGF-β isoforms, CCL5, TNF-α and IL-4 act as MC chemoattractants in a bellshaped dose- dependent manner. TGF-β proved to be an extremely potent attractant giving an optimal migratory response at 40fM and TGF-β3 being the most effective isoform. The chemokine CCL5 induced migration through interaction with the receptors CCR1 and CCR4 expressed on MC. Furthermore, we also found that TNF-α produced by T<sub>H</sub>1-lymphocytes and IL-4 produced by T<sub>H</sub>2-lymphocytes are MC chemoattractants.</p><p>In conclusion, with this thesis we have identified six new human mast cell chemoattractants and provide evidence that BAL fluid and synovial fluid from patients with asthma and rheumatoid arthritis, respectivly, contain MC chemoattractants. This information provides important clues in understanding the mechanisms behind MC recruitment to sites of inflammation.</p>
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Suri, Rakesh Mark. "Dendritic cell maturation, migration and function." Thesis, University of Oxford, 1998. https://ora.ox.ac.uk/objects/uuid:47d2be37-0508-47d6-8b97-a3cf8e39f9f6.
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Dendritic cells (DC) have a fundamental role in priming naive T-cell responses and a suspected importance in the regulation of central and peripheral tolerance. Before DC can be responsibly used in human clinical trials, the generation of both immature and mature subsets must be standardised and their in vivo migratory and functional characteristics explored. The generation of human blood monocyte-derived DC in either fetal calf serum (PCS) or autologous plasma (HP) were compared. Phenotypic and functional assays demonstrated that DC derived from either system were similarly immature and underwent comparable maturation in response to LPS, TNF-α and MCM (decreasing potencies.) Furthermore, we demonstrated that adherent cells from HP cultures were likely DC but failed to react with the anti-rat CD8 antibody OX-8 which labels nonadherent DC. DC grown from mouse bone marrow (BMDC) using GM-CSF (GM) plus (IL4) were capable of undergoing further maturation with TNF-α or LPS. In contrast, the growth of BMDC in GM alone, gave rise to N418+ immature DC which could not be matured subsequently using TNF-α, LPS or IL1-β under our conditions. The migration of immature and mature BMDC was compared after IV injection. Fluorochrome labelled cells were found in splenic T-cell areas 24 hours after injection of all DC subsets into either syngeneic or allogeneic hosts. Furthermore, DC could be re-isolated from spleen and characterised by FACS analysis at various times after administration. Tc-<sup>99m</sup> radiolabel studies demonstrated similar quantitative migration of BMDC subsets and primary splenic DC (LODACS) to peripheral tissues (spleen, liver and lung) by 24 hours after injection. Emerging evidence suggests that inhibition of costimulatory signalling during antigen presentation may lead to specific unresponsiveness. The ability of immature versus mature donor strain DC pre-treatment to alter cardiac allograft survival was investigated. Only GM-DC (immature) but not more mature GM/IL4-DC subsets were capable of inducing significant graft survival prolongation (MST>100d). Furthermore, the effect was dependant upon pre-treatment 7d before transplantation and was strain specific. The CD4+ T-cell priming patterns of immature versus mature BMDC were investigated using TCR transgenic mice recognising OVA plus MHCII. Mature OVApulsed DC were able to induce antigen-specific T-cell proliferation, activation marker upregulation and intracellular IL2, IL4 and TNF-α production, while immature GMDC proliferation was less, activation marker expression limited, and no IL4 seen. Our findings represent the first demonstration that cytokine cultured DC migrate similarly to primary DC after IV injection. Furthermore, the comparable migratory patterns of immature and mature BMDC subsets contrasts with differences in CD4+ T-cell priming responses in spleen and the unique ability of immature GM-DC to selectively induce cardiac allograft prolongation.
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Kuo, Cheng-Hwa. "Bioengineering scaffolds for cell migration assay." Thesis, University of Cambridge, 2014. https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.707983.
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Mills, Shirley. "Chemokine signalling in malignant cell migration." Thesis, University of East Anglia, 2018. https://ueaeprints.uea.ac.uk/69973/.
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Communication within and between cells is called signalling; elucidation of cell signalling in diseases, especially metastatic cancers, creates opportunities for developing therapeutic interventions. Signalling initiation occurs when a cell surface receptor binds a ligand; the signal then transmits via phosphorylation events through cytosolic signalling proteins to nuclear or effector proteins that orchestrate a cellular response. G-protein coupled receptors (GPCRs) are one type of receptor; a sub-family of GPCRs are chemokine receptors, their ligands, chemokines, can trigger directional migration. Homeostatic chemokine-triggered migration can be hijacked by cancer cells to facilitate metastasis. This study explored various poorly understood aspects of chemokine signalling that may support metastasis with the aim of identifying therapeutic targets. Methodology employed THP-1, Jurkat and MCF7 cell-lines, the manipulation of signalling by antagonists, siRNA knockdown or plasmid modification, followed by calcium and chemotaxis assays, protein visualisation using immunofluorescence, flow cytometry and western blot. Investigations found that in THP-1 cofilin phosphorylation temporally relates to CXCL12-stimulation and to chemotactic migration. In THP-1, but not Jurkat, JAK2 and STAT3 signalling support chemotaxis to CXCL12 and CCL2. Various NSAIDs, Aspirin and Paracetamol drug-specifically influenced chemokine-induced migration and cofilin activity. Rac1, FAK/Pyk2 and Pi3K were found important for chemotaxis to CXC- but not CC-chemokines and to modulate cofilin phosphorylation. Rac1 inhibitor NSC23766 was found to compete with CXCR4 ligands. Many signalling proteins involved in cancer, including GRKs, Src, Raf, MEK, ERK, Cdc42, ROCK, β-catenin and p38MAPK were shown to positively influence chemotactic migration, also Arrestin-2 to support chemotaxis to CXCL12, and Arrestin-3 chemotaxis to CCL3. Dynamin inhibitors and siRNA knockdown produced chemokine, cell type, and dynamin domain-specific responses, Dynamin's G-domain being important for CXCL12- and PH domain for CCL3-induced migration. PKC's role in malignancies was found contradictory and isoform specific; PKCε and PKCδ supporting chemotaxis to CXCL12 but not CCL3, whereas PKCα and PKCζ influenced migration to both CXCL12 and CCL3. This thesis offers novel insights into the complexities of chemokine-induced migration. It examines many key signalling proteins implicated in cancer; reports that NSC23766 offers promise as a lead compound for developing CXCR4 biased antagonists; and offers possible mechanisms, through cofilin phosphorylation and effects on cell migration, for the mixed epidemiology reported for different NSAID's with respect to their influences on cancer incidence and progression, and suggests Ibuprofen may offer anti-metastatic efficacy.
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Jefferyes, Samuel D. R. "Modelling shape fluctuations during cell migration." Thesis, University of Warwick, 2014. http://wrap.warwick.ac.uk/70995/.
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Cell migration is of crucial importance for many physiological processes, including embryonic development, wound healing and immune response. Defects in cell migration are the cause of chronic in ammatory diseases, mental retardation and cancer metastasis. Cell movement is driven by actin-mediated cell protrusion, substrate adhesion and contraction of the cell body. The emergent behaviour of the intracellular processes described above is a change in the morphology of the cell. This inspires the main hypothesis of this work which is that there is a measurable relationship between cell morphology dynamics and migratory behaviour, and that quantitative models of this relationship can create useful tools for investigating the mechanisms by which a cell regulates its own motility. Here we analyse cell shapes of migrating human retinal pigment epithelial cells with the aim to map cell shape changes to cellular behaviour. We develop a non-linear model for learning the intrinsic low-dimensional structure of cell shape space and use the resultant shape representation to analyse quantitative relationships between shape and migration behaviour. The biggest algorithmic challenge overcome in this thesis was developing a method for efficiently and appropriately measuring the shape difference between pairs of cells that may have come from independent image scenes. This difference measure must be capable of coping with the widely varying morphologies exhibited by migrating epithelial cells. We present a new, rapid, landmark-free, shape difference measure called the Best Alignment Metric (BAM). We show that BAM performs highly within our framework, generating a shape space representation of a very large dataset without any prior information on the importance of any given shape feature. We demonstrate quantitative evidence for a model of cell turning based on repolarisation and discuss the impact our proposed framework could have on the continued study of migratory mechanisms.
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Limestoll, Scott R. "Discrete Modeling of Cell Island Migration." Case Western Reserve University School of Graduate Studies / OhioLINK, 2009. http://rave.ohiolink.edu/etdc/view?acc_num=case1228413862.
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19
Hatzikirou, H., K. Böttger, and A. Deutsch. "Model-based Comparison of Cell Density-dependent Cell Migration Strategies." Cambridge University Press, 2015. https://tud.qucosa.de/id/qucosa%3A39048.
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Here, we investigate different cell density-dependent migration strategies. In particular, we consider strategies which differ in the precise regulation of transitions between resting and motile phenotypes. We develop a lattice-gas cellular automaton (LGCA) model for each migration strategy. Using a mean-field approximation we quantify the corresponding spreading dynamics at the cell population level. Our results allow for the prediction of cell population spreading based on experimentally accessible single cell migration parameters.
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Xia, Weiliang, and 夏偉梁. "Role of cytokines in junction restructuring and germ cell migration inmammalian testes." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2006. http://hub.hku.hk/bib/B37101134.
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21
Eaton, Laura. "Skin dendritic cells : activation, maturation and migration." Thesis, University of Manchester, 2012. https://www.research.manchester.ac.uk/portal/en/theses/skin-dendritic-cells-activation-maturation-and-migration(0831ed5e-c580-406c-a404-4b1eb59b040d).html.
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Langerhans’ cells (LC) are the dendritic cells (DC) of the epidermis and, as sentinels of the immune system, act as a bridge between the innate and adaptive immune responses. When LC, and other DC, recognise an antigen or pathogen they mature and are stimulated to migrate to the lymph nodes, where they orchestrate immune responses. Pathogen derived toll-like receptor (TLR) ligands, and chemical allergens, are recognised as being potentially harmful and stimulate LC to mobilise and mature. Cytokine signals, including tumour necrosis factor (TNF)-α, interleukin (IL)-1β, and IL-18, all induce LC migration and are required for initiating LC mobilisation in response to certain contact allergens. Subsequently, chemokines promote the migration and localisation of LC within the draining lymph nodes. Chemokines are also involved in shaping the adaptive immune response by promoting differential T cell activation, such as T helper (Th)1 or Th2 responses, which are involved in immunity against different pathogens, and also in the development of different types of chemical allergy. The hypothesis is that LC phenotype (activation, migration and chemokine production), is dependent on the nature of the challenge ligand. The murine LC-like cell line XS106 was used to investigate the response of LC following stimulation with TLR ligands and chemical allergens. In addition, LC migration in response to these stimuli was investigated in vivo and the role of TNF-α was examined using mice deficient in either one of the two TNF-α receptors; TNF-R1 or TNF-R2.XS106 cells and freshly isolated LC were associated with a selective type 2 immune response, as determined by preferential expression of type 2 associated chemokines. Furthermore, XS106 cells responded to type 2, but not to type 1, associated TLR ligands. In contrast, all of the TLR ligands tested induced the migration of LC from the epidermis in vivo. Similarly, chemical allergens failed to induce a maximal response of XS106 cells, but did induce the migration of LC in vivo. There were differences in LC migration between the two mouse strains tested, with C57/BL6 strain mice being less responsive to administration of TNF-α and the contact allergen oxazolone compared with BALB/c strain mice. However, C57/BL6 and BALB/c strain mice responded similarly after exposure to the contact allergen 2,4-dinitrochlorobenzene (DNCB). Furthermore, DNCB was able to induce LC migration in mice deficient in TNF-R2, the TNF-α receptor expressed by LC.Collectively, these data suggest a paradigm in which keratinocytes and LC in the epidermis have distinct roles in promoting type 1 and type 2 immune responses, respectively. Therefore, LC may not be activated directly by certain TLR ligands or chemical allergens that are associated with type 1 responses. Consequently the migration of LC in vivo after encounter with these stimuli may be secondary to interaction with keratinocytes, or with other skin resident cells. Together, LC and keratinocytes allow the epidermis to respond to a range of pathogens, in addition to developing the necessary type 1 and type 2 responses. Chemical allergens may have divergent cytokine signalling requirements for the induction of LC migration as, unlike other contact allergens (and other stimuli such as irritant and ultraviolet [UV]B exposure), DNCB may induce LC migration independently of TNF-α.
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De, Pascalis Chiara. "Role of intermediate filaments in collective cell migration of glial cells." Thesis, Paris 6, 2017. http://www.theses.fr/2017PA066026.
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Pendant la morphogenèse, la réparation des tissus et le cancer, les cellules peuvent migrer en manière mésenchymateuse et collective. Le cytosquelette est essentiel pour la migration, mais alors que l'actine et les microtubules ont été largement étudiés, le rôle des filaments intermédiaires (FIs) est encore largement inconnu. La déplétion des FI diminue souvant la vitesse de migration et les FI sont fréquemment surexprimé dans les tumeurs invasives. Pour ces propriétés, nous supposons que les FIs peuvent jouer un rôle clé dans la mécanique cellulaire pendant la migration.Pour étudier le rôle des FI dans la migration collective, nous avons utilisé des astrocytes, les principales cellules gliales du système nerveux central. Les astrocytes migrent collectivement pendant le développement et l'astrogliose en réponse à des signaux pathologiques ou traumatiques. Les astrocytes expriment trois principales FI cytoplasmiques: nestine, GFAP (protéine acide fibrillaire fibreuse) et vimentine, qui forment un réseau dense. Les FI sont surexprimé pendant l'astrogliose et dans les glioblastomes, des tumeurs cérébrales hautement invasives et létales. On ignore si la surexpression des FI est responsable de l'invasion du glioblastome.Au cours de la migration collective dans un test de blessure, les FI contrôlent le positionnement du noyau, la polarité et la migration. On montre que les FI régulent la migration collective dirigée de manière dépendante de la rigidité. Ils agissent avec la protéine connecteur cytoplasmique plectine pour contrôler les point focaux et les jonctions adhérentes. Les FI contrôlent la dynamique et l'organisation de l'actine et régulent la distribution des tractions cellulaires et des contraintes dans la monocouche migrante. Ces résultats démontrent le rôle crucial des FI dans les propriétés mécaniques des cellules migrantes<br>During morphogenesis, tissue repair and cancer, cells can migrate in a mesenchymal and collective manner. The cytoskeleton is essential for migration, but whereas actin and microtubules have been extensively studied, the role of intermediate filaments (IFs) is still largely unknown. IF depletion generally decreases migration speed and IF proteins are frequently found upregulated in invasive tumours. Because of IF properties, we hypothesise that they may be key players in cell mechanics during migration. To study the role of IFs in collective migration we used astrocytes, the main glial cells of the central nervous system. Astrocytes migrate collectively during development and astrogliosis in response to pathological or traumatic signals. Astrocytes express three main cytoplasmic IFs: nestin, GFAP (Glial Fibrillary Acidic Protein) and vimentin, which form a dense network. IF proteins are upregulated during astrogliosis and glioblastomas, highly invasive and lethal brain tumours. Whether upregulation of IFs is responsible for glioblastoma invasion is still unknown. During wound-induced collective migration, IFs control nuclear positioning, polarisation and migration. We found that IFs regulate collective directed migration in a stiffness-dependent manner. They act in concert with the cytolinker protein plectin to control focal adhesions and adherens junctions. IFs control actin dynamics and organisation and regulate the distribution of cell tractions and stresses across the migrating cell monolayer. These results demonstrate the crucial role of IFs in the mechanical properties of migrating cells
23
De, Pascalis Chiara. "Role of intermediate filaments in collective cell migration of glial cells." Electronic Thesis or Diss., Paris 6, 2017. http://www.theses.fr/2017PA066026.
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Pendant la morphogenèse, la réparation des tissus et le cancer, les cellules peuvent migrer en manière mésenchymateuse et collective. Le cytosquelette est essentiel pour la migration, mais alors que l'actine et les microtubules ont été largement étudiés, le rôle des filaments intermédiaires (FIs) est encore largement inconnu. La déplétion des FI diminue souvant la vitesse de migration et les FI sont fréquemment surexprimé dans les tumeurs invasives. Pour ces propriétés, nous supposons que les FIs peuvent jouer un rôle clé dans la mécanique cellulaire pendant la migration.Pour étudier le rôle des FI dans la migration collective, nous avons utilisé des astrocytes, les principales cellules gliales du système nerveux central. Les astrocytes migrent collectivement pendant le développement et l'astrogliose en réponse à des signaux pathologiques ou traumatiques. Les astrocytes expriment trois principales FI cytoplasmiques: nestine, GFAP (protéine acide fibrillaire fibreuse) et vimentine, qui forment un réseau dense. Les FI sont surexprimé pendant l'astrogliose et dans les glioblastomes, des tumeurs cérébrales hautement invasives et létales. On ignore si la surexpression des FI est responsable de l'invasion du glioblastome.Au cours de la migration collective dans un test de blessure, les FI contrôlent le positionnement du noyau, la polarité et la migration. On montre que les FI régulent la migration collective dirigée de manière dépendante de la rigidité. Ils agissent avec la protéine connecteur cytoplasmique plectine pour contrôler les point focaux et les jonctions adhérentes. Les FI contrôlent la dynamique et l'organisation de l'actine et régulent la distribution des tractions cellulaires et des contraintes dans la monocouche migrante. Ces résultats démontrent le rôle crucial des FI dans les propriétés mécaniques des cellules migrantes<br>During morphogenesis, tissue repair and cancer, cells can migrate in a mesenchymal and collective manner. The cytoskeleton is essential for migration, but whereas actin and microtubules have been extensively studied, the role of intermediate filaments (IFs) is still largely unknown. IF depletion generally decreases migration speed and IF proteins are frequently found upregulated in invasive tumours. Because of IF properties, we hypothesise that they may be key players in cell mechanics during migration. To study the role of IFs in collective migration we used astrocytes, the main glial cells of the central nervous system. Astrocytes migrate collectively during development and astrogliosis in response to pathological or traumatic signals. Astrocytes express three main cytoplasmic IFs: nestin, GFAP (Glial Fibrillary Acidic Protein) and vimentin, which form a dense network. IF proteins are upregulated during astrogliosis and glioblastomas, highly invasive and lethal brain tumours. Whether upregulation of IFs is responsible for glioblastoma invasion is still unknown. During wound-induced collective migration, IFs control nuclear positioning, polarisation and migration. We found that IFs regulate collective directed migration in a stiffness-dependent manner. They act in concert with the cytolinker protein plectin to control focal adhesions and adherens junctions. IFs control actin dynamics and organisation and regulate the distribution of cell tractions and stresses across the migrating cell monolayer. These results demonstrate the crucial role of IFs in the mechanical properties of migrating cells
24
Xia, Weiliang. "Role of cytokines in junction restructuring and germ cell migration in mammalian testes." Click to view the E-thesis via HKUTO, 2006. http://sunzi.lib.hku.hk/hkuto/record/B37101134.
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25
Ng, Mei Rosa. "Mechanical Regulation of Epithelial Cell Collective Migration." Thesis, Harvard University, 2012. http://dissertations.umi.com/gsas.harvard:10578.
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Cell migration is a fundamental biological process involved in tissue development, wound repair, and diseases such as cancer metastasis. It is a biomechanical process involving the adhesion of a cell to a substratum, usually an elastic extracellular matrix, as well as the physical contraction of the cell driven by intracellular actomyosin network. In the migration of cells as a group, known as collective migration, the cells are also physically linked to one another through cell-cell adhesions. How mechanical interactions with cell substratum and with neighboring cells regulate movements during collective migration, nevertheless, is poorly understood. To address this question, the effects of substrate stiffness on sheet migration of MCF10A epithelial cells were systematically analyzed. Speed, persistence, directionality and coordination of individual cells within the migrating sheet were all found to increase with substrate stiffening. Substrate stiffening also enhanced the propagation of coordinated movement from the sheet edge into the monolayer, which correlated with an upregulation of myosin-II activity in sheet edge cells. This mechano-response was dependent on cadherin-mediated cell-cell adhesions, which are required for the transmission of directional cue. Importantly, myosin-II contractility modulated cadherin- dependent cell-cell coordination, suggesting that contractile forces at cadherin adhesions regulate collective migration. To measure forces transmitted through cell-cell adhesions, a quantitative approach was developed in which cell-cell forces were deduced from cell-substrate traction forces, based on force balance principles and simple cell mechanics modeling. This method enabled the analysis of cell-cell mechanical interactions in small cell clusters of complex topology. The dynamic fluctuations of cell-cell forces over time revealed that force transmission between non-adjacent cells is typically limited, but is enhanced when the cell across which forces are being transmitted has reduced myosin-IIA or talin-1. This suggests that cells in a group may differentially regulate their levels of myosin-II contractility and cell-matrix mechanotransduction to promote longer-range force transmission during collective migration. Together, the results in this dissertation led to a working model of collective cell migration as regulated by cell-matrix mechanical properties and cell-cell mechanical interactions. This model, as well as the quantitative techniques developed here, will drive future studies on the mechanisms underlying collective migration.
26
Zhao, Zhiqiang. "Electric field-directed cell migration and endothelialization." Thesis, Available from the University of Aberdeen Library and Historic Collections Digital Resources. Restricted: no access until June 30, 2014, 2009. http://digitool.abdn.ac.uk:80/webclient/DeliveryManager?application=DIGITOOL-3&owner=resourcediscovery&custom_att_2=simple_viewer&pid=26544.
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27
Czuchra, Aleksandra. "Cdc42 and beta1 integrin in cell migration." Diss., lmu, 2005. http://nbn-resolving.de/urn:nbn:de:bvb:19-47081.
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28
Jiang, Pengju. "Filamin and its interactions in cell migration." Thesis, University of Oxford, 2007. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.487265.
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Human filamin is a large dimeric, modular protein made up of two calponin homology domains and twenty-four immunoglobulin-like (Ig_FLMN) domains. Filamin cross-links actin filaments and is deeply involved in cell migration processes, largely through interactions with plasma membrane proteins, especially integrins. In the work presented here, the structural properties of filamin fragments involved in integrin binding have been studied. NMR investigations of individual dissected Ig_FLMN modules from human . filamin A (called FLNa here) revealed that, although homologous at the sequence level, they have variable folding properties. A series of NMR titrations located the binding interface between the cytoplasmic tails of integrins and filamin modules, showing that binding of FLNa19 and FLNa21 to the tails was very similar. Further analysis of NMR experimental results quantitatively characterized a dimerization of the integrin-filamin complex in solution. Inter-module interactions in a triple module (FLNa19-21) were also observed and studied. NMRstudies on module pairs of filamin (FLNaI9-20 and FLNa20-21) disclosed that part ofFLNa20 'zips' along FLNa21 in a similar pattern as integrin tails. NMR studies show that this structure is, however, readily disrupted by addition of integrin tails. The observed affinities, dimerization behaviour and the structure of FLNa19-21 led to an 'integrin clip' hypothesis. This model was supported by evidence that suggested a module rearrangement of FLNa19-21 was induced by integrin binding. Several potential regulation mechanisms for filamin-integrin binding, including selective expression of isoforrns, splicing variation and phosphorylation, were also studied. Based on previous knowledge of Ig_FLMN complexes, a strategy to predict filamin binding affinity was developed and applied to the binding site detennination for two newly identified filamin binding proteins,' migfilin and FILIP; this was successfully confinned by NMR titration experiments.
29
Schioppa, Tiziana. "Effects of tumour hypoxia on cell migration." Thesis, Open University, 2006. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.434200.
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Cell adaptation to hypoxia requires activation of transcriptional programs that coordinate expression of genes involved in oxygen delivery (via- angiogenesis) and metabolic adaptation (via glycolisis). During migration and invasion of normal and pathological tissues, cells may encounter different oxygen levels, due to poor or altered vascularization, and recent evidence has suggested that chemotaxis is a cell function which may be affected by oxygen availability. This thesis describes how oxygen avaibility is a determinant parameter in the setting of chemotactic responsiveness to Stromal-Derived Factor 1 (SDF-1, CXCL12). Low oxygen concentration induces high expression of the CXCL12 receptor CXCR4, in different cell types (monocytes, monocyte-derived macrophages, tumor associated macrophages, endothelial cells, cancer cells and dendritic cells) as both mRNA and protein expression, which is paralleled by increased chemotactic responsiveness to its specific ligand. Furthermore, preliminary results on dendritic cells (DC) show that hypoxia may affect their maturation (CCR7'°'/CCR5h'gh) and functions. In particular, hypoxia-derived DC do not migrate in response to the CCR7 ligand CCL 19, while they do express higher levels of pro-inflammatory cytokines (IL-12, TNF-a), as compared to normoxia-derived DC. CXCR4 induction by hypoxia is dependent on both activation of hypoxia-inducible factor 1 (HIF-la) and transcript stabilization. Our data identify the hypoxia/HIF-1/CXCR4 pathway as a relevant molecular circuit in the functional tuning of the chemokine system and provide novel insights into the mechanisms controlling cell migration in hypoxic regions, with potential relevance in the pathogenesis of human diseases, including chronic inflammatory diseases and cancer
30
Prentice, Mott Harrison Valentine. "Chemical and Physical Determinants of Cell Migration." Thesis, Harvard University, 2014. http://dissertations.umi.com/gsas.harvard:11494.
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The phenomenon of directed cell motion in response to external directional cues has drawn significant interest for more than a century, with the first recorded observations of bacterial chemotaxis at the end of the 19th century. Furthermore, movies generated by David Rogers while at Vanderbilt University of a peripheral blood neutrophil tracking a bacterium are a staple of any college biology class to demonstrate the phenomenon of eukaryotic chemotaxis. In just the last decade, our understanding of the biochemical mechanisms underlying the process of directed eukaryotic cell migration. As a result, several generalized processes have been identified, connecting multiple phenomena from cancer metastasis to axon guidance. Making further sense of the complex biochemical pathways requires both quantitative mathematical models and fine control over the external cellular environment. To this end, microfluidics has proven extremely useful, allowing for precise quantification of both the external environment and the cellular response.
31
Bahm, Isabel. "PDGF signalling during Neural Crest Cell migration." Thesis, University College London (University of London), 2018. http://discovery.ucl.ac.uk/10041758/.
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Neural crest cells are a transient cell population, which migrates through the vertebrate embryonic body, and eventually gives rise to a many different cell types in the adult. Contact inhibition of locomotion (CIL) is a fundamental property of the collective migrating neural crest cells. CIL describes a process by which colliding cells change their direction upon collision and move away from each other, which has been linked to cell dispersion, boundary formation and metastasis. CIL is acquired in neural crest cells during Epithelial-to-Mesenchymal-Transition (EMT), by a switch in the expression of cadherins, from E to N-cadherin. To examine what governs this change I study PDGF signalling during Xenopus laevis cranial neural crest migration. Here I show that PDGFRα and its ligand PDGF-A are expressed in pre-migratory and migrating cranial neural crest cells. Inhibition of PDGF-A/PDGFRα impairs neural crest migration in vivo and cell dispersion in vitro. I find that PDGFRα inhibition leads to a decrease of N-cadherin levels in neural crest cells. Further, I demonstrate that PDGFRα signalling controls N-cadherin dependent CIL. This cellular response is controlled by the PI3K/AKT signalling pathway as a downstream effector of the PDGFRα cellular response in cranial neural crest cells. This data lead me to propose a novel mechanism by which PDGF signalling as a tissue-autonomous regulator of EMT is regulating N-cadherin dependent CIL during cranial neural crest cell migration in Xenopus laevis.
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Vanderleyden, Ine. "Follicular regulatory T cell migration and differentiation." Thesis, University of Cambridge, 2019. https://www.repository.cam.ac.uk/handle/1810/288422.
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The germinal centre (GC) response is critical for generating highly effective humoral immune responses and immunological memory that forms the basis of successful immunisation. Control of the output of the GC response requires Follicular regulatory T (Tfr) cells, a subset of Foxp3+ Treg cells located within germinal centres. Tfr cells were first characterised in detail in 2011 and because of this relatively little is known about the exact role of Tfr cells within the GC, and the mechanism/s through which they exert their suppressive function. At the outset of this work, the major barrier to understanding Tfr cell biology was the lack of appropriate tools to study Tfr cells specifically, without affecting Tfh cells or other Treg cell subsets. This thesis set out to develop a strain of mice that specifically lacks Tfr cells. A unique feature of Tfr cells is their CXCR5-dependent localisation within the GC. Therefore, genetic strategies that exclude Treg cells from entering the GC are a rational approach to generating a mouse model that lacks Tfr cells. To this end, I generated a strain of mice that lacks CXCR5 on Foxp3+ Treg cells. These animals show a ~50% reduction in GC localised Tfr cells, and a GC response that is comparable to control animals. These data indicated that redundant mechanisms are involved in Treg cell homing to the GC. I identified CXCR4 as a chemokine receptor that is also highly expressed on Tfr cells, and hypothesised that it may also be involved in Tfr cell localisation to the GC. Surprisingly, simultaneous deletion of both CXCR4 and CXCR5 in Treg cells resulted in a less marked reduction in Tfr cells compared to deletion of CXCR5 alone, suggesting that CXCR4 might be involved in negative regulation of Treg homing to the GC. These data identify both CXCR4 and CXCR5 as key regulators of Tfr cell biology. Bcl6 drives Tfr cell differentiation, but how this transcriptional repressor facilitates commitment to the Tfr cell subset is unknown. I hypothesised that Bcl6 drives Tfr cell differentiation by repressing Tbx21, the transcriptional regulator involved in the differentiation of Th1-like Treg cells. I tested this hypothesis in Bcl6fl/fl CD4cre/+ animals and unexpectedly found that loss of Bcl6 regulates Treg cell differentiation in the absence of immunisation or infection. I have demonstrated that thymic loss of Bcl6 results in an increase in activated effector Treg cells, which occurs very early in life. These data point to a novel role for Bcl6 in preventing early thymic Treg activation, indicating that Bcl6 has a global role in Treg development and differentiation that is not simply limited to Tfr cells.
33
Pinho, Ana Catarina Dinis de. "Unveiling the APP role in cell migration." Master's thesis, Universidade de Aveiro, 2013. http://hdl.handle.net/10773/11629.
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Mestrado em Biomedicina Molecular<br>A proteína precursora de amilóide de Alzheimer (PPA) é uma glicoproteína
transmembranar com propriedades de adesão, descrita como reguladora
positiva de migração celular. Embora ubíqua, a isoforma 695 da PPA está
enriquecida no cérebro e pode funcionar na migração neuronal de novos
neurónios que emergem de nichos neurogénicos existentes no cérebro adulto.
No presente trabalho, objetivámos desvendar o papel da PPA e do seu
fragmento secretado (sPPA) na migração celular, particularmente na migração
de células do tipo neuronal, e os mecanismos moleculares subjacentes.
Realizaram-se estudos de biologia celular em células SH-SY5Y humanas do
tipo neuronal transfectadas com o cDNA de fusão PPA-GFP ou o vector
EGFP, e sujeitas ao ensaio de ‘Scratch Wound Healing’ na presença ou
ausência de sPPA. A eficiência de migração das células SH-SY5Y foi
monitorizada a cada hora através de imagens de microscopia. O número de
células migratórias recrutadas, e a distância e velocidade de migração da
margem foram os parâmetros monitorizados nas células não transfectadas,
para analisar o papel parácrino do sPPA. A coordenação, distância e
velocidade de migração celular, e a distância migrada “fora-da-trajectória”,
foram determinadas por análise da trajectória de cada célula transfectada, para
estudar o papel autócrino da PPA transmembranar. A influência da PPA no
fenótipo migratório e na distribuição da F-actina foram analisadas em células
SH-SY5Y fixadas, e em condições ‘in vivo’ em células HeLa fluorescentes coexpressando
PPA-GFP e um marcador fluorescente de F-actina (LifeAct-RFP).
Estas células migratórias foram ainda sujeitas a análise por FRAP para estudar
os efeitos da PPA na dinâmica do citoesqueleto de F-actina. Foi também
avaliado o efeito da PPA na activação da Cdc42, um membro da família das
Rho GTPases que regula a polarização celular e a formação de filopodia,
influenciando assim o direcionamento da migração.
Os nossos resultados mostram que o sPPA aumenta o número de células
migratórias em períodos mais tardios, diminui a velocidade migratória da
margem e aumenta a distância migrada “fora-da-trajectória”. A PPA
transmembranar foi observada como tendo um papel na coordenação e
persistência direcional da migração celular, numa forma dependente da
desfosforilação do seu resíduo S655. Adicionalmente, análises morfológicas
mostraram que a PPA ajuda as células a adquirir a distribuição de F-actina
assimétrica polarizada característica de células migratórias. Os dados de
FRAP sugerem que a PPA aumenta a estabilidade da F-actina quer na frente
quer na traseira das células migratórias, aumentando a eficiência da migração
celular uma vez que a adesão célula-substrato pode orientar a direccionalidade
da migração. Finalmente, observámos que a PPA liga à Cdc42 e aumenta a
sua ativação, outro mecanismo pelo qual a PPA pode determinar a migração
direcionada. Estes resultados ajudam a desvendar os mecanismos
moleculares subjacentes ao papel da PPA na migração celular, com potenciais
aplicações no estudo da migração neuronal na neurogénese adulta.<br>The Alzheimer’s amyloid precursor protein (APP) is a transmembranar
glycoprotein with adhesive properties, reported to positively regulate cell
migration. Although ubiquitous, the APP 695 isoform is brain enriched and may
function in neuronal migration of newly born neurons arising from adult brain
neurogenic niches.
In the present work we aimed to unveil the roles of APP and its secreted
fragment (sAPP) in cell migration, particularly in neuronal-like migration, and
the underlying molecular mechanisms. Cell biology studies were first performed
in neuronal-like human SH-SY5Y neuroblastoma cells transfected with an APPGFP
fusion construct or the EGFP vector, and subjected to the well-established
‘Scratch Wound Healing’ assay in the presence or absence of sAPP. The
efficiency of SH-SY5Y cells migration was monitored every hour by microscopy
imaging. The number of recruited migrating cells, and the leading-edge
migration distance and velocity were the parameters monitored in nontransfected
cells, to analyze the sAPP paracrine role. Cell coordination,
migration distance and velocity, and “out-of-track” distance during cell
migration, were determined by single-cell track analysis of transfected cells to
study the autocrine role of full length APP. The influence of APP in the
migratory phenotype and in F-actin distribution were analyzed in SH-SY5Y
fixed cells, and in fluorescing HeLa cells co-expressing APP-GFP and a live Factin
red fluorescent marker (LifeAct-RFP), by live cell imaging. These
migrating cells were further subjected to FRAP analysis to study the APP
effects on F-actin cytoskeleton dynamics. Finally, we also evaluated the effects
of APP on the activation of Cdc42, a Rho GTPase family member that main
regulates cell polarization and filopodia generation, influencing directional
migration.
Our results show that sAPP is capable to increase the number of cells recruited
to migrate at later periods, but decreases the migratory velocity of the leading
edge and increases the “out-of-track” migrated distance. Full-length APP was
observed to have a role in the coordination and directional persistence of cells
migration, in a S655-dephosphorylation dependent manner. Additionally, the
morphological analyses showed that APP helps SH-SY5Y cells to acquire the
polarized asymmetric F-actin distribution characteristic of migrating cells. FRAP
data suggest that APP increases the stability of both front and rear F-actin of
migrating cells, which may increase cell migration efficiency, as cell-substrate
adhesion can guide the directionality of migration. Finally, we observed that
APP binds to and enhances Cdc42 activation, another mechanism by which it
can determine directional migration. These results help to unveil the molecular
mechanisms underlying APP role in cell migration, with potential applications in
the field of neuronal migration in adult neurogenesis.
34
Van, Lonkhuyzen Derek Robert. "Novel modulators of cell growth and migration." Thesis, Queensland University of Technology, 2007. https://eprints.qut.edu.au/16549/1/Derek_Van_Lonkhuyzen_Thesis.pdf.
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Recent observations have demonstrated that Insulin-like Growth Factors (IGFs) are able to form complexes with the extracellular matrix protein Vitronectin (VN). These complexes of VN:IGFBP:IGF-I significantly enhance the proliferation and migration of various cell lines including skin and corneal epithelial cells, as well as primary cells derived from human skin and corneal tissue. These enhanced effects arise from co- activation of the IGF-binding type-1 IGF receptor (IGF-1R) as well as activation of the VN-binding αv-integrins. Further studies suggest that these complexes can replace the requirement for serum in the ex vivo expansion of cells. In order to translate the VN:IGFBP:IGF-I technology into techniques for the improved culture of cells, we have designed, expressed and purified synthetic chimeric molecules, consisting of various domains of VN and mature IGF-I, using a baculovirus based expression system. The recombinant VN:IGF-I (rVN:IGF-I) chimeras were secreted into conditioned media of transfected Sf9 insect cells. Purification of the chimeras was achieved via methods including heparin-sepharose chromatography, Q-sepharose ion-exchange chromatography and Ni2+-NTA affinity chromatography. The rVN:IGF-I chimeras were detectable by Western blot analysis using a poly-clonal anti-VN antibody. Functional characterisation studies indicate that the chimeras promote cellular growth and migration to a similar extent as the VN:IGFBP:IGF-I complexes at 10x and 30x molar ratios. Additionally, function blocking antibodies directed to the IGF-1R and the VN binding αv-integrin were able to abolish this effect indicating that co-activation of these receptors is critical to the migratory effect of the chimeras. A functional chimera may lead to the development of cell culture techniques and methodologies that are devoid of xenogeneic or allogeneic support systems, thus paving the way to approved tissue engineering therapeutics that incorporate ex vivo expanded adult stem and progenitor cells.
35
Van, Lonkhuyzen Derek Robert. "Novel modulators of cell growth and migration." Queensland University of Technology, 2007. http://eprints.qut.edu.au/16549/.
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Recent observations have demonstrated that Insulin-like Growth Factors (IGFs) are able to form complexes with the extracellular matrix protein Vitronectin (VN). These complexes of VN:IGFBP:IGF-I significantly enhance the proliferation and migration of various cell lines including skin and corneal epithelial cells, as well as primary cells derived from human skin and corneal tissue. These enhanced effects arise from co- activation of the IGF-binding type-1 IGF receptor (IGF-1R) as well as activation of the VN-binding αv-integrins. Further studies suggest that these complexes can replace the requirement for serum in the ex vivo expansion of cells. In order to translate the VN:IGFBP:IGF-I technology into techniques for the improved culture of cells, we have designed, expressed and purified synthetic chimeric molecules, consisting of various domains of VN and mature IGF-I, using a baculovirus based expression system. The recombinant VN:IGF-I (rVN:IGF-I) chimeras were secreted into conditioned media of transfected Sf9 insect cells. Purification of the chimeras was achieved via methods including heparin-sepharose chromatography, Q-sepharose ion-exchange chromatography and Ni2+-NTA affinity chromatography. The rVN:IGF-I chimeras were detectable by Western blot analysis using a poly-clonal anti-VN antibody. Functional characterisation studies indicate that the chimeras promote cellular growth and migration to a similar extent as the VN:IGFBP:IGF-I complexes at 10x and 30x molar ratios. Additionally, function blocking antibodies directed to the IGF-1R and the VN binding αv-integrin were able to abolish this effect indicating that co-activation of these receptors is critical to the migratory effect of the chimeras. A functional chimera may lead to the development of cell culture techniques and methodologies that are devoid of xenogeneic or allogeneic support systems, thus paving the way to approved tissue engineering therapeutics that incorporate ex vivo expanded adult stem and progenitor cells.
36
CRESTANI, MICHELE. "MECHANOPROPERTIES, HETEROGENEITY AND CELL MIGRATION IN GLIOBLASTOMA." Doctoral thesis, Università degli Studi di Milano, 2022. https://hdl.handle.net/2434/946015.
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Glioblastomas (GBMs) are primary brain tumors endowed with inter- and intra-patient
heterogeneity and extreme di↵usivity. As heterogeneity is studied with genomic and
transcriptomic analysis, little is known on how it is reflected on cell migration, mechanoproperties
and motility modes. Generally, the tumor cells invade the brain moving on
brain vasculature or white matter tracks: Patient-Derived Xenograft (PDX) has been a
standard to reproduce them in order to study GBM invasion. However, PDX presents
many disadvantages, including time consumption, hard standardization, high cost and
ethical concerns.
The present PhD thesis report aims at summarizing the existing literature through
an historical journey that gradually walks the reader towards the state of the art in
the biological knowledge, therapeutic treatments, and bioengineering of GBM. It also
reports the results of this PhD work. They include novel bioengineering tools for
studying the mechanoproperties in GBM and the development of methods to dissect
their migration and motility modes. Finally, a stand-alone assay aims at fostering a
discussion on how the scientific mindset and science have evolved and are evolving to
drive technological innovation in nowadays’ world.
The main goal of this PhD work was to develop bioengineering tools to crack
mechanoproperties and GBM motility. Initially, by utilizing clones of patient-derived
GBM cells that were either highly proliferative or highly invasive, I co-studied their cellular
architecture, migratory, and biophysical properties. One of the milestones of this
PhD work consists in the link between that invasiveness and cellular fitness. The most
invasive cells were sti↵er, developed higher mechanical forces on the substrate, and
moved stochastically. The mechano-chemical-induced expression of the formin FMN1
supports the mechanical cohesion of the cytoskeleton and enhances cell’s mechanoproperties,
leading to a higher motility and invasive phenotype.
In order to scale up the motility screen to several GBM clones, I co-developed SP2G
(SPheroid SPreading on Grids), the live imaging of GBM spheroids spreading on grid
micropatterns mimicking the brain vasculature. To counteract the issues in PDX and
rapidly identify the most invasive sub-populations hidden in heterogeneous GBMs, we
developed an in vivo mimicry platform named SP2G (SPheroid SPreading on Grids).
Live imaging of tumor-derived spheroids spreading on gridded micro patterns imitating
the brain vasculature mimicked 3D motility features observed in brain or 3D matrices.
Using patient-derived samples coupled with a semi-automated ImageJ/Fiji macro suite,
SP2G easily characterized and sorted di↵erences in cell migration and motility modes
through a set of 6 parameters (area expansion, di↵usivity, boundary speed, collective
migration, directional persistence, hurdling). Moreover, SP2G exposed the hidden
intra-patient heterogeneity in cell motility that correlated molecularly to specific integrins.
Thus, SP2G is intended as a versatile and potentially pan-cancer workflow to
identify the invasive tumor sub-populations in patient-derived specimens. SP2G represents
an integrative tool, available as open-source Fiji macro suite, for therapeutic
evaluations at single patient level.
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Capuana, Lavinia. "Role of PTEN during collective cell migration." Electronic Thesis or Diss., Sorbonne université, 2019. https://accesdistant.sorbonne-universite.fr/login?url=https://theses-intra.sorbonne-universite.fr/2019SORUS051.pdf.
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La migration cellulaire correspond à l’habilité des cellules de se déplacer d’un point à un autre. Certaines cellules se déplacent individuellement tandis que d’autres, sous l’influence de conditions physiologiques ou pathologiques, migrent collectivement en groupes étroitement associées. L’efficacité de ce processus dépend de la capacité des cellules à coordonner les étapes clés de la migration cellulaire. Tout d’abord les cellules établissent conjointement un axe de polarité avant-arrière pour restreindre l’activité protrusive à l’avant du groupe de cellules. Puis la régulation dynamique des contacts cellules-cellules et cellules-matrice extracellulaire permet le mouvement coordonné du groupe. La migration collective est observée aussi bien lors des processus de morphogénèse embryonnaire que lors du développement agressif des tumeurs. Les glioblastomes (GBM) sont des cancers des cellules gliales qui représentent la forme la plus agressive des tumeurs primaires du cerveau. Le taux de survie à 5 ans extrêmement bas (<5%) serait principalement dû aux capacités invasives des cellules de GBM, individuellement et collectivement, qui empêchent l’efficacité des traitements actuels. PTEN (Phosphatase et TENsin homolog) est un gène suppresseur de tumeur dont la fonction est altérée dans plus de 60% des GBM. De précédents travaux ont suggéré que la perte de fonction de PTEN augmenterait les propriétés invasives des cellules tumorales. Néanmoins le mécanisme moléculaire contribuant à l’impact sur la migration cellulaire reste inconnu. Au cours de ma thèse j’ai démontré que l’activité protéine phosphatase de PTEN, mais non l’activité lipide phosphatase, a un rôle crucial dans la migration collective. En effet lors de la migration collective des cellules gliales in vitro et des cellules endothéliales in vivo, seule l’inhibition spécifique de l’activité protéine phosphatases augmente leur vitesse de migration. L’altération de l’activité protéine phosphatase impacte l’organisation du cytosquelette d’actine via deux voies de signalisation différentes ciblant la cofiline et VASP. Cette réorganisation affecte à la fois la force protrusive des cellules et la dynamique des contacts intercellulaires; fournissant ainsi une explication mécanistique au phénotype observé pour les cellules de GBM dépourvues de PTEN. L’ensemble de ces résultats définisse l’activité protéine phosphatase de PTEN comme nouvelle cible thérapeutique potentielle contre le développement invasif des tumeurs dénuées de PTEN<br>Cell migration is crucial during morphogenesis and also in the adult where it participates in tissue renewal, immune response, wound healing as well as in cancer invasion and metastasis. In certain cases, cells move as individuals while some other processes require collective cell migration (Rorth 2012). In order to migrate collectively, cells need to establish and maintain a front-rear polarity axis, redistribute proteins in a polarised fashion and form cell-cell and cell-matrix interaction. Collective cell migration is crucial for many physiological processes, from embryonic development where it is involved in gastrulation and morphogenesis to the adult where it participates in wound healing, tissue renewal and immune responses. Many pathologies have been linked with aberrant collective cell migration, the first of all being cancer spreading (Rorth 2009, Friedl, Sahai et al. 2012, Te Boekhorst, Preziosi et al. 2016). During my PhD, I focused on the PTEN dependent mechanisms controlling collective cell migration. A wide number of genes are altered during oncogenesis including inactivation of tumour suppressors such as p53, p16 and retinoblastoma (Rb) and overexpression of gene encoding epidermal growth factor (EGF) (Tamura, Gu et al. 1999). PTEN is one such tumour suppressor gene which is frequently mutated or deleted in a wide range of human cancers, from glioblastomas to prostate, breast, kidney, lung, testes and thyroid cancers. In particular, PTEN`s function is altered in more than 60% of glioblastomas. It is altered mostly in high-grade invasive glioblastomas but not in low-grade gliomas suggesting an important correlation between PTEN absence and invasive properties of the cancer cells (Rasheed, Stenzel et al. 1997, Dey, Crosswell et al. 2008). In addition, PTEN is known to regulate several cellular functions including cell migration and lots of the mechanisms involved in single cell migration have been extensively studied (Davies, Gibbs et al. 1999, Iijima and Devreotes 2002, Gerisch, Schroth-Diez et al. 2012). Glioblastoma form the most common and lethal primary intracerebral tumours (Davis, Kupelian et al. 2001). Tumour spreading in the brain parenchyma is largely responsible for the resistance of gliomas to cancer treatment and yet no therapeutic treatment has been found to prevent tumour infiltration. The mechanisms by which cells invade the central nervous system have not yet been directly observed and for some aspects they still remain elusive (Davies, Gibbs et al. 1999). Glioblastoma can arise from astrocytes or their precursors and they have an incidence of approximately 5 cases per 100.000 inhabitants (Furnari, Fenton et al. 2007). Astrocytes are the main glial cells of the central nervous system. They participate in the regulation of brain homeostasis and in the formation of the blood-brain barrier (Kimelberg and Nedergaard 2010). Astrocyte migrate in a collective fashion during development (Gnanaguru, Bachay et al. 2013) and in the adult brain, they have been shown to undergo astrogliosis in response to inflammation or trauma. Here they are able to elongate, polarise and eventually migrate toward the site of interest in order to create a glial scar (Sofroniew 2014). For these many reasons, in the lab we use primary rat astrocyte as preferential model to study the mechanism of collective cell migration (Etienne-Manneville 2006) [...]
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Hu, Yang. "Regulation of dendritic cell and monocyte migration by interferons /." Access full-text from WCMC:, 2006. http://proquest.umi.com/pqdweb?did=1296095631&sid=1&Fmt=2&clientId=8424&RQT=309&VName=PQD.
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Brooks, Rebecca. "Coordinating cell-cell contacts with cell-matrix contacts in fibroblast migration during wound healing." Thesis, University of Bristol, 2016. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.690373.
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Following injury, fibroblasts migrate into the wound bed, where they play essential roles in effective wound healing through matrix deposition and contraction. Fibroblast migration relies on cell-matrix and cell-cell contacts, both of which are regulated by transmembrane receptors that are differentially regulated during wound healing. The fibronectin receptor syndecan-4 is increased upon wounding, which promotes fibroblast migration through activation of small GTPases and the recycling of integrin a5~1. Members of the Eph family of receptor tyrosine kinases, which regulate cellcell contacts, are also differentially regulated upon wounding. Little is known about whether there is a relationship between the syndecan-4 and Eph receptors, and how this might regulate the balance between cell -cell and cell-matrix contacts, and therefore fibroblast migration and clustering. Using transient knockdown and genetic knockout models, this project demonstrates that syndecan-4 downregulates EphA2, a receptor that mediates cell-cell repulsion, through a PKCa- and Fyn-dependent mechanism. In syndecan-4 knockout mouse embryonic fibroblasts, elevated EphA2 expression increases sensitivity to the EphA2 ligand ephrinA 1 and increases the rate and frequency of cell-cell repulsion when compared to wild type, demonstrating that the relationship between syndecan-4 and EphA2 has a direct effect on fibroblast clustering. Importantly, the findings are translated in vivo; EphA2 expression is increased in syndecan-4 knockout mouse wounds compared to wild type. This may contribute to the healing defect previously observed in syndecan-4 knockout mice 1. We hypothesise that the balance between syndecan-4 and EphA2 signalling regulates the switch between fibroblast clustering or scattering, and therefore coordinates the initiation and resolution of healing.
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Wu, Xun. "Quantitative cell migration analysis of CCR7-mediated lymphocytes migration using a microfluidic device." The Royal Society of Chemistry, 2013. http://hdl.handle.net/1993/23886.
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Lymphocyte migration is crucial for adaptive immunity. CCR7 and its ligands mediate the migration and positioning of T cells in lymph nodes but the underlying mechanism is complex. The research in this thesis investigated CCR7-mediated T cell migration using a microfluidics-based approach. A microfluidic method suitable for quantitative migration analysis of genetically modified lymphocyte transfectants was developed. Using this method, I demonstrated chemotaxis of Jurkat transfectants expressing wild-type or C-terminal mutated CCR7 to a CCL19 gradient, and characterized the difference in transfectant migration mediated by wild-type and mutant CCR7. The fluorescent tag allows identification of CCR7-expressing transfectants in cell migration analysis, and microscopy assessment of CCR7 dynamics in migrating cells. Furthermore, my results also showed interesting migratory behaviours of CCR7 Jurkat transfectants in a specific co-existing CCL19 and CCL21 fields. This developed method will be broadly useful for studying cell migration signalling.
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Yang, Yongliang. "Emergent Leader Cells in Collective Cell Migration in In Vitro Wound Healing Assay." Diss., The University of Arizona, 2014. http://hdl.handle.net/10150/332896.
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Collective cell migration is critical for various physiological and pathological processes. In vitro wound healing assay has been widely used to study collective cell migration due to its technical simplicity and ability of revealing the complexity of collective cell migration. This project studies the function and importance of leader cells, the cells pulling cell monolayer migrating into free space, in endothelium and skin epithelial regeneration via plasma lithography enhanced in vitro wound healing assay. Despite leader cells have been identified in in vitro wound healing assays, little is known about their regulation and function on collective cell migration. First, I investigated the role of leader cells in endothelial cell collective migration. I found that the leader cell density is positively related with the cell monolayer migration rates. Second, we used this knowledge to study the effects of arsenic treatment on skin regeneration via in vitro wound healing assay. We found that low concentration of arsenic treatment can accelerate the keratinocyte monolayer migration. We further found that arsenic affected cell migration by modulating leader cell density through Nrf2 signaling pathway. As a conclusion of these studies, we evaluated the function of leader cells in collective cell migration, and elucidated the mechanism of arsenic treatment on skin regeneration.
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Zhang, Congyingzi. "Morphological study of cell protrusions during redirected migration in human fibroblast cells." Bowling Green State University / OhioLINK, 2013. http://rave.ohiolink.edu/etdc/view?acc_num=bgsu1367724529.
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Nilsson, Wiktor, and Emil Andersson. "Cytokine-induced immune cell migration towards tumour cells in a microchip environment." Thesis, KTH, Skolan för teknikvetenskap (SCI), 2016. http://urn.kb.se/resolve?urn=urn:nbn:se:kth:diva-195835.
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The purpose of this project was to study the migration patterns of human immune cells in response to human renal cancer cells. This is useful in the study of different cancer treatments and the body’s own response to cancer. Cancer cells can release cytokines which can be detected by immune cells with the correct receptors. The specific type of immune cell that was studied, was the type of lymphocyte called Natural killer cell, abbreviated to NK cell. These lymphocytes have the characteristics that they can differentiate between a cancer cell and a healthy cell, and then have the capability to kill the cancer cell by different means. On the surface of cells there exist receptors. These receptors can interact with signal molecules in the environment near the cell. In this study the effect on the migration caused by the interaction between the receptor CXCR2 and the chemokine CXCL2 have been studied. This was done by transfecting some NK-92 cells with the receptor CXCR2 and the rest with the receptor NGFR then subjecting them to a CXCL2 chemokine gradient. This gradient originated from human renal cancer cells known to produce this chemokine. The specific cancer cells used was the human renal cancer cell line 786-0 which NK-92 cells are known to have the ability to kill when coming in contact with them. It is because of this trait it is of interest to study if the average movement is altered significantly by this receptor induced movement compared to the control NK-92 NGFR. To determine if a significant difference in preferred direction of migration could be discerned between the NK cells expressing either the receptor CXCR2 or NGFR, two analytic methods were devised and applied. The first method was a visualization of the cell migration in the direction of the chemokine gradient, this analyze had no quantitative properties but served as way to determine a general migration. The second, and more precise method involved 3D cell identification, cell tracing, and quantifying the migration. This method yielded quantifiable results that could be analyzed further. A biocompatible microchip with a small passage was utilized to study the migration of the NK cells subjected to this chemokine gradient. Two different approaches to this problem were made. The first approach was to seed the cells onto the chip in a fluid and observe the migration of the sedimented cells the two dimensional surface the glass bottom of the chip constituted. After several attempts with the fluid approach the conclusion was made that because the NK-92 cells aren’t adherent, fluid flows were found to be the main cause for the most of the NK-92 cells movement. A few attempts were made to stop the fluid from flowing over the passage by utilizing a plug placed in the center of the passage during the seeding of the cells and removed before the experiment, but this was without success. Since this flow made all unassisted migration by the cells impossible, no useful data could be obtained from this method. This introduces the second approach which was to suspended the cells in collagen. In these experiment no apparent movement by the NK-92 cells was observed that could originate from fluid movement but did instead seem to be unassisted cell migration. It was found that in an open fluidic environment, fluidic phenomena preponderated the cells own migration, and in the collagen environment the cell migration was to small to yield any obvious results. The analytic methods devised to trace cells and measure the cell migration worked well and gave quantifiable results. In the 3D experiments these methods were able to trace the NK cells and study the migration of the cells with different receptors.
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Koch, Britta. "Scaffold dimensionality and confinement determine single cell morphology and migration." Doctoral thesis, Saechsische Landesbibliothek- Staats- und Universitaetsbibliothek Dresden, 2016. http://nbn-resolving.de/urn:nbn:de:bsz:14-qucosa-194717.
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This thesis describes a highly interdisciplinary approach to discern the differing impact of scaffold dimensionality and physical space restrictions on the behavior of single cells. Rolled-up nanotechnology is employed to fabricate three-dimensional (3D) SiO/SiO2 microtube geometries of varied diameter, that after a biofunctionalization step are shown to support the growth of U2OS and six different types of stem cells. Cell confinement quantifiable through the given microtube diameter is tolerated by U2OS cells through a remarkable elongation of the cell body and nucleus down to a certain threshold, while the integrity of the DNA is maintained.
This confinement for NSPCs also leads to the approaching of the in vivo morphology, underlining the space-restrictive property of live tissue. The dimensionality of the cell culture scaffold however is identified as the major determiner of NSPC migration characteristics and leads to a morphologically distinct mesenchymal to amoeboid migration mode transition. The 3D microtube migration is characterized by exclusively filopodia protrusion formation, a higher dependence on actin polymerization and adopts aspects of in vivo-reported saltatory movement. The reported findings contribute to the determination of biomaterial scaffold design principles and advance our current understanding of how physical properties of the extracellular environment affect cell migration characteristics.
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Blazakis, Konstantinos N. "Computational methods for investigating cell motility with applications to neutrophil cell migration." Thesis, University of Sussex, 2015. http://sro.sussex.ac.uk/id/eprint/56990/.
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Cell motility is closely linked to many important physiological and pathological events such as the immune response, wound healing, tissue differentiation, embryogenesis, in ammation, tumour invasion and metastasis. Understanding the ability of cells to alter their shape, deform and migrate is of vital importance in many biological studies. The rapid development in microscopy and imaging techniques has generated a huge amount of discrete data on migrating cells in vivo and in vitro. A key challenge is the use of discrete experimental observations to develop novel methods and algorithms that track cells and construct continuous trajectories of their motion as well as characterising key geometric quantities associated with cell migration. Therefore, in this work using robust numerical tools we focus on proposing and implementing mathematical methodologies for cell movement and apply them to model neutrophil cell migration. We derive and implement a computational framework that encompasses modelling of cell motility and cell tracking based on phase field and optimal control theory. The cell membrane is represented by an evolving curve and approximated by a diffuse interface; while the motion of the cell is driven by a force balance acting normal on the cell membrane. This approach allows us to characterise the locus of the centroid cell-surface position. In addition, we describe a surface partial differential equation framework that can be coupled with the phase-field framework, thereby offering a wholistic approach for modelling biochemical processes and biomechanics properties associated with cell migration.
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Thiam, Hawa-Racine. "Cell migration under confinement : how can a cell squeeze through narrow gaps ?" Thesis, Paris 5, 2014. http://www.theses.fr/2014PA05T048/document.
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La migration cellulaire possède deux volets antagonistes ; nécessaire à plusieurs processus physiologiques tels que la réponse immunitaire, elle peut également induire la mort d’un organisme en permettant les cellules cancéreuses d’envahir des organes sains. In vivo, la migration s’effectue dans des milieux complexes et confinés qui imposent une forte déformabilité aux cellules migratoires. Récemment, divers études ont montré que le noyau impose la limite de la déformabilité cellulaire lors de la migration en 3D (Wolf et al. JCB, 2013; Harada et al. JCB, 2013). Il a, en effet, été montré que la migration cellulaire peut être augmentée en diminuant la rigidité nucléaire (Wolf et al. JCB, 2013). Cependant, il existe une limite de rigidité nucléaire en dessous de laquelle la migration cellulaire peut être inhibée via l’inhibition de la survie cellulaire (Harada et al. JCB, 2013). Les cellules cancéreuses qui migrent à des vitesses relativement faibles (µm/heure) et ont des noyaux rigides surmontent la limite imposée par la déformation nucléaire en dégradant et élargissant le milieu extracellulaire. Les cellules immunitaires telles que les neutrophiles qui migrent rapidement (10 µm/mn) et ont des noyaux mous sont connus pour mourir aux sites d’infections. Les cellules dendritiques, de la famille des cellules immunitaires, ont une fonction de présentation d’antigènes qui requiert à la fois une grande capacité migratoire et de survie. Elles représentent donc un modèle cellulaire intéressant pour l’étude de la déformation nucléaire chez les cellules qui migrent rapidement et survivent longtemps. Durant mon doctorat, j’ai étudié le mécanisme grâce auquel les cellules dendritiques déforment leurs noyaux afin de migrer de manière efficace en milieux confinés tout en préservant un haut taux de survie. J’ai utilisé un système expérimental nouveau et original consistant en des microcannaux avec des constrictions (Heuzé et al. MMB, 2011). Ces canaux, combinés à des manipulations génétiques et de la video microscopie nous ont permis de montré que les cellules dendritiques possèdent un mécanisme spécifique, indépendant de celui utilisé pour leur migration, leur permettant de déformer leurs noyaux tout en migrant dans des milieux hautement confinés. Ce mécanisme est basé sur la génération d’un réseau d’actin, autour du noyau, nucléé par Arp2/3 et indépendant du moteur Myosin II. Ce réseau d’actine co-localise avec des sites de rupture de la Lamin A/C. De plus, réduire la quantité de Lamin A/C dans les cellules dendritiques inhibe la formation de ce réseau d’actin perinucléaire. Basés sur ces résultats, nous avons proposé un nouveau mécanisme de déformation du noyau lors de la migration en milieux confinés basé sur Arp2/3 qui, en nucléant un réseau d’actine autour du noyau permet de casser la lamin A/C diminuant ainsi la tension de surface nucléaire et permettant le passage noyau<br>Cell migration has two opposite faces; necessary for many physiological processes such as immune response, it can also lead to the organism death by allowing metastatic cells to invade new organs. In vivo migration often occurs in complex 3D environments which impose high cellular deformability. Recently, cellular deformability during 3D migration has been shown to be limited by the nucleus (Wolf et al. JCB, 2013). For instance, cell migration can be increased by decreasing nuclear stiffness. However, below a given nuclear stiffness 3D cell migration can be reduced as a result of impaired cell survival (Harada et al. JCB, 2014). Cancer cells which display slow migration and have rather stiff nuclei have been shown to overcome the physical limits of 3D migration through adhesion combined to matrix degradation or high actomyosin contraction (Wolf et al. JCB, 2013). Immune cells such as neutrophils which are fast moving cells with soft nuclei have been reported to die at sites of infection. Interestingly, dendritic cells function as antigen presenting cells requires high migratory ability as well as high survival. They thus constitute an interesting model for studying nuclear deformation in fast moving and long lived cells. During my PhD, I studied the mechanism by which dendritic cells deform their nuclei to achieve proper migration in highly confining space while preserving a high survival rate. I used an original micro fabricated experimental set up (Heuzé et al. MMB, 2011) consisting of microchannels with constrictions to mimic cellular transmigration. Those channels combined with genetic manipulation and live cell imaging followed by image processing were used to assess the mechanism dendritic cells use to deform their nucleus, which we found to be specific and not required for cell motility per se. I showed that dendritic cells overcome the physical limitation imposed by nuclear deformation through small gaps by nucleating an Arp2/3 based actin network around the nucleus. Surprisingly, the formation of this actin network is independent of myosin II based contraction. This actin accumulation around the nucleus co-localized with sites of nuclear Lamin A/C breakage. Moreover, Lamin A/C depletion in dendritic cells leads to the disappearance of this actin ring and the release of the need for Arp2/3 for nuclear deformation. We thus propose a new mechanism of nuclear squeezing through narrow gaps based on an Arp2/3 nucleated actin meshwork which, by transiently breaking the Lamin A/C network, releases the nuclear surface tension and allows nuclear thus cell passage through micrometric constrictions. Lamin A/C repolymerization around the nucleus at the exit of constrictions would then restore nuclear stiffness, allowing cell survival. Interestingly, this actin accumulation around the nucleus was also observed in vivo in migrating macrophages but not in HL-60 derived neutrophils. Taken together, our data suggest that the Arp2/3 based nuclear squeezing mechanism would be a general feature of highly migratory cells which need to survive long enough to accomplish their functions
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Yu, Jiaole, and 于皎乐. "Intrinsic and extrinsic factors affecting the migratory mechanisms of human mesenchymal stem cells." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2012. http://hdl.handle.net/10722/197130.
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The potential applications of mesenchymal stem cells (MSCs) have been widely advocated, however, many barriers hinder their clinical utilization. Enhancement of the homing of human MSCs (hMSCs) to the target tissues remains a clinical challenge. To overcome this hurdle, the mechanisms responsible for migration and engraftment of hMSCs have to be defined. My study aimed to explore both the underlying mechanisms and means of enhancing the migration of hMSCs.
A graft versus host disease (GvHD) injury model and a novel orthotopic neuroblastoma model were established to delineate the distinct property of hMSCs homing towards either injured or cancerous tissues. This highly specific homing process was further revealed to be in a CXCR4-dependent manner.
Notably, a novel gene, exchange protein directly activated by cAMP (Epac), was demonstrated to be actively involved in the hMSCs homing process. hMSCs expressed functional Epac and its activation significantly enhanced the migration and adhesion of hMSCs. Furthermore, Epac activation directly contributed to the chemotactic response of hMSCs to SDF-1, suggesting that Epac is linked to the stromal cell derived factor-1 (SDF-1) signaling cascades. Importantly, the homing of hMSCs towards injured tissues in vivo could be dramatically increased by Epac activation.
hMSCs are adherent cells and their migration to distant tissues thus requires detachment into a suspension state. This disruption of cell-extracellular matrix interaction, known as anoikis stress, triggers programmed cell death, leading to a marked decrease in the efficiency of cell trafficking and engraftment. Anoikis stress induced massive cell death has emerged as the major challenge in the application of hMSCs. How some of the hMSCs can overcome this adversity and migrate towards distant destinations remains largely unexplored. It was observed that the surviving hMSCs circumvented anoikis stress by forming self-supporting cellular aggregates. Compared to adherent hMSCs, aggregated-hMSCs had better migratory response to both SDF-1α and SDF-1α analogue (CTCE-0214). Such enhanced migratory effect was proven to be CXCR4-dependent both in vitro and in vivo by using a CXCR4 specific antagonist (AMD3100). Although the viability of hMSCs under anoikis stress dramatically decreased, CTCE-0214 could promote cell survival and facilitate the migration of hMSCs towards injured targets. This phenomenon could be partially explained by the increase in anti-apoptosis effect via up-regulated Bcl-2 expression and autophagy activation under CTCE-0214 treatment.
The exact effects of hMSCs on tumor growth and progression have long been controversial. Significant fasten growth and promoted metastasis of neuroblastoma in vivo was observed in hMSCs co-transplanted mice in this study. Reciprocally, hMSCs could not only be recruited by primary tumor, but also be selectively attracted by metastatic loci. This recruitment was significantly reduced when hMSCs were pre-treated with AMD3100, suggesting that the SDF-1/CXCR4 axis was a prime mover in this process.
In summary, my study demonstrated that the migratory property of hMSCs could be enhanced by novel intrinsic and extrinsic factors using both in vitro and in vivo models. This study provides a new prospective on MSCs biology during the ex vivo manipulation process and I proposed means to overcome some of these hindrance so we can maximize the efficacy of clinical MSCs application in the future.<br>published_or_final_version<br>Paediatrics and Adolescent Medicine<br>Doctoral<br>Doctor of Philosophy
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Munevar, Steven. "Mechanics of Fibroblast Migration: a Dissertation." eScholarship@UMMS, 2003. https://escholarship.umassmed.edu/gsbs_diss/36.
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Cell migration involves complex mechanical interactions between cells or between cells and the underlying substrate. Using a newly developed technique, "traction force microscopy", I have been able to visualize the dynamic characteristics of mechanical forces exerted by migrating fibroblasts such as magnitude, direction, and shear. For NIH 3T3 fibroblasts, I found that the lamellipodium provides nearly all of the force necessary for cell migration. A high shear zone separates the lamellipodium from the remainder of the cell body, suggesting that they are mechanically distinct entities. The timing of the tractions at the leading edge, as well as the spatial distribution, bears no apparent relationship to concurrent local protrusive activities, yet changes in traction force patterns often precede changes in migration direction. In H-ras transformed cells I found isolated regions of weak, transient traction forces in pseudopods all along the cell that appeared to act against one another. The resulting shear pattern suggested that there were multiple disorganized mechanical domains. These results support a frontal towing model for cell migration where the dynamic traction forces at the leading edge served to actively pull the cell body forward. In H-ras transformed cells, the weak poorly coordinated traction forces coupled with weak cell substrate-adhesions were likely responsible for the abnormal motile behavior of these cells. To probe the mechanical interactions beneath various regions of migrating fibroblasts, a cell substrate inhibitor (GRGDTP peptide) was locally applied while imaging stress distribution on the substrate utilizing traction force microscopy. I found that both spontaneous and GRGDTP induced detachment of the trailing edge resulted in extensive cell shortening with no change in overall traction force magnitude or cell migration. Conversely, leading edge disruption resulted in a dramatic global loss of traction forces pnor to any significant cell shortening. These results suggested that fibroblasts transmit their contractile forces to the substrate through two distinct types of adhesions. Leading edge adhesions were unique in their ability to transmit active propulsive forces whereas trailing end adhesions created passive resistance during cell migration and readily redistributed their loads upon detachment. I have also investigated how fibroblasts regulate traction forces based on mechanical input. My results showed that stretching forces applied through the flexible substrate induced increases in both intracellular calcium concentration and traction forces in fibroblasts. Treatment with gadolinium, a well known stretch-activated ion channel inhibitor, was found to inhibit both traction forces and cell migration without inhibiting cellular spread morphology or protrusive activities. Gadolinium treatment also caused a pronounced decrease in vinculin and phosphotyrosine concentrations from focal adhesions. Local application of gadolinium to the trailing region had no detectable effect on overall traction forces or cell migration, whereas local application to the leading edge caused a global inhibition of traction forces and an inhibition of migration. These observations suggest that stretch activated entry of calcium ions in the frontal region serves to regulate the organization of focal adhesions and the output of mechanical forces. Together my experiments elucidate how fibroblasts exert mechanical forces to propel their movements, and how fibroblasts utilize mechanical input to regulate their movements.
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Juremalm, Mikael. "The Role of Chemokines in Mast Cell Migration." Doctoral thesis, Uppsala University, Department of Genetics and Pathology, 2003. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-3273.
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<p>Mast cells are very potent multifunctional effector cells of the immune system normally distributed throughout connective tissues. An accumulation of mast cells has been described in several pathological conditions such as allergic- and autoimmune inflammations and in certain tumours. This necessitates two different processes: 1) Recruitment of mast cell progenitors from peripheral blood; 2) Accretion of mature mast cells at sites of inflammation and tumour areas. Both processes are depending on the local production of chemotactic factors. The aim of this study was to investigate the role of chemokines and their corresponding receptors in mast cell chemotaxis. </p><p>By cloning and mRNA-screening of cord blood derived mast cells several chemokine receptors were found to be expressed. Functional expression was confirmed of chemokine receptors CXCR4, CCR1 and CCR4. CXCL12, the only known ligand for CXCR4, acted as a mast cell chemotaxin and induced migration of progenitor cells with capacity to differentiate into mast cells. Of several ligands known to bind CCR1 and CCR4, only CCL5 induced migration of mast cells. The migration to CCL5 was mediated through both CCR1 and CCR4. In contrast, the ligands to CCR4, CCL17 and CCL22, could inhibit CCL5-induced migration. Expression of CCR1 and CCR4 could also be confirmed on mast cells in lung from asthmatic patients. Furthermore, we could demonstrate that mast cells were attracted by CCL5 produced by tumour cells in Hodgkin´s lymphoma.</p><p>In conclusion, the work in this thesis has identified two chemokines that regulates mast cell migration. This knowledge helps us understand the mechanisms behind homing of mast cell progenitors from the blood into the tissue and the accumulation of mature mast cells at sites of inflammation and tumourigenesis.</p>
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Kiosses, William B. "Endothelial cell migration and cytoskeletal organization in situ." Thesis, National Library of Canada = Bibliothèque nationale du Canada, 1997. http://www.collectionscanada.ca/obj/s4/f2/dsk2/tape16/PQDD_0012/NQ28288.pdf.
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