Dissertations / Theses: 'Leader cells in cell migration'

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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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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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Dean, Zachary S. "Collective Migration Models: Dynamic Monitoring of Leader Cells in Migratory/Invasive Disease Processes." Diss., The University of Arizona, 2015. http://hdl.handle.net/10150/560817.

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Leader cells are a fundamental biological process that have only been investigated since the early 2000s. These cells have often been observed emerging at the edge of an artificial wound in 2D epithelial cell collective invasion, created with either a mechanical scrape from a pipette tip or from the removal of a plastic, physical blocker. During migration, the moving cells maintain cell-cell contacts, an important quality of collective migration; the leader cells originate from either the first or the second row, they increase in size compared to other cells, and they establish ruffled lamellipodia. Recent studies in 3D have also shown that cells emerging from an invading collective group that also exhibit leader-like properties. Exactly how leader cells influence and interact with follower cells as well as other cells types during collective migration, however, is another matter, and is a subject of intense investigation between many different labs and researchers. The majority of leader cell research to date has involved epithelial cells, but as collective migration is implicated in many different pathogenic diseases, such as cancer and wound healing, a better understanding of leader cells in many cell types and environments will allow significant improvement to therapies and treatments for a wide variety of disease processes. In fact, more recent studies on collective migration and invasion have broadened the field to include other cell types, including mesenchymal cancer cells and fibroblasts. However, the proper technology for picking out dynamic, single cells within a moving and changing cell population over time has severely limited previous investigation into leader cell formation and influence over other cells. In line with these previous studies, we not only bring new technology capable of dynamically monitoring leader cell formation, but we propose that leader cell behavior is more than just an epithelial process, and that it is a critical physiological process in multiple cell types and diseases.

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Sharma, Puja. "A Suspended Fiber Network Platform for the Investigation of Single and Collective Cell Behavior." Diss., Virginia Tech, 2016. http://hdl.handle.net/10919/82709.

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Cells interact with their immediate fibrous extracellular matrix (ECM); alignment of which has been shown influence metastasis. Specifically, intra-vital imaging studies on cell invasion from tumor-matrix interface and wounds along aligned fibers describe invasion to occur as singular leader (tip) cells, or as collective mass of a few chain or multiple tip cells. Recapitulation of these behaviors in vitro promises to provide new insights in how, when and where cells get the stimulus to break cell-cell junctions and ensue invasion by migrating along aligned tracks. Using Spinneret based Tunable Engineered Parameters (STEP) technique, we fabricated precise layout of suspended fibers of varying diameters (300, 500 and 1000 nm) mimicking ECM dimensions, which were interfaced with cell monolayers to study invasion. We demonstrated that nanofiber diameter and their spacing were key determinants in cells to invade either as singularly, chains of few cells or multiple-chains collectively. Through time-lapse microscopy, we reported that singular cells exhibited a peculiar invasive behavior of recoiling analogous to release of a stretched rubber band; detachment speed of which was influenced with fiber diameter (250, 425 and 400 µm/hr on small, medium and large diameter fibers respectively). We found that cells initiated invasion by putting protrusion on fibers; dynamics of which we captured using a contrasting network of mismatched diameters deposited orthogonally. We found that vimentin, a key intermediate filament upregulated in cancer invasion localized within a protrusion only when the protrusion had widened at the base, signifying maturation. To develop a comprehensive picture of invasion, we also developed strategies to quantify migratory speeds and the forces exerted by cells on fibers. Finally, we extended our findings of cell invasion to report a new wound healing assay to examine gap closure. We found that gaps spanned by crosshatch network of fibers closed faster than those on parallel fibers and importantly, we reported that gaps of 375 µm or larger did not close over a 45-day period. In summary, the methods and novel findings detailed from this study can be extended to ask multiple sophisticated hypotheses in physiologically relevant phenomenon like wound healing, morphogenesis, and cancer metastasis.
Ph. D.

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Falk, Anna. "Stem cells : proliferation, differentiation, migration /." Stockholm, 2005. http://diss.kib.ki.se/2006/91-7140-497-X/.

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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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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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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.

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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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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 in vivo or in vitro (body fluids collected from patients with asthma or rheumatoid arthritis and T_H1- and T_H2-cytokines) and to recombinant cytokines (transforming growth factor -β (TGF-β) and CCL5/RANTES).

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_H1-lymphocytes and IL-4 produced by T_H2-lymphocytes are MC chemoattractants.

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.

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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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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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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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Ferro, Valerie Anne. "The role of endothelial cells in promoting adhesion, spreading and migration of B16F10 cells." Thesis, University of St Andrews, 1989. http://hdl.handle.net/10023/14067.

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For the successful establishment of secondary tumours, blood-borne metastatic tumour cells must adhere and spread on the vascular endothelium before they can migrate through it to form secondary growths in the tissue beneath. In this study an in vitro assay was developed to study the behavourial interactions between B16F10 cells and Bovine aortic endothelial cells. It was hypothesized that molecules synthesized by the endothelial cells may be involved in the mediation of the adhesion, spreading and migration events and hence that such molecules may possibly be involved in the process of haematogenic metastasis. Endothelial derived extracts were obtained from the cell surface and from conditioned medium. The extracts were tested for their adhesion promoting abilities in a quick dot blot adhesion assay. To verify that these molecules promoted adhesion, antibodies were raised against the extracts. Partial characterisation of the molecules was achieved using SDS-PAGE and immunoprobing. The extracts were also tested for their spreading and migration promoting properties. An attempt was made to block the adhesion, spreading and migration events using antibodies directed against components of the extracts. Clearly, if endothelial-derived molecules are involved in metastasis, then preventing the mediation of adhesion, spreading and migration may ultimately have relevance in the clinical situation.

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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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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 c-kit gene; and in vitro developed mast cells.

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.

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-1⁵⁶⁰ and HMC-1^{560, 816}, are used in different laboratories around the world. HMC-1⁵⁶⁰ and HMC-1^{560, 816} 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.

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

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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
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

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Amunjela, Johanna Ndamwena. "The roles of POPDC proteins in the migration and proliferation of breast cancer cells." Thesis, University of Aberdeen, 2017. http://digitool.abdn.ac.uk:80/webclient/DeliveryManager?pid=235948.

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Despite advances breast cancer management, it remains a leading cause of death in women globally. Breast cancer is molecularly heterogeneous with some subtypes that are challenging to therapeutically target. This necessitates identification and validation of novel targets for breast cancer therapy. This study hypothesised that Popeye domain-containing (POPDC) proteins are dysregulated to promote breast malignancy. The study aimed to determine the potential of POPDC proteins as novel targets for inhibiting breast cancer cell migration and proliferation. Western blot and immunofluorescence assays demonstrated that POPDC1 and POPDC2 were significantly suppressed in malignant breast cells relative to non-malignant breast cells. In ductal carcinoma tissues, POPDC1 was significantly suppressed without correlation to clinical progression. In contrast, POPDC2 and POPDC3 were overexpressed in ductal carcinoma tissues and significantly correlated to HER2+ status and high tumour grade. Secondly, cell membrane expression of POPDC1 and POPDC2 were significantly reduced in malignant cells instead shifted to endosomal trafficking vesicles. Thirdly, suppression and gain of function studies showed that POPDC suppression significantly promoted cell migration and proliferation, while gain of POPDC function significantly inhibited cell migration and proliferation. The study also demonstrated that cAMP interacted with POPDC1, regulates POPDC1 expression levels and potentially controls POPDC1-mediated inhibition of cell migration and proliferation in breast cancer. Finally, this study showed for the first time that EGFR negatively regulates POPDC1 expression in breast cancer cells and the overexpression of POPDC1 can reduce EGFR-mediated cell migration and proliferation in breast cancer cells. In conclusion, POPDC protein expression, localisation and functions change in breast cancer. POPDC1 was also identified as a novel therapeutic target for inhibiting breast cancer cell migration and proliferation that could potentially be targeted to inhibit EGFR-driven breast malignancy. The study also demonstrated POPDC2 and POPDC3 are dysregulated in breast cancer, but in a less consistent and more complex manner.

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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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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.

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.

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.

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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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Ng, Colin Uber. "STEP-enabled Force Measurement Platform of Single Migratory Cells." Thesis, Virginia Tech, 2014. http://hdl.handle.net/10919/25329.

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Spinneret based Tunable Engineered Parameters (STEP) Platform is a recently reported pseudo-dry spinning and non-electrospinning technique that allows for the deposition of aligned polymeric nano-fibers with control on fiber diameters and orientation in single and multiple layers (diameter: sub 100nm micron, length: mm-cm), deposition (parallelism 2.5 degrees) and spacing (microns)). A wide range of polymers such as PLGA, PLA, PS, and PU have been utilized for their unique material properties in scaffold design. In this thesis two unique bioscaffolds are demonstrated for the measurement of group cell migration for wound closure and single cell contractility force for the study of force modulation. The wound healing assay bridges the gap between confluent reservoirs of NIH3T3 fibroblasts through arrangement of a suspended array of fibers guiding group cell migration along the fiber axis. This platform demonstrates that topographical and geometrical features of suspended fibers play a very important role in wound closure. Spacing, alignment and orientation were optimized to shown an increased rate of closure. In the second complementary assay, we report a fused-fiber network of suspended fibers capable of measuring single cell forces. Results from our experiments demonstrate that force behavior is dependent on mechanical properties such as stiffness and geometry of fiber networks. We also demonstrate changes in spatial and temporal organization of focal adhesion zyxin in response to single cell migration on these networks.
Master of Science

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SGUBIN, MICHELA. "HMGA1-p27-stathmin axis promotes migration in triple-negative breast cancer cells." Doctoral thesis, Università degli Studi di Trieste, 2020. http://hdl.handle.net/11368/2961109.

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My research project focused on Triple Negative Breast Cancer (TNBC), which is the most aggressive breast cancer subtype, characterized by the absence of ER, PR and HER2 receptors. Up to now, no targeted therapeutic opportunities for patients are available. One of the key players in the promotion of TNBC aggressiveness is the oncofetal protein HMGA1, an architectural chromatin factor involved in the regulation of gene transcription. In this work we aimed to identify the molecular pathways through which HMGA1 could promote invasiveness in TNBC. By bioinformatic analysis in a cohort of TCGA breast cancer samples, we found an inverse correlation between HMGA1 expression and p27 protein, a well-known CDK inhibitor that has CDK-independent cytoplasmic functions such as the modulation of cell migration. Moreover, in patients with high levels of HMGA1, we observed an enrichment in the expression of a molecular partner of p27, the microtubule-destabilizing protein stathmin. Then, we confirmed the functional relationship observed by TCGA analysis demonstrating that p27 was upregulated at the protein level following the silencing of HMGA1 in two TNBC cell lines (MDA-MB-231 and MDA-MB-157), while stathmin was down-modulated. Moreover, via qRT-PCR, we observed that p27 mRNA level was not modulated by HMGA1, implying a post-translational level of regulation. In fact, by cycloheximide assay, we showed that p27 protein was stabilized after HMGA1 silencing. Moreover, we found that p27 localized in the cytoplasm and, after HMGA1 depletion, was phosphorylated in the cytoplasmic-retaining sites S10 and T198. Looking at stathmin involvement in TNBC, we determined that it is implicated in the promotion of MDA-MB-231 microtubule dynamicity and migration. By silencing the expression of HMGA1 in the same cell line, we demonstrated that stathmin diminishes its interaction with tubulin and it is responsible of motility promotion downstream HMGA1. Thus, we co-silenced HMGA1, p27 and stathmin in MDA-MB-231 cells and we analysed the trans-well migratory abilities of cells showing that HMGA1 promotes the migration through the regulation of p27 and stathmin. One of the chemotherapeutic drugs in the first line treatment for TNBC is paclitaxel, an antineoplastic drug that acts interfering with microtubule function. In literature, both HMGA1 and stathmin have been shown to be involved in paclitaxel chemoresistance. Therefore, we tried to sensitize TNBC cells by targeting the HMGA1-p27-stathmin axis. Upon HMGA1-silencing of MDA-MB-231 cells, we were able to reduce the motility of cells treated with paclitaxel, sensitizing them to the treatment. Finally, we determined that the HMGA1 depletion in MDA-MB-231 cells injected in the mammary fat pad of nude mice, was able to sensitize the primary tumor volume to paclitaxel treatments. Overall, we identify an HMGA1/p27/stathmin axis involved in the promotion of migration that could be considered as a possible target in combination with standard paclitaxel chemotherapy in TNBC patients.

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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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23

Hoque, Apu E. (Ehsanul). "Migration and invasion pattern analysis of oral cancer cells in vitro." Doctoral thesis, Oulun yliopisto, 2018. http://urn.fi/urn:isbn:9789526220239.

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Abstract Desmoglein 3 (Dsg3) is an adhesion receptor in desmosomes, but relatively little is known about its role in cancer. In this study, the function of Dsg3 was investigated in oral squamous cell carcinoma (SCC) cell lines in vitro using locally established human leiomyoma tumor microenvironment (TME) matrices. Since Dsg3 has been identified as a key regulator in cell adhesion, we hypothesized that it may play a role in oral SCC cells adhesion and motility. Thus, one aim of the study was to explore this hypothesis by both gain and loss of function methods in four human buccal mucosa SCC SqCC/Y1 cell lines: transduction of vector control (Ct), full-length (FL) or two different C-terminally truncated Dsg3 mutants (Δ238 and Δ560). Live cell imaging was performed for 2D migration and 3D sandwich, alongside other assays. In 3D sandwich, we tested the effects of the monoclonal antibody, AK23, targeting the extracellular domain of Dsg3 in SqCC/Y1 cells. Our results showed that loss of Dsg3 disrupted cell adhesion and protein expression. In 2D assays, FL and Dsg3 mutants migrated faster with higher accumulated distances than Ct. In contrast with 2D, mutants showed accelerated invasion over the Ct in 3D models. The AK23 antibody inhibited only the invasion of FL cells. The TME in vivo consists of cellular and matrix elements playing a leading role in carcinoma progression. To study carcinoma cells invasion in vitro, mouse Matrigel® and rat type 1 collagen are the most commonly used matrices in 3D models. Since they are non-human in origin, they do not perfectly mimic human TME. To address this, we have developed a solid organotypic myoma disc model derived from human uterus leiomyoma tumor. Here, we introduce a novel Myogel, prepared from leiomyoma similar to Matrigel®. We validated Myogel for cell-TME interactions in 3D models, using SqCC/Y1 and HSC-3 cell lines. Compared with Matrigel® and type I collagen, oral SCC cell lines invaded more efficiently in Myogel containing matrices. This study describes promising 3D models using human TME mimicking Myogel which is suitable to analyze oral SCC cells both in carcinoma monocultures and in co-cultures, such as with TME fibroblasts. We also introduce a possible novel therapeutic target against Dsg3 to suppress cancer cell invasion
Tiivistelmä Desmogleiini 3 (Dsg3) on desmosomien adheesioreseptori, jonka merkityksestä syövässä tiedetään vähän. Koska Dsg3 on tärkeä epiteelisolujen välisissä liitoksissa, oletimme sillä olevan vaikutusta myös suun karsinoomasolujen tarttumisessa ja niiden liikkuvuudessa. Testasimme hypoteesiamme muuttamalla Dsg3:n toimintaa ihmisen posken karsinoomasolulinjassa SqCC/Y1, josta oli aiemmin valmistettu neljä erilaista muunnosta: tyhjän vektorin sisältävä kontrollisolulinja (Ct), kokopitkää Dsg3 tuottava solulinja (FL), sekä kaksi Dsg3 C-päästä lyhennettyä mutanttisolulinjaa (Δ238 ja Δ560). Immunofluoresenssi-menetelmää käyttäen analysoimme solulinjoissamme solujen välisiä liitoksia. Lisäksi mittasimme solujen liikkeitä 2D-migraatio- ja 3D-sandwich-kokeissa. Testasimme myös Dsg3:n solunulkoista osaa tunnistavan monoklonaalisen vasta-aineen (AK23) vaikutusta solujen invaasioon. Osoitimme, että Dsg3:n rakenteen muuttaminen ja toiminnan estyminen häiritsi solujen tarttumista. 2D-kokeissa sekä FL että mutanttilinjat (Δ238 ja Δ560) migroivat kontrollisoluja nopeammin ja pidemmälle, mutta 3D-kokeissa vain mutanttilinjat invasoituivat kontrollisoluja tehokkaammin. AK23-vasta-aine esti vain FL-solujen invaasiota. Syöpäsolujen 3D-invaasiota mittaavissa kokeissa käytetään yleensä hiiren kasvaimesta valmistettua kaupallista Matrigeeliä® tai rotan kudoksista eristettyä tyypin I kollageenia. Tutkimusryhmämme on jo aiemmin kehittänyt organotyyppisen myoomamallin, jossa valmistamme myoomakudosnapit ihmisen kohdun leiomyoomakasvaimista. Tässä työssä valmistimme leiomyoomasta Myogeelia, vertasimme sitä Matrigeeliin®, sekä tutkimme tarkemmin Myogeeli-valmisteen soveltuvuutta 3D-tutkimuksiin. Totesimme, että kielen (HSC-3) ja posken (SqCC/Y1) karsinoomasolut invasoituivat tehokkaimmin Myogeeli-pitoisissa matrikseissa kuin Matrigeeliä® tai kollageeniä sisältävissä kasvatusalustoissa. Tutkimustulostemme perusteella Myogeeli-pohjaiset 3D-mallit soveltuvat hyvin sekä syöpäsolulinjojen invaasiotutkimuksiin että yhteisviljelmiin, joissa syöpäsoluja viljellään yhdessä syöpäkasvaimen ympärillä olevien solujen, kuten fibroblastien, kanssa

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24

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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25

Esmaeili, Pourfarhangi Kamyar. "Movie8: FUCCI-MDA-MB-231 cells migration on 2D gelatin." Diss., Cancer Invasion; Cell Migration; Chemotaxis; Contact Guidance; Invadopodia; Mechanobiology, 2019. http://cdm16002.contentdm.oclc.org/cdm/ref/collection/p245801coll10/id/584750.

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Bioengineering;
Ph.D.;
Metastasis is the leading cause of death among cancer patients. The metastatic cascade, during which cancer cells from the primary tumor reach a distant organ and form multiple secondary tumors, consists of a series of events starting with cancer cells invasion through the surrounding tissue of the primary tumor. Invading cells may perform proteolytic degradation of the surrounding extracellular matrix (ECM) and directed migration in order to disseminate through the tissue. Both of the mentioned processes are profoundly affected by several parameters originating from the tumor microenvironment (extrinsic) and tumor cells themselves (intrinsic). However, due to the complexity of the invasion process and heterogeneity of the tumor tissue, the exact effect of many of these parameters are yet to be elucidated. ECM proteolysis is widely performed by cancer cells to facilitate the invasion process through the dense and highly cross-linked tumor tissue. It has been shown in vivo that the proteolytic activity of the cancer cells correlates with the cross-linking level of their surrounding ECM. Therefore, the first part of this thesis seeks to understand how ECM cross-linking regulates cancer cells proteolytic activity. This chapter first quantitatively characterizes the correlation between ECM cross-linking and the dynamics of cancer cells proteolytic activity and then identifies ß1-integrin subunit as a master regulator of this process. Once cancer cells degrade their immediate ECM, they directionally migrate through it. Bundles of aligned collagen fibers and gradients of soluble growth factors are two well-known cues of directed migration that are abundantly present in tumor tissues stimulating contact guidance and chemotaxis, respectively. While such cues direct the cells towards a specific direction, they are also known to stimulate cell cycle progression. Moreover, due to the complexity of the tumor tissue, cells may be exposed to both cues simultaneously, and this co-stimulation may happen in the same or different directions. Hence, in the next two chapters of this thesis, the effect of cell cycle progression and contact guidance-chemotaxis dual-cue environments on directional migration of invading cells are assessed. First, we show that cell cycle progression affects contact guidance and not random motility of the cells. Next, we show how exposure of cancer cells to contact guidance-chemotaxis dual-cue environments can improve distinctive aspects of cancer invasion depending on the spatial conformation of the two cues. In this dissertation, we strive to achieve the defined milestones by developing novel mathematical and experimental models of cancer invasion as well as utilizing fluorescent time-lapse microscopy and automated image and signal processing techniques. The results of this study improve our knowledge about the role of the studied extrinsic and intrinsic cues in cancer invasion.
Temple University--Theses

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26

Esmaeili, Pourfarhangi Kamyar. "Movie9: FUCCI-MDA-MB-231 cells migration inside the microchannels." Diss., Cancer Invasion; Cell Migration; Chemotaxis; Contact Guidance; Invadopodia; Mechanobiology, 2019. http://cdm16002.contentdm.oclc.org/cdm/ref/collection/p245801coll10/id/584759.

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Bioengineering;
Ph.D.;
Metastasis is the leading cause of death among cancer patients. The metastatic cascade, during which cancer cells from the primary tumor reach a distant organ and form multiple secondary tumors, consists of a series of events starting with cancer cells invasion through the surrounding tissue of the primary tumor. Invading cells may perform proteolytic degradation of the surrounding extracellular matrix (ECM) and directed migration in order to disseminate through the tissue. Both of the mentioned processes are profoundly affected by several parameters originating from the tumor microenvironment (extrinsic) and tumor cells themselves (intrinsic). However, due to the complexity of the invasion process and heterogeneity of the tumor tissue, the exact effect of many of these parameters are yet to be elucidated. ECM proteolysis is widely performed by cancer cells to facilitate the invasion process through the dense and highly cross-linked tumor tissue. It has been shown in vivo that the proteolytic activity of the cancer cells correlates with the cross-linking level of their surrounding ECM. Therefore, the first part of this thesis seeks to understand how ECM cross-linking regulates cancer cells proteolytic activity. This chapter first quantitatively characterizes the correlation between ECM cross-linking and the dynamics of cancer cells proteolytic activity and then identifies ß1-integrin subunit as a master regulator of this process. Once cancer cells degrade their immediate ECM, they directionally migrate through it. Bundles of aligned collagen fibers and gradients of soluble growth factors are two well-known cues of directed migration that are abundantly present in tumor tissues stimulating contact guidance and chemotaxis, respectively. While such cues direct the cells towards a specific direction, they are also known to stimulate cell cycle progression. Moreover, due to the complexity of the tumor tissue, cells may be exposed to both cues simultaneously, and this co-stimulation may happen in the same or different directions. Hence, in the next two chapters of this thesis, the effect of cell cycle progression and contact guidance-chemotaxis dual-cue environments on directional migration of invading cells are assessed. First, we show that cell cycle progression affects contact guidance and not random motility of the cells. Next, we show how exposure of cancer cells to contact guidance-chemotaxis dual-cue environments can improve distinctive aspects of cancer invasion depending on the spatial conformation of the two cues. In this dissertation, we strive to achieve the defined milestones by developing novel mathematical and experimental models of cancer invasion as well as utilizing fluorescent time-lapse microscopy and automated image and signal processing techniques. The results of this study improve our knowledge about the role of the studied extrinsic and intrinsic cues in cancer invasion.
Temple University--Theses

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27

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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Kang, Jane. "Migration of blood cells in non-uniform suspension for a dialyzer design." Diss., Georgia Institute of Technology, 2015. http://hdl.handle.net/1853/53871.

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Hemodialysis is a renal replacement therapy that removes waste solutes from the blood stream using concentration gradients across a membrane. In order to overcome several shortcomings and increase the waste removal rate, a new dialyzer (filter) design is proposed in this study. In the new dialyzer design, the blood concurrently flows with a sheath fluid in a micro-fluidic channel. Because the blood stream directly contacts the sheath stream, it is important to prevent blood cell migration from the blood stream to the sheath stream while providing enough time for the waste solutes to diffuse into the sheath stream. This research was intended to understand the migration behavior of red blood cells (RBC) and platelets in non-uniform suspension flow, where the blood and sheath flows in direct contact, and apply the results to identify the feasible design space of the proposed dialyzer. The effect of different flow conditions and channel geometry on the blood cell extraction ratios (ER), the ratio of cells lost into the sheath stream, in non-uniform suspension flows was parametrically studied using Lattice Boltzmann and Spectrin Link (LB-SL) method based direct numerical simulation (DNS). Analyzing ER over the flow distance showed that the channel size and the area ratio of sheath to channel are the main variables that affect the ER. Based on the relationship found, a meta-model of RBC ER was created, although platelet ERs showed only a general trend. Based on the study, feasible conditions that will retain blood cells in the blood stream were identified. Then, the DNS results of blood cell ER were used with a molecule diffusion model and a hemodialysis system model to study the feasibility of the proposed dialyzer design that maximizes middle molecule filtration with limited blood cell and protein loss. No feasible design was found in the studied range suggesting that relying purely on the diffusion based on the direct contact for the removal of middle molecules is not a feasible solution with the small channel size (~700 µm) due to the loss of protein. It suggested that in order to increase the middle molecule removal while maintain the protein level, clearance ratio of middle molecule to protein should be increased using large channel size, small sheath stream thickness, long tubule length, and slow blood flow velocity. The intellectual merit of this research lies in understanding the migration behavior of blood cells in a non-uniform suspension. This knowledge helped to establish the feasibility of the proposed dialyzer design and can be applied in a variety of applications for the manipulation of cells in a micro-fluidic channel.

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Vora, Parvez Firoz. "Molecular regulation of myelination by Oligodendrocyte Progenitor cells." Experimental Neurology (Elsevier), 2010. http://hdl.handle.net/1993/8463.

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Oligodendrocytes (OL) are the myelinating cells of the central nervous system (CNS). A series of complex cell signaling events in the CNS ensures successful myelination. Various molecular cues including growth factors, transcription factors and cytokines regulate myelination by inducing OL migration, proliferation and differentiation. Plateletderived growth factor A (PDGF-A) and fibroblast growth factor 2 (FGF2) are two of the most well characterized regulators of OP migration. The current study hypothesizes that PDGF-A and FGF2 regulate the migration of OP through transient activation of the extracellular signal-regulated protein kinase (ERK) signaling pathway. The results show that activation of ERK is required for OP migration. It also demonstrates the significance of threshold levels of growth factors and temporal regulation for OP migration. Furthermore, the chemokine CXCL1 has been shown to play a critical role in regulating the dispersal of OP during development, although the mechanisms underlying this regulation are unknown. Previous studies have shown that calcium flux is required for OP migration. CXCL1 induces calcium flux in cells; therefore we hypothesized that CXCL1 inhibition of OP migration was regulated via changes in intracellular calcium flux. However, our results show that CXCL1 inhibition of OP migration is independent of calcium signaling. In addition, we show that CXCL1 inhibition of OP migration is specific to PDGF-A induced migration. Lastly, the current study identifies a transcriptional regulator, methyl-CpG-binding protein 2 (MeCP2) as regulating the expression of myelin specific genes in a transgenic mouse. Interestingly, gene expression of myelin associated proteins myelin basic protein (MBP), myelin associated glycoprotein (MAG)and proteolipid protein (PLP), which play an important role in regulation of OL differentiation and subsequent formation of myelin of the myelin sheath, where found to be dysregulated. Overall, these findings reveal previously unknown roles of various intrinsic factors in successive phases of OL development. It aims to provide a better understanding of complexity to myelin development, function and disease.

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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.
published_or_final_version
Paediatrics and Adolescent Medicine
Doctoral
Doctor of Philosophy

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31

Chau, Dinh Le Mary. "Role of Notch1 in Cardiac Cell Differentiation and Migration: A Dissertation." eScholarship@UMMS, 2007. https://escholarship.umassmed.edu/gsbs_diss/338.

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The cardiac conduction system is responsible for maintaining and orchestrating the rhythmic contractions of the heart. Results from lineage tracing studies indicate that precursor cells in the ventricles give rise to both cardiac muscle and conduction cells. Using chick embryonic hearts, we have found that Notch signaling plays an important role in the differentiation of cardiac muscle and conduction cell lineages in the ventricles. Notch1 expression coincides with a conduction marker at early stages of conduction system development. Mis-expression of constitutively active Notch1 (NIC) in early heart tubes exhibited multiple effects on cardiac cell differentiation. Cells expressing NIC had a significant decrease in the expression of cardiac muscle markers, but an increase in the expression of conduction cell markers. Loss-of-function studies further support that Notch1 signaling is important for the differentiation of these cardiac cell types. Functional electrophysiology studies show that the expression of constitutively active Notch1 resulted in abnormalities in ventricular conduction pathway patterns. During cardiogenesis, groups of myocardial cells become separated from each other, and migrate to form the trabeculae. These finger-like projections found within the ventricular chamber coalesce to generate the muscular portions of the interventricular septum, the thickened myocardium, and future sites of the conduction system. We have found that Notch signaling regulates the migration of cardiac cells during cardiogenesis. Over-expression of constitutively active Notch causes cells to localize more centrally within the heart, while loss-of-Notch function results in cells distributed within the periphery of the heart. Staining of heart sections shows that Notch signaling regulates the expression of N-cadherin, the predominant adhesion molecule in cardiomyocytes. We find that the effects of Notch on cell migration are two-fold: delamination and cell motility. Time-lapse studies demonstrate that Notch signaling increases cell motility, but does not affect speed or directionality of migration. Furthermore, we find that the effects of Notch on cell migration is independent of its effects on differentiation.

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32

Levine, Benjamin David Dobens Leonard L. "Interactions between bunched, slow border cells, cut and notch signaling regulate follicle cell migrations during drosophila oogenesis." Diss., UMK access, 2007.

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Thesis (Ph. D.)--School of Biological Sciences. University of Missouri--Kansas City, 2007.
"A dissertation in molecular biology and biochemistry and cell biology and biophysics." Advisor: Leonard D. Dobens. Typescript. Vita. Title from "catalog record" of the print edition Description based on contents viewed May 23, 2008. Includes bibliographical references (leaves 109-115). Online version of the print edition.

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Ammann, Kaitlyn R., Katrina J. DeCook, Phat L. Tran, Valerie M. Merkle, Pak K. Wong, and Marvin J. Slepian. "Collective cell migration of smooth muscle and endothelial cells: impact of injury versus non-injury stimuli." BioMed Central, 2015. http://hdl.handle.net/10150/610313.

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BACKGROUND: Cell migration is a vital process for growth and repair. In vitro migration assays, utilized to study cell migration, often rely on physical scraping of a cell monolayer to induce cell migration. The physical act of scrape injury results in numerous factors stimulating cell migration - some injury-related, some solely due to gap creation and loss of contact inhibition. Eliminating the effects of cell injury would be useful to examine the relative contribution of injury versus other mechanisms to cell migration. Cell exclusion assays can tease out the effects of injury and have become a new avenue for migration studies. Here, we developed two simple non-injury techniques for cell exclusion: 1) a Pyrex® cylinder - for outward migration of cells and 2) a polydimethylsiloxane (PDMS) insert - for inward migration of cells. Utilizing these assays smooth muscle cells (SMCs) and human umbilical vein endothelial cells (HUVECs) migratory behavior was studied on both polystyrene and gelatin-coated surfaces. RESULTS: Differences in migratory behavior could be detected for both smooth muscle cells (SMCs) and endothelial cells (ECs) when utilizing injury versus non-injury assays. SMCs migrated faster than HUVECs when stimulated by injury in the scrape wound assay, with rates of 1.26 % per hour and 1.59 % per hour on polystyrene and gelatin surfaces, respectively. The fastest overall migration took place with HUVECs on a gelatin-coated surface, with the in-growth assay, at a rate of 2.05 % per hour. The slowest migration occurred with the same conditions but on a polystyrene surface at a rate of 0.33 % per hour. CONCLUSION: For SMCs, injury is a dominating factor in migration when compared to the two cell exclusion assays, regardless of the surface tested: polystyrene or gelatin. In contrast, the migrating surface, namely gelatin, was a dominating factor for HUVEC migration, providing an increase in cell migration over the polystyrene surface. Overall, the cell exclusion assays - the in-growth and out-growth assays, provide a means to determine pure migratory behavior of cells in comparison to migration confounded by cell wounding and injury.

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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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35

Nino, Jorge Luis Galeano. "Cytoskeletal dynamics of Cytotoxic T cells during migration in the tumour microenvironment." Thesis, The University of Sydney, 2015. http://hdl.handle.net/2123/13608.

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Typically, migrating T cells display an elongated polarized shape with a very dynamic leading edge and a uropod in the rear. This ‘amoeboid’ movement guarantees a fast migration driven by the formation of polarized protrusions at the front. The actomyosin cytoskeleton is responsible for the generation of the forces that are involved in this process. This thesis aims to determine what is the effect of T cell migration when different components of the actomyosin cortex were inhibited using a pharmacological approach. We found that the inhibition of each component of the actomyosin cortex, T cells display different conformation of the actin filaments and produce different type of protrusion. Furthermore, T cell migration is an important feature for the killing and clearance of canner cells. It has been reported that T cells can migrate efficiently in any kind of tissue whilst scanning for cognate antigen. On the other hand, it is known that the tumor microenvironment secretes immunosuppressive cytokines such as TGF-β impairing the antitumor activity of T cells. Therefore, we aim to determine how TGF-β affects the migration behavior of T cells and its consequences in the scanning strategy to search their cognate antigen.

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36

Esmaeili, Pourfarhangi Kamyar. "Movie13: HS-578T cells migration in the orthogonal dual-cue condition." Diss., Temple University Libraries, 2019. http://cdm16002.contentdm.oclc.org/cdm/ref/collection/p245801coll10/id/584755.

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Bioengineering;
Ph.D.;
Metastasis is the leading cause of death among cancer patients. The metastatic cascade, during which cancer cells from the primary tumor reach a distant organ and form multiple secondary tumors, consists of a series of events starting with cancer cells invasion through the surrounding tissue of the primary tumor. Invading cells may perform proteolytic degradation of the surrounding extracellular matrix (ECM) and directed migration in order to disseminate through the tissue. Both of the mentioned processes are profoundly affected by several parameters originating from the tumor microenvironment (extrinsic) and tumor cells themselves (intrinsic). However, due to the complexity of the invasion process and heterogeneity of the tumor tissue, the exact effect of many of these parameters are yet to be elucidated. ECM proteolysis is widely performed by cancer cells to facilitate the invasion process through the dense and highly cross-linked tumor tissue. It has been shown in vivo that the proteolytic activity of the cancer cells correlates with the cross-linking level of their surrounding ECM. Therefore, the first part of this thesis seeks to understand how ECM cross-linking regulates cancer cells proteolytic activity. This chapter first quantitatively characterizes the correlation between ECM cross-linking and the dynamics of cancer cells proteolytic activity and then identifies ß1-integrin subunit as a master regulator of this process. Once cancer cells degrade their immediate ECM, they directionally migrate through it. Bundles of aligned collagen fibers and gradients of soluble growth factors are two well-known cues of directed migration that are abundantly present in tumor tissues stimulating contact guidance and chemotaxis, respectively. While such cues direct the cells towards a specific direction, they are also known to stimulate cell cycle progression. Moreover, due to the complexity of the tumor tissue, cells may be exposed to both cues simultaneously, and this co-stimulation may happen in the same or different directions. Hence, in the next two chapters of this thesis, the effect of cell cycle progression and contact guidance-chemotaxis dual-cue environments on directional migration of invading cells are assessed. First, we show that cell cycle progression affects contact guidance and not random motility of the cells. Next, we show how exposure of cancer cells to contact guidance-chemotaxis dual-cue environments can improve distinctive aspects of cancer invasion depending on the spatial conformation of the two cues. In this dissertation, we strive to achieve the defined milestones by developing novel mathematical and experimental models of cancer invasion as well as utilizing fluorescent time-lapse microscopy and automated image and signal processing techniques. The results of this study improve our knowledge about the role of the studied extrinsic and intrinsic cues in cancer invasion.
Temple University--Theses

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37

Alert, Zenón Ricard. "Forces and flows in cells and tissues. Blebs, active gels, and collective cell migration." Doctoral thesis, Universitat de Barcelona, 2018. http://hdl.handle.net/10803/461383.

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In this thesis, we have studied mechanical aspects of some biological processes in cells and tissues, which we addressed by developing theoretical models based on the physics of soft active matter. The thesis contains three parts that focus on different biological systems. In Part I, we study the adhesion between the plasma membrane and the actin cortex of eukaryotic cells. We propose a continuum model for membrane-cortex adhesion that couples the mechanics and hydrodynamics of the membrane to the force-dependent binding kinetics of the linker proteins. We predict the critical pressure difference that causes membrane-cortex detachment, and we discuss how cortical tension can be inferred from micropipette suction experiments. Then, we study the fluctuations of an adhered membrane, and suggest ways in which our predictions could allow probing membrane-cortex adhesion in fluctuation spectroscopy experiments. Then, we employ the proposed model to study the nucleation of blebs, which are balloon-like membrane protrusions arising from a local membrane-cortex detachment. We show that bleb nucleation is governed by membrane peeling, the fracture propagation process whereby adjacent membrane-cortex bonds break sequentially. Through this mechanism, bleb nucleation is not determined by the energy of a local detachment like in the classical nucleation picture, but rather by the kinetics of membrane-cortex linkers. We predict the critical radius for bleb nucleation through membrane peeling and the corresponding effective energy barrier. Finally, we simulate a fluctuating adhered membrane to obtain the probability distribution of bleb nucleation times. In Part II, we study the dynamics of active polar gels, which are soft materials, usually transiently-crosslinked polymeric networks, that are maintained out of equilibrium by internal processes that continuously transduce energy. We derive the constitutive equations of an active polar gel from a mesoscopic model for the dynamics of the molecules that crosslink the polar elements of the system. This way, we establish a connection between the molecular properties and the macroscopic behaviour of active polar gels. Specifically, we explicitly obtain the transport coefficients in terms of molecular parameters, showing that all transport coefficients have an active contribution that stems from breaking detailed balance for the crosslinker binding kinetics. In Part III, we study cell colonies and tissues, focusing in collective cell migration and tissue morphology. First, we propose a particle-based description of cell colonies to study how the different organizations of cells in tissues emerge from intercellular interactions. The model intends to capture generic cellular behaviours such as cell migration, adhesion, and cell-cell overlapping. In addition, it models the so-called contact inhibition of locomotion (CIL), which repolarizes cell migration away from cell-cell contacts, as a torque on the migration direction. We show how CIL yields an effective repulsion between cells, which allows to predict transitions between non-cohesive, cohesive, and 3D tissues. We conclude that, at low cell-cell adhesion, CIL hinders the formation of cohesive tissues. Yet, in continuous cell monolayers, CIL gives rise to self-organized collective motion, ensures tensile stresses in the monolayer, and opposes cell extrusion, thereby hindering the collapse of the monolayer into a 3D aggregate. Then, we focus on the spreading of epithelial monolayers, which we address by means of a continuum model based on the theory of active polar gels. First, we concentrate on the wetting transition of epithelial tissues, which separates monolayer spreading from retraction towards a 3D aggregate — namely the equivalent of a fluid droplet. We show that a critical radius exists for the wetting transition, which does not exist in the classical wetting picture. Thus, we show how the wetting properties of tissues emerge from active cellular forces, evidencing that the wetting transition has an active nature. Finally, we study the morphological stability of the front of a spreading monolayer. The model predicts that traction forces cause a long-wavelength instability of the monolayer front, whereas tissue contractility has a stabilizing effect. The predicted instability can explain the formation of finger-like multicellular protrusions observed during epithelial spreading. It can also explain the symmetry breaking of tissue shape observed during monolayer dewetting. By fitting the predictions to experimental data, we infer the monolayer viscosity and the noise intensity of tissue shape fluctuations, which we suggest to have an active origin.
En aquesta tesi hem estudiat aspectes mecànics d'alguns processos biològics en cèl·lules i teixits, que hem abordat desenvolupant models teòrics basats en la física de la matèria tova activa. La tesi té tres parts centrades en sistemes biològics diferents. En la primera part s'estudia l'adhesió entre la membrana plasmàtica i el còrtex d'actina de les cèl·lules eucariotes. Proposem un model continu per l'adhesió membrana-còrtex que acobla la mecànica i la hidrodinàmica de la membrana amb la cinètica de les proteïnes que ancoren la membrana al còrtex. Prediem la pressió crítica pel desenganxament i estudiem les fluctuacions de la membrana adherida. Després, ens centrem en la nucleació de butllofes cel·lulars, que són protrusions degudes a desenganxaments locals de la membrana. Mostrem que la nucleació de butllofes cel·lulars està governada pel procés de pelat de la membrana, pel qual proteïnes connectores adjacents es desenganxen seqüencialment. Per aquest mecanisme, la nucleació de butllofes no està determinada per l'energia com en l'escenari clàssic sinó per la cinètica dels connectors. A la segona part es deriven les equacions constitutives d'un gel polar actiu a partir d'un model mesoscòpic per la dinàmica de les molècules entrellaçadores. Així, prediem explícitament els coeficients de transport dels gels polars actius en termes de paràmetres moleculars. Tots els coeficients de transport tenen una contribució activa, provinent del trencament de balanç detallat per la cinètica dels entrellaçadors. A la tercera part estudiem colònies cel·lulars i teixits. Primer, proposem un model de partícules per estudiar com les diferents organitzacions dels teixits emergeixen de les interaccions intercel·lulars. El model captura comportaments cel·lulars genèrics i, en particular, la inhibició de la motilitat per contacte. Es mostra com aquesta interacció dóna una repulsió efectiva entre cèl·lules. Després, s'estudia l'escampament de monocapes epitelials en base a un model continu basat en la teoria dels gels polars actius. Primer es mostra que, a diferència del que passa en l'escenari clàssic, la transició de mullat d'un teixit té un radi crític determinat per les forces cel·lulars actives. Finalment, es prediu que, a causa de les forces de tracció, el front d'una monocapa en expansió, fet que explica observacions experimentals.

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38

Ghosh, Somadri. "A signalling function of phosphatidylinositol 3,4-bisphosphate in cell migration of breast cancer cells." Doctoral thesis, Universite Libre de Bruxelles, 2018. http://hdl.handle.net/2013/ULB-DIPOT:oai:dipot.ulb.ac.be:2013/268960.

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SHIP2 is a phosphatase that belongs to the family of the phosphoinositide 5-phosphatases. It is known to dephosphorylate PI(3,4,5)P3 to PI(3,4)P2 imparting a tight control of the PI 3-kinase pathway. Over the last decade, SHIP2 has been described as a tumor promotor or tumor suppressor in several cancer types such as glioblastoma, colorectal cancer or breast cancer cells. Several studies have proposed a role of SHIP2 in breast cancer cells, but its tumor promoting function was unclear at the beginning of this thesis especially in terms of its mode of regulation. In 2013, the INPPL1 gene that encodes SHIP2 has been found to be mutated in opsismodysplasia (OPS), a rare autosomal recessive disease characterized by delayed bone maturation but no molecular mechanism was provided to explain the mechanism. In this thesis, we first contributed to establish a negative regulation of SHIP2 on cell migration in 1321 N1 glioblastoma (GBM) cells. Our studies revealed a dephosphorylation activity of SHIP2 on PI(4,5)P2 at the plasma membrane to control cell migration. This study was done in collaboration with Dr. Elong Edimo in the lab. We have also shown that the regulation of cell motility cannot be generalized to all the GBM cells. In LN229 and U-251 GBM cells we observed a positive regulation of cell migration by SHIP2. We next took advantage of a unique model comparing fibroblasts derived from non-affected and OPS patients (in collaboration with Dr. Valérie Cormier-Daire). We have shown that the fibroblasts from the OPS patients are SHIP2 deficient and migrate slower as compared to fibroblasts from non-affected individuals. Finally, the major part of the thesis was the study of breast cancer cells: in the model MDA-MB-231 cells, we established a positive regulation of SHIP2 on cell migration. We extended this regulation on cell migration to different breast cancer cell models using a SHIP2 inhibitor AS1949490. We confirmed that this inhibitor blocks the phosphatase activity of SHIP2 and showed its selectivity towards SHIP2 in cell migration assay. In MDA-MB-231 cells we deciphered a second messenger role of PI(3,4)P2 to control cell migration. Our data in this model rely on the use of SHIP2 depleted cells obtained by lentiviral infection and shRNA. We confirmed the positive role of SHIP2 on cell migration in the model of rat chondrosarcoma SHIP2CRISPR cells (in collaboration with Dr. Pavel Krejci).A major goal of this thesis was achieved thanks to in-vivo studies: using MDA-MB-231 cells injected in SCID mice, we found a tumor promoting role of SHIP2 by determining the tumor weight. We also observed less lung metastasis of SHIP2 depleted injected cells as compared to control cells suggesting SHIP2 to be important for invasiveness of triple negative breast cancers.
Doctorat en Sciences biomédicales et pharmaceutiques (Médecine)
info:eu-repo/semantics/nonPublished

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39

Prat, Alexandre. "Human brain endothelial cells under inflammatory challenge : relevance to MS and T cell migration." Thesis, McGill University, 2001. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=37815.

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Multiple sclerosis (MS) is considered an immune-mediated disorder of the central nervous system (CNS) characterized by multifocal areas of inflammation and demyelination. Lesion formation depends on migration of lymphocytes from the systemic compartment into the CNS through the blood-brain barrier. We have defined molecular and functional properties of human brain derived microvascular endothelial cells and of T lymphocytes that regulate the migration process and analysed how changes in these properties, in response to inflammatory conditions, contribute to the pathogenesis of multiple sclerosis. Rates of migration of T lymphocytes derived from patients with MS across either a fibronectin and/or endothelial cell barrier in vitro were increased compared to cells obtained from healthy controls. In the MS patients, migration rate correlated with disease activity, defined by clinical and MRI criteria and with IFN gamma production by T cells. Migration was reduced in patients receiving current therapies for MS. Adhesion molecules, chemokines and matrix metalloproteinases were all found to regulate the migration of MS derived lymphocytes through proteins of the basement membrane and human brain endothelial cells. We further demonstrated that the migratory properties of lymphocytes and both permeability and chemokine production by human brain endothelial cells, can be regulated via signalling through the specific kinin B1 receptor that is up-regulated on lymphocytes and human brain endothelial cells during inflammation, providing a potential novel therapeutic approach to modulate lymphocyte-endothelial cell interactions.

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40

Carlini, V. "CELL CYCLE AND MIGRATION CONTROL IN PROSTATE AND COLON CANCER CELLS BY CLIC1 PROTEIN." Doctoral thesis, Università degli Studi di Milano, 2017. http://hdl.handle.net/2434/522972.

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The intracellular chloride channel 1 (CLIC1) is a metamorphic protein, belonging to a recently discovered and still largely unexplored ion channel family. It displays the unique characteristic of being expressed both in a cytoplasmic and in a transmembrane form, the latter able to form a chloride selective ion channel. One of the main factors known to regulate this membrane insertion is the increase of oxidative level of the cells. If on one hand, the transient CLIC1 functional expression in the membrane could mediate several physiological cell responses, on the other hand, its chronic membrane translocation can lead to severe pathological conditions, including cancer. In particular two tumors, prostate cancer (PCa) and colon cancer (CRC), are characterized by elevated oxidative level and growing scientific evidence have suggested the involvement of CLIC1 in the tumorigenesis of these diseases. PCa and CRC are two of the most diffuse cancers and a leading cause of tumor fatality worldwide. Detecting the disease in a very early stage and finding a treatment able to prevent metastasis are critical clinical challenges to achieve a successful treatment for these malignancies. This thesis was focused in the direction of understanding the possible role of CLIC1 in the development and progression of PCa and CRC. Results obtained have shown that CLIC1 functional expression in plasma membrane occurs selectively in malignant cells, compared to benign or normal cells. Moreover, it has been demonstrated that CLIC1 membrane chloride current promotes proliferation, cell cycle progression from G1 to S phase and migration of cancer cells. All these findings suggest that CLIC1 may actively contribute to development of PCa and CRC and their progression towards a more aggressive form. It can be reasonably hypothesize that elevated oxidative levels present in cancer cells compared to normal cells cause the chronic overexpression of CLIC1 in the plasma membrane only of malignant cells. Therefore, targeting this protein could make it possible to hit selectively the tumor cells without damaging their normal counterpart. In this scenario, CLIC1 appears not only as a promising pharmacological target but also as a suitable biomarker. The only effective inhibitor of CLIC1 activity to date identified is highly toxic in vivo. For this reason, finding other compounds able to specifically block the channel but causing negligible side effects is necessary. In light with this purpose, our laboratory has recently proposed the anti-diabetic drug metformin as CLIC1 channel blocker. Results obtained have demonstrated that metformin displays a significant antitumoral activity on PCa and CRC cells, inhibiting both cell proliferation and migration. This anti-neoplastic effect is dependent on the inhibition of CLIC1 channel together with other intracellular targets. Overall these findings provide new support on the antineoplastic role of metformin and encourage the research of more specific and more effective compounds for CLIC1 channel, in order to minimize side effects.

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41

Chubb, Jonathan Robert. "An analysis of the role of the RasS protein in dictyostelium cell movement and endocytosis." Thesis, University College London (University of London), 2000. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.311944.

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42

Morrone, Luigi. "The Influence of 3D Cell Organization in Tumor Spheroid on Natural Killer Cell Infiltration and Migration." Thesis, KTH, Skolan för kemi, bioteknologi och hälsa (CBH), 2020. http://urn.kb.se/resolve?urn=urn:nbn:se:kth:diva-286605.

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Natural Killer cells are a type of lymphocyte belonging to the innate immune system and they operate cell-mediated cytotoxicity and release of pro-inflammatory cytokines against cancerous cells. However, in vivo testings have shown a reduced activity of NK cells against solid tumors probably due to the negative influence of the immunosuppressive tumor microenvironment. Multicellular tumor spheroids may constitute an advantageous model in cancer biology for studying the mechanisms behind cancer immune editing since it more closely mimics the complexity of the human body compared with the 2D model counterpart. This study investigated the interaction between NK cells isolated from blood and tumor spheroids obtained from A498 renal carcinoma cells, using light-sheet microscopy imaging which allows satisfactory cell tracking in the inner layers of the spheroids. NK cells not only indeed interact with tumor spheroids, but many of them were able to penetrate the spheroids inducing some changes in the structure of the latter. NK cells were also tracked over time, displaying the migration path and calculating the speed. The fluorescence intensity of the NK cells was found reduced as soon as they penetrate the spheroid but, conversely, the speed seems to increase inside the spheroid, a possible sign of the fallibility of the tracking algorithm in this specific case. We propose solutions for more sophisticated future implementations, involving the use of marks during the experimental phase and drift corrections at the data analysis level.

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43

Tello, Velasquez Johana Paola. "Identification of Natural Compounds that Regulate Glial Cell Proliferation and Migration for Spinal Cord Injury Transplantation Purposes." Thesis, Griffith University, 2016. http://hdl.handle.net/10072/366849.

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Transplantation of glial cells, particularly olfactory ensheathing cells (OECs) and Schwann cells (SCs) is one of the most promising strategies for the treatment of spinal cord injury and for other neural repair therapies. Effective proliferation and migration of glial cells are essential to optimize clinical applications; therefore identification of molecules that can promote and regulate these biological features is of great interest. The use of neurotrophic factors has long been considered as a potential approach, but, because of their high molecular weight; most are unstable. An important number of natural products have been reported in the literature to be able to mimic the effect of these neurogenic factors, mostly Curcuminoides (derived from the root turmeric) and Linckosides (isolated from the starfish Linckia laevigata). These products have been demonstrated to be neuroprotective and neurogenic on nerve cells, however it is not comprehensively known if these neurogenic natural compounds can influence the biological activity of glial cells. This thesis presents the evaluation of the effects of four known natural neurogenic compounds on the behaviour of OECs and SCs using proliferation assays and time-lapse microscopy analysis methods.
Thesis (PhD Doctorate)
Doctor of Philosophy (PhD)
School of Natural Sciences
Science, Environment, Engineering and Technology
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44

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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45

PHADNGAM, SURATCHANEE. "In Cell Imaging Techniques to Monitor Glucose Uptake, Cell Migration, and Vesicular Traffic: A Functional Study in Cancer Cells." Doctoral thesis, Università del Piemonte Orientale, 2016. http://hdl.handle.net/11579/115172.

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46

Rich, Kirsty. "Matrix metalloproteinases in asthma : the role of mast cells and basophils." Thesis, University of Southampton, 1999. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.285664.

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47

Abedi, Syeda Husna Bano. "Mechanisms of migration of vascular smooth muscle and endothelial cells : role of the focal adhesion kinase pathway." Thesis, King's College London (University of London), 1998. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.286793.

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48

Findlay, Amy Siobhan. "The molecular basis of epthelial cell migration : maintenance and repair of the ocular surface." Thesis, University of Aberdeen, 2015. http://digitool.abdn.ac.uk:80/webclient/DeliveryManager?pid=228963.

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In vertebrates the cornea must maintain its transparency throughout adult life to ensure sight, and understanding the mechanisms underpinning corneal homeostasis are fundamental to developing new treatments to cure or prevent blindness. This study investigated the role the planar cell polarity pathway plays in the directed migration of adult corneal epithelial cells, in maintaining the homeostatic environment of the eye and during wound healing. RT-PCR confirmed, for the first time, the expression of multiple core PCP genes within human corneal epithelial (HCE) cells. Components of the PCP pathway were pharmacologically and genetically manipulated during wound healing of corneal epithelial cells and the importance of the downstream target JNK, and core PCP gene Vangl2, during wound healing was demonstrated. Manipulation of core PCP components was found also to directly affect the ability of HCE cells to realign and migrate in response to physical topographical cues in vitro. This study therefore indicated that PCP may regulate the directed migration of corneal epithelial cells as they travel over the basement membrane. Using conditional knockout mice the loss of Vangl2, a core PCP gene, and its effect on both planar and the apical-basal polarity of the corneal epithelium was investigated. Severe morphological defects were observed in Vangl2-null mice indicative of underlying problems in apical-basal polarity of the epithelial cells. The basement membrane of Vangl2-null cells was largely absent in vivo, which suggested that at least some of the planar defects were secondary to an unexpected failure of apical-basal polarity. This study has shown for the first time that PCP plays a crucial role in the maintenance of an adult vertebrate tissue, particularly during wound healing and maintenance of the corneal epithelium. It has also indicated a role for the core PCP gene, Vangl2, in setting up apical-basal polarity of these adult cells.

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49

Esmaeili, Pourfarhangi Kamyar. "Movie14: A HS-578T cells migration in the orthogonal dual-cue condition." Diss., Cancer Invasion; Cell Migration; Chemotaxis; Contact Guidance; Invadopodia; Mechanobiology, 2019. http://cdm16002.contentdm.oclc.org/cdm/ref/collection/p245801coll10/id/584752.

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Bioengineering;
Ph.D.;
Metastasis is the leading cause of death among cancer patients. The metastatic cascade, during which cancer cells from the primary tumor reach a distant organ and form multiple secondary tumors, consists of a series of events starting with cancer cells invasion through the surrounding tissue of the primary tumor. Invading cells may perform proteolytic degradation of the surrounding extracellular matrix (ECM) and directed migration in order to disseminate through the tissue. Both of the mentioned processes are profoundly affected by several parameters originating from the tumor microenvironment (extrinsic) and tumor cells themselves (intrinsic). However, due to the complexity of the invasion process and heterogeneity of the tumor tissue, the exact effect of many of these parameters are yet to be elucidated. ECM proteolysis is widely performed by cancer cells to facilitate the invasion process through the dense and highly cross-linked tumor tissue. It has been shown in vivo that the proteolytic activity of the cancer cells correlates with the cross-linking level of their surrounding ECM. Therefore, the first part of this thesis seeks to understand how ECM cross-linking regulates cancer cells proteolytic activity. This chapter first quantitatively characterizes the correlation between ECM cross-linking and the dynamics of cancer cells proteolytic activity and then identifies ß1-integrin subunit as a master regulator of this process. Once cancer cells degrade their immediate ECM, they directionally migrate through it. Bundles of aligned collagen fibers and gradients of soluble growth factors are two well-known cues of directed migration that are abundantly present in tumor tissues stimulating contact guidance and chemotaxis, respectively. While such cues direct the cells towards a specific direction, they are also known to stimulate cell cycle progression. Moreover, due to the complexity of the tumor tissue, cells may be exposed to both cues simultaneously, and this co-stimulation may happen in the same or different directions. Hence, in the next two chapters of this thesis, the effect of cell cycle progression and contact guidance-chemotaxis dual-cue environments on directional migration of invading cells are assessed. First, we show that cell cycle progression affects contact guidance and not random motility of the cells. Next, we show how exposure of cancer cells to contact guidance-chemotaxis dual-cue environments can improve distinctive aspects of cancer invasion depending on the spatial conformation of the two cues. In this dissertation, we strive to achieve the defined milestones by developing novel mathematical and experimental models of cancer invasion as well as utilizing fluorescent time-lapse microscopy and automated image and signal processing techniques. The results of this study improve our knowledge about the role of the studied extrinsic and intrinsic cues in cancer invasion.
Temple University--Theses

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50

Tanizaki, Hideaki. "Rho-mDia1 pathway is required for adhesion, migration, and T cell stimulation in dendritic cells." Kyoto University, 2011. http://hdl.handle.net/2433/142071.

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Dissertations / Theses on the topic 'Leader cells in cell migration'

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