Rozprawy doktorskie: „Cell mechanobiology”

1

Youngstrom, Daniel W. "Mesenchymal Stem Cell Mechanobiology and Tendon Regeneration". Diss., Virginia Tech, 2015. http://hdl.handle.net/10919/64422.

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Tendon function is essential for quality of life, yet the pathogenesis and healing of tendinopathy remains poorly understood compared to other musculoskeletal disorders. The aim of regenerative medicine is to replace traditional tissue and organ transplantation by harnessing the developmental potential of stem cells to restore structure and function to damaged tissues. The recently discovered interdependency of cell phenotype and biophysical environment has created a paradigm shift in cell biology. This dissertation introduces a dynamic in vitro model for tendon function, dysfunction and development, engineered to characterize the mechanobiological relationships dictating stem cell fate decisions so that they may be therapeutically exploited for tendon healing. Cells respond to mechanical deformation via a complex set of behaviors involving force-sensitive membrane receptor activity, changes in cytoskeletal contractility and transcriptional regulation. Effective ex vivo model systems are needed to emulate the native environment of a tissue and to translate cell-matrix forces with high fidelity. A naturally-derived decellularized tendon scaffold (DTS) was invented to serve as a biomimetic tissue culture platform, preserving the structure and function of native extracellular matrix. DTS in concert with a newly designed dynamic mechanical strain system comprises a tendon bioreactor that is able to emulate the three-dimensional topography, extracellular matrix proteins, and mechanical strain that cells would experience in vivo. Mesenchymal stem cells seeded on decellularized tendon scaffolds subject to cyclic mechanical deformation developed strain-dependent alterations in phenotype and measurably improved tissue mechanical properties. The relative tenogenic efficacies of adult stem cells derived from bone marrow, adipose and tendon were then compared in this system, revealing characteristics suggesting tendon-derived mesenchymal stem cells are predisposed to differentiate toward tendon better than other cell sources in this model. The results of the described experiments have demonstrated that adult mesenchymal stem cells are responsive to mechanical stimulation and, while exhibiting heterogeneity based on donor tissue, are broadly capable of tenocytic differentiation and tissue neogenesis in response to specific ultrastructural and biomechanical cues. This knowledge of cellular mechanotransduction has direct clinical implications for how we treat, rehabilitate and engineer tendon after injury.
Ph. D.

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2

Gonzalez-Molina, Jordi. "Cell-biomaterial mechanical interactions : from cancer mechanobiology to cell therapies". Thesis, University College London (University of London), 2018. http://discovery.ucl.ac.uk/10052561/.

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The physical characteristics of the cell microenvironment greatly affect cellular processes such as survival, proliferation, migration, and differentiation. Biomaterials with well-defined physical and chemical properties have been used to better understand the cell microenvironment. Furthermore, the physicochemical properties of biomaterials can be modulated to induce host body responses and therapeutic cell behaviour. Based on these premises, the work presented in this thesis investigated the effect of soluble polymers commonly used in cell therapies on the physical properties of the extracellular microenvironment. It was found, that viscosity-enhancing polymers induce mesenchymal migration in liver cancer cells, an effect derived from changes in integrin-dependent cell – substrate adhesion dynamics and mechanosensing. Also, the role of extracellular polymers on endothelial-derived cell alignment was explored indicating that molecular soluble polymers enhance cell elongation and alignment in a molecular weight-dependent manner. In addition, the effect of hydrogel density and crosslinking causing mechanical confinement was found to affect cancer cell growth and cell cycle progression, leading to an enhanced content in polyploid cells. Finally, the effect of mechanical confinement on liver cancer cells was taken advantage of to improve the production of biomass for a bioartificial liver device by modulating the degree of crosslinking of alginate hydrogel. In conclusion, the work presented here indicates that physical properties of both the extracellular fluid and matrix greatly affect cell behaviour and can be exploited to improve biomaterial design for in vitro testing and clinical applications.

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3

Smith, Rochelle. "Cancer Cell Mechanics in Chemoresistance and Chemotherapeutic Drug Exposure". Master's thesis, Faculty of Health Sciences, 2019. http://hdl.handle.net/11427/31268.

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Cancer remains a problem worldwide as one of the leading causes of morbidity and mortality. Many cancer patients experience recurrence and ultimately death due to treatment failure or the development of chemoresistance. The concept of chemoresistance however is complex, recent studies have highlighted that cellular structure and extra-cellular composition, mechanics and structure play a role in the development of chemoresistance. The mechanical properties of cells impact their architecture, migration patterns, intracellular trafficking and many other cellular functions. Studies have also revealed that cellular mechanical properties are modified during cancer progression. We investigated these mechanical properties and changes to them by using a malignant melanoma cell line (WM1158) and a chemoresistant malignant melanoma cell line (SK-MEL29). Malignant melanoma was the cell line of choice as it is one of the most prominent types of cancer known to develop chemoresistance. The aim of this study was to identify the effects of chemotherapeutic drug exposure on the mechanical properties and cytoskeletal composition of drug sensitive and drug resistant malignant melanoma cells. To achieve this, a combination of Multiple particle tracking microrheology (MPTM), quantitative RT-PCR and Western blotting techniques were utilised to demonstrate changes in cytoskeletal elements that are responsible for cellular mechanics. MPTM was developed as an approach to map intracellular mechanical properties of living cells and track the intracellular particles by Brownian motion to establish a viscoelastic model and compare it with the power-law approach. A quantification of the MPTM allowed capturing of the cell stiffness using the mean squared displacement (MSD) of cell under different conditions. The cytoskeletal elements actin and β-tubulin were analysed in qRT-PCR and Western blot as they form the key elements governing a cell’s mechanical stability and response to mechanical stimuli. The findings from this study revealed cell stiffness decreases as cancer progress, thereby cells become stiffer. The same pattern was evident for chemoresistant malignant cells and revealed that they had a loss of elasticity in comparison to their counter non-resistant malignant cells. With regards to protein levels and mRNA expression, the chemotherapeutic drug affected the cytoskeleton causing cells to undergo morphological changes which, however, was not seen in chemoresistant cells. The results from this study indicated that measuring mechanical properties of cells provides an efficient marker for cancer diagnosis and deeper understanding of cancer mechanobiology.

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4

Wang, Ji. "Suspended Micro/Nanofiber Hierarchical Scaffolds for Studying Cell Mechanobiology". Thesis, Virginia Tech, 2015. http://hdl.handle.net/10919/76884.

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Extracellular matrix (ECM) is a fibrous natural cell environment, possessing complicated micro-and nano- architectures, which provides signaling cues and influences cell behavior. Mimicking this three dimensional environment in vitro is a challenge in developmental and disease biology. Here, suspended multilayer hierarchical nanofiber assemblies fabricated using the non-electrospinning STEP (Spinneret based Tunable Engineered Parameter) fiber manufacturing technique with controlled fiber diameter (microns to less than 100 nm), orientation and spacing in single and multiple layers are demonstrated as biological scaffolds. Hierarchical nanofiber assemblies were developed to control single cell shape (shape index from 0.15 to 0.57), nuclei shape (shape index 0.75 to 0.99) and focal adhesion cluster length (8-15 micrometer). To further investigate single cell-ECM biophysical interactions, nanofiber nets fused in crisscross patterns were manufactured to measure the "inside out" contractile forces of single mesenchymal stem cells (MSCs). The contractile forces (18-320 nano Newton) were found to scale with fiber structural stiffness (2 -100 nano Newton/micrometer). Cells were observed to shed debris on fibers, which were found to exert forces (15-20 nano Newton). Upon CO? deprivation, cells were observed to monotonically reduce cell spread area and contractile forces. During the apoptotic process, cells exerted both expansive and contractile forces. The platform developed in this study allows a wide parametric investigation of biophysical cues which influence cell behaviors with implications in tissue engineering, developmental biology, and disease biology.
Master of Science

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5

Nichols, Anne Elizabeth Carmack. "Scleraxis-mediated regulation of tendon and ligament cell mechanobiology". Diss., Virginia Tech, 2018. http://hdl.handle.net/10919/86631.

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Tendon and ligament injuries are common orthopedic problems that have an enormous impact on the quality of life of affected patients. Despite the frequency at which these injuries occur, current treatments are unable to restore native function to the damaged tissue. Because of this, reinjury is common. It is well known that mechanical stimulation is beneficial for promoting tendon and ligament development and tissue homeostasis; however, the specific mechanisms remain unclear. The transcription factor scleraxis (Scx) is an interesting candidate for mediating the tendon and ligament mechanoresponse, as it has been shown that Scx expression is induced by cyclic mechanical strain in tenocytes and is required for mechanically-induced stem cell tenogenesis. Moreover, Scx expression is increased in adult tendons following exercise. The studies described in this dissertation therefore focus on the combined role of Scx and mechanical stimulation in two contexts: 1) influencing ligament cell differentiation and 2) regulating adult tenocyte behavior. In the first study, transient Scx overexpression combined with mechanical strain in a 3D collagen hydrogel model was investigated as a means of deriving mature ligament cells from stem cells for use in ligament tissue engineering. Scx overexpression in C3H10T1/2 cells cultured in collagen hydrogels under static strain resulted in increased construct contraction and cell elongation, but no concurrent increase in the expression of ligament-related genes or production of glycosaminoglycans (GAG). When combined with low levels of cyclic strain, Scx overexpression resulted in increased mechanical properties of the tissue constructs, increased GAG production, and increased expression of ligament-related genes compared to cyclic strain alone. Together, these results demonstrate that Scx overexpression combined with cyclic strain can induce ligament cell differentiation and suggest that Scx does so by improving the mechanosensitivity of cells to cyclic strain. In the second study, the role of Scx in adult tenocyte mechanotransduction was explored using RNA-sequencing (RNA-seq) and small interfering RNA (siRNA) technologies. Equine tenocytes were exposed to siRNA targeting Scx or a control siRNA and maintained under cyclic mechanical strain prior to being submitted for RNA-seq. Comparison of the resulting transcriptomes revealed that Scx knockdown decreased the expression of several genes encoding important focal adhesion adaptor proteins. Correspondingly, Scx-depleted tenocytes showed abnormally long focal adhesions, decreased cytoskeletal stiffness, and an impaired ability to migrate on soft surfaces. This suggests that Scx regulates the tenocyte mechanoresponse by promoting the expression of focal adhesion-related genes. Combined, the results of these studies support a role for Scx in tendon and ligament cell mechanotransduction and identify the regulation of genes related to maintaining the cell-extracellular matrix connection and cytoskeletal dynamics as a potential mechanism. These findings enhance our understanding of how mechanical stimulation influences cell behavior and provide new research directions and methodologies for future studies of tendon and ligament mechanobiology.
Ph. D.

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6

Kamble, Harshad. "Design and Development of Cell Stretching Platforms for Mechanobiology Studies". Thesis, Griffith University, 2017. http://hdl.handle.net/10072/370968.

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Cells within the human body are continuously exposed to various mechanical stimuli due to organ function, movement and growth. Cellular response to such mechanical stimuli is known as a mechanobiological signalling, which is an integral part of the cell homeostasis. It is widely accepted that maladaptation of mechanobiological signalling may lead to dysfunction and/or disease. Thus, better understanding of mechanobiological signalling has become a key area of interest for researchers in the field of regenerative medicine and tissue engineering. However, complexity involved in the in vivo biological systems has been a major hurdle for comprehensive mechanobiological investigations. This technological gap motivates researchers to develop in vitro devices capable of introducing mechanical strain onto a cell culture and to closely mimic the in vivo physiological conditions. For example, various cell stretching approaches have been developed to induce mechanical strain onto a cell culture and trigger cellular responses such as migration, proliferation and orientation. However, very few existing cell stretching platforms fulfil the major requirement of a robust cell stretching tool such as high experimental throughput, well-characterised and controllable strain pattern, ease of operation, compatible with a wide range of imaging systems and most importantly high biological relevance for systematic mechanobiological investigation. Thus, the present thesis focuses on the development of robust cell stretching platforms based on electromagnet and pneumatic actuations to address these existing limitations and subsequently to establish a systematic approach for in-depth mechanobiological investigation. To provide a systematic approach for detailed study, the first necessary step is quantification of the parameter. Thus, in the Chapter three of this thesis, a novel cell stretching platform based on a single sided uniaxial stretching approach was developed to apply tensile strain onto the cell culture and observe cellular response of the cells towards different strains in the same field of view with lower fabrication and operation complexity. The effectiveness of the platform was demonstrated by observing the response of cells in culture under different strain amplitudes. In the Chapter four, a standardised numerical tool was developed for the singlesided uniaxial cell stretching platform. The numerical tool provided guidelines for the optimization parameters and paved way for the development of a double-sided cell stretching platform described in Chapter five. The developed platform was capable of investigating the cellular behaviour for a wide range of homogenous strain amplitudes with cyclic and static stretching conditions. Although the developed electromagnetically cell stretching platforms provided a standardised tool for systematic mechanobiological investigation, the biological relevance could still be improved. Thus, the Chapter six involved the development of a novel pneumatically actuated array-based cell stretching platform, which concurrently induced a range of cyclic strain onto the cell culture. It was developed to achieve cell patterns, which provided an improved biological relevance for mechanobiological studies. The toroidal shaped strain pattern was utilised to achieve circumferential cellular alignment of cells similar to that of in vivo smooth muscle in the vascular wall. Furthermore, the dimensions of the platform followed those of standard 96 well plates. This simple and effective design approach ensured a high compatibility with pre-clinical tools and protocols, which is critical for highthroughput cell-stretching assays. Collectively, the findings for these chapters and the thesis at large, suggest the high clinical compatibility and biological relevance of the cell stretching devices reported in this thesis provide promising platform for systematic mechanobiological investigations.
Thesis (PhD Doctorate)
Doctor of Philosophy (PhD)
School of Natural Sciences
Science, Environment, Engineering and Technology
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7

Balachandran, Kartik. "Aortic valve mechanobiology - the effect of cyclic stretch". Diss., Georgia Institute of Technology, 2010. http://hdl.handle.net/1853/39486.

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Aortic valve disease is among the third most common cardiovascular disease worldwide, and is also a strong predictor for other cardiac related deaths. Altered mechanical forces are believed to cause changes in aortic valve biosynthetic activity, eventually leading to valve disease, however little is known about the cellular and molecular events involved in these processes. To gain a fundamental understanding into aortic valve disease mechanobiology, an ex vivo experimental model was used to study the effects of normal and elevated cyclic stretch on aortic valve remodeling and degenerative disease. The hypothesis of this proposal was that elevated cyclic stretch will result in increased expression of markers related to degenerative valve disease. Three aspects of aortic valve disease were studied: (i) Altered extracellular matrix remodeling; (ii) Aortic Valve Calcification; and (iii) Serotonin-induced valvulopathy. Results showed that elevated stretch resulted in increased matrix remodeling and calcification via a bone morphogenic protein-dependent pathway. In addition, elevated stretch and serotonin resulted in increased collagen biosynthesis and tissue stiffness via a serotonin-2A receptor-mediated pathway. This work adds to current knowledge on aortic valve disease mechanisms, and could pave the way for the development of novel treatments for valve disease and for the design of tissue engineered valve constructs.

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8

Mahajan, Gautam. "MECHANOBIOLOGY OF BRAIN-DERIVED CELLS DURING DEVELOPMENTAL STAGES". Cleveland State University / OhioLINK, 2019. http://rave.ohiolink.edu/etdc/view?acc_num=csu1578332547849308.

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McBride, Sarah Howe. "MULTISCALE MECHANOBIOLOGY OF PERIOSTEAL BONE GENERATION: CELL SCALE STUDIES TO TRANSLATIONAL MODELS". Case Western Reserve University School of Graduate Studies / OhioLINK, 2010. http://rave.ohiolink.edu/etdc/view?acc_num=case1291048293.

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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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11

Walker, Matthew. "Dynamic Mechanical Regulation of Cells in 3D Microtissues". Thesis, Université d'Ottawa / University of Ottawa, 2020. http://hdl.handle.net/10393/40555.

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It has been well established that the fundamental behaviors of mammalian cells are influenced by the physical cues that they experience from their surrounding environment. With respect to cells in our bodies, mechanically-driven morphological and phenotypic changes to our cells have been linked to responses critical to both normal development and disease progression, including lung, heart, muscle and bone disorders, and cancer. Although significant advancements to our understanding of cell behavior have been made using 2D cell culture methods, questions regarding how physical stretch guides cell behavior in more complex 3D biological systems remain unanswered. To address these questions, we used microfabrication techniques to develop vacuum-actuated stretchers for high throughput stretching and dynamic mechanical screening of 3D microtissue cultures. This thesis contains five research chapters that have utilized these devices to advance our understanding of how cells feel stretch and how it influences their behavior in a 3D matrix. In the first research chapter (chapter 2), we characterized how stretch is transferred from the tissue-level to the single-cell level and we investigated the cytoskeletal reinforcement response to long-term mechanical conditioning. In the second research chapter (chapter 3), we examined the effects of an acute dynamic stretch and found that 3D cultures soften through actin depolymerization to homeostatically maintain a mean tension. This softening response to stretch may lengthen tissues in our body, and thus may be an important mechanism by which airway resistance and arterial blood pressure are controlled. In the third and forth research chapters (chapter 4-5), we investigated the time dependencies of microtissues cultures and we found that their behavior differed from our knowledge of the rheological behavior of cells in 2D culture. Microtissues instead followed a stretched exponential model that seemed to be set by a dynamic equilibrium between cytoskeletal assembly and disassembly rates. The difference in the behavior from cells in 2D may reflect the profound changes to the structure and distribution of the cytoskeleton that occur when cells are grown on flat surfaces vs. within a 3D environment. In the fifth and final research chapter (chapter 6), we examined how mechanical forces may contribute to the progression of tissue fibrosis through activating latent TGF-β1. Our results suggest that mechanical stretch contributes to a feed forward loop that preserves a myofibroblastic phenotype. Together these investigations further our understanding of how cells respond to mechanical stimuli within 3D environments, and thus, mark a significant contribution to the fields of mechanobiology and cell mechanics.

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12

GALLI, CAMILLA. "DYNAMIC INTERPLAY BETWEEN SPECTRIN, ACTIN AND PLASMA MEMBRANE DURING CELL MECHANORESPONSE". Doctoral thesis, Università degli Studi di Milano, 2020. http://hdl.handle.net/2434/697440.

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The spectrin cytoskeleton is a major component of the mammalian cell cortex. While long known and ubiquitously expressed, its dynamic behaviour and cooperation with other major components of the cell cortex is poorly understood. Here we investigated spectrin reactions upon different mechanical cues, such as cell-driven perturbations, like cell adhesion, spreading and contraction, or environmentally driven ones, like compression, stretch and osmotic changes. Upon all of these challenges we observed that spectrin meshwork spatially adapts and reorganizes under the plasma membrane together with the acto-myosin cytoskeleton. Working together to maintain cell integrity, both cytoskeletons define specific membrane territories. Actin-rich regions control protrusions, adhesions and stress fibers, whereas spectrin-rich regions concentrate in retractile zones, covering low actin density territories of the cortex. Given this interplay, we wondered if spectrin could be potentially involved in the spatial and temporal regulation of membrane trafficking. We followed spectrin, actin and clathrin dynamics through live TIRF microscopy and observed an inverted correlation between spectrin and actin densities and endocytic capacities, suggesting a spectrin contribution to clathrin-mediated endocytosis. Our results pinpoint a role for spectrin in the support of the lipid bilayer in regions where actin cytoskeleton is not established, creating a fencing mechanism for actin remodelling and cargoes internalization. All these mechanisms potentially unveil why the spectrin family of protein is evolutionary highly conserved and ubiquitously expressed in eukaryotic cells, and might explain its involvement in a broad range of pathological condition.

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13

Li, Tong. "Cross-scale biophysics modelling of F-actin cytoskeleton in cell". Thesis, Queensland University of Technology, 2015. https://eprints.qut.edu.au/82293/1/Tong_Li_Thesis.pdf.

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This thesis is a comparative study of the modelling of mechanical behaviours of F-actin cytoskeleton which is an important structural component in living cells. A new granular model was developed for F-actin cytoskeleton based on the concept of multiscale modelling. This framework overcomes difficulties encountered in physical modelling of cytoskeleton in conventional continuum mechanics modelling, and the computational challenges in all-atom molecular dynamics simulation. The thermostat algorithm was further modified to better predict the thermodynamic properties of F-actin cytoskeleton in modelling. This multiscale modelling framework was applied in explaining the physical mechanisms of cytoskeleton responses to external mechanical loads.

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Evans, Sarah Frances. "Top Down and Bottom Up Approaches to Elucidating Multiscale Periosteal Mechanobiology: Tissue Level and Cell Scale Studies". Case Western Reserve University School of Graduate Studies / OhioLINK, 2012. http://rave.ohiolink.edu/etdc/view?acc_num=case1331646902.

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Liverani, Chiara <1984&gt. "Investigating the Mechanobiology of Cancer Cell-ECM Interaction: The Impact of Substrate Stiffness in Breast Cancer Progression". Doctoral thesis, Alma Mater Studiorum - Università di Bologna, 2018. http://amsdottorato.unibo.it/8308/7/Tesi%20dottorato%20Liverani.pdf.

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The loss of tissue homeostasis and mechanoreciprocity are considered one of the hallmarks of cancer. Here we have applied a porous type I collagen-based three-dimensional (3D) scaffold to study how breast cancer cells interact with and alter extracellular collagen. We assessed the modifications induced by tumor cells on the micro- and macro- characteristic of extracellular collagen and on its compressive stiffness. Mechanical testing was conducted both with an in-house built low-force compressive device and by Dynamic Mechanical Analysis. The stiffness of single collagen fibers was assessed by Atomic Force Microscopy. When cultured on collagen scaffolds, the two cell lines generated coherent tissue-like structures. MCF7 displayed an epithelial morphology with a tightly cohesive cobblestone appearance, while MDA-MB-231 showed a mesenchymal phenotype with lower cell-to-cell contact. MDA-MB-231, which belongs to the aggressive basal-like subtype, increased scaffold stiffness from 46.9 kPa, to 57.9 kPa, and overexpressed the matrix-modifying enzyme, lysyl oxidase (LOX), whereas luminal A MCF-7 cells did not alter the mechanical characteristics of extracellular collagen. When the activity of LOX was blocked, MDA-MB-231 were unable to alter the scaffold stiffness: the compressive modulus increased by 8.9%, in contrast to the increase observed without LOX inhibition (23%). No significant changes were found between the Young’s modulus of fibers taken from control scaffolds compared to fibers taken from scaffolds after culture with MDA-MB-231. Overall this work provides evidence that invasive, mesenchymal-like breast cancer cells produce high levels of the crosslinking enzyme LOX, and are able to increase the stiffness of extracellular collagen and to alter its structural characteristics. A causal relationship between this behavior of cancer cells and expression of the enzyme LOX was also provided. Our model offers a relevant in vitro tool to reproduce and investigate the biomechanical interplay subsisting between cancer cells and the surrounding ECM.

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16

Esmaeili, Pourfarhangi Kamyar. "Movie1: MTLn3 cell switching from Migration to Invadopodia state". Diss., Temple University Libraries, 2019. http://cdm16002.contentdm.oclc.org/cdm/ref/collection/p245801coll10/id/584756.

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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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17

McKenzie, Andrew J. "Mechanoregulation of leading edge PKA activity during ovarian cancer cell migration". ScholarWorks @ UVM, 2014. http://scholarworks.uvm.edu/graddis/273.

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Ovarian cancer is the deadliest of all the gynecologic cancers and is known for its clinically occult and asymptomatic dissemination. Most ovarian malignancies are diagnosed in the late stages of the disease and the high rate of morbidity is thought to be due, in part, to the highly metastatic nature of ovarian carcinomas. Cancer metastasis relies on the ability of cells to migrate away from primary tumors and invade into target tissues. Though the processes are distinct, cancer cell invasion relies on the underlying migration machinery to invade target tissues. Cell migration requires the coordinated effort of numerous spatially-regulated signaling pathways to extend protrusions, create new adhesion to the extracellular matrix (ECM), translocate the cell body, and retract the cell rear. Our lab established that the cyclic-AMP dependent protein kinase (PKA) subunits and enzymatic activity are localized to the leading edge of migrating cells and are required for cell movement. Despite the importance for localized PKA activity during migration, neither its role in regulating ovarian cancer cell migration and invasion nor the mechanism regulating leading edge PKA activity have been determined. Therefore, the objective of the enclosed work is to establish the importance of PKA for ovarian cancer cell migration and invasion and elucidate the molecular mechanism governing leading edge PKA. We demonstrate, for the first time, that PKA activity and spatial distribution through A-Kinase Anchoring Proteins (AKAPs) is required for efficient ovarian cancer cell migration and invasion. Additionally, we establish a link between leading edge PKA activity in migrating cells, ECM stiffness sensing, and the regulation of both PKA activity and ovarian cancer cell migration by the mechanical properties of the ECM. Finally, we delineate the hierarchy of cell signaling events that regulate leading edge PKA activity and, ultimately, the migration of ovarian cancer cells. Specifically, we elucidate a mechanism where leading edge protrusions elicit leading edge calcium currents through the stretch-activated calcium channel (SACC) of the transient receptor potential family melastatin 7 (TrpM7) to activate actomyosin contractility. ECM substrate stiffness is sensed by the actin cytoskeleton and actomyosin contractility, which, in turn, regulates the activity of leading edge PKA activity. These studies have provided important insights into the regulation of cell migration and have established the mechanistic details governing leading edge PKA activity during cell migration.

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18

Esmaeili, Pourfarhangi Kamyar. "Movie2: MDA-MB-231 cell switching between Migration and Invadopodia states". Diss., Temple University Libraries, 2019. http://cdm16002.contentdm.oclc.org/cdm/ref/collection/p245801coll10/id/584754.

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Streszczenie:

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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19

Sheets, Kevin Tyler. "Cell-Fiber Interactions: A New Route to Mechano-Biological Investigations in Developmental and Disease Biology". Diss., Virginia Tech, 2014. http://hdl.handle.net/10919/70855.

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Cells in the body interact with a predominantly fibrous microenvironment and constantly adapt to changes in their neighboring physiochemical environment, which has implications in developmental and disease biology. A myriad of in vitro platforms including 2D flat and 3D gel substrates with and without anisotropy have demonstrated cellular alterations to subtle changes in topography. Recently, our work using suspended fibers as a new in vitro biological assay has revealed that cells are able to sense and respond to changes in fiber curvature and structural stiffness as evidenced by alterations to cytoskeleton arrangement, including focal adhesion cluster lengths and nucleus shape indices, leading to altered migration speeds. It is hypothesized that these behaviors occur due to modulation of cellular inside-out forces in response to changes in the external fibrous environment (outside-in). Thus, in this study, we investigate the role of fiber curvature and structural stiffness in force modulation of single cells attached to suspended fibers. Using our previously reported non-electrospinning Spinneret based Tunable Engineered Parameters (STEP) fiber manufacturing platform, we present our findings on single cell inside-out and outside-in forces using fibers of three diameters (250 nm, 400 nm and 800 nm) representing a wide range of structural stiffness (3-45 nN/μm). To investigate cellular adaptability to external perturbation, we present the development of a first-of-its-kind force measurement 'nanonet' platform capable of investigating cell adhesion forces in response to symmetric and non-symmetric (injury model) loading. Our combined findings are multi-fold: (i) Cells on suspended fibers are able to form focal adhesion clusters approximately four times longer than those on flat substrates, which gives them potential to double their migration speeds, (ii) Nanonets as force probes show that the contractility-based inside-out forces are nearly equally distributed on both sides of the cell body, and that overall force magnitudes are dependent on fiber structural stiffness, and (iii) External perturbation can evenly (symmetric) or unevenly (non-symmetric) distribute forces within the cell, and the resulting bias causes diameter-dependent outside-in adhesion force response. Finally, we demonstrate the power of the developed force measurement platform by extending our studies to cell-cell junctional forces as well as single-cell disease models including cancer and aortic aneurysm.
Ph. D.

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20

Xu, Zhenyuan. "The Role of the Extracellular Matrix in Schwann Cell Phenotype". University of Cincinnati / OhioLINK, 2021. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1623251473003085.

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21

Gnanasambandam, Bhargavee. "Design of Modified Traction Force Microscopy for Cell Response to De Novo ECM". Case Western Reserve University School of Graduate Studies / OhioLINK, 2020. http://rave.ohiolink.edu/etdc/view?acc_num=case1591698756910799.

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22

Martin, Madge Audrey Marie. "Bone remodelling and mechanomics: Bridging organ, tissue, and cell scales to understand bone structure and function". Thesis, Queensland University of Technology, 2020. https://eprints.qut.edu.au/203101/1/Madge%20Audrey%20Marie%20Martin%20Thesis.pdf.

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The structure and chemical composition of our bones change over the course of life through a multi-physical process called bone remodeling. In particular, one cells living in the pores of bone tissue sense variations in their environment. In this context, we focus on mechanomics, the description of the action of mechanics on biological tissues. We explore several approaches to mechanistic modeling of bone remodeling: one addresses the question at the cellular level, the other at the organ level. We finally propose a unifying theory combining biochemical and mechanical aspects. Finally, we introduce a clinical application to adolescent idiopathic scoliosis.

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23

Esmaeili, Pourfarhangi Kamyar. "Movie10: Computational image segmentation and tracking performed by LEVER". Diss., Temple University Libraries, 2019. http://cdm16002.contentdm.oclc.org/cdm/ref/collection/p245801coll10/id/584746.

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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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24

Esmaeili, Pourfarhangi Kamyar. "Movie12: FUCCI-MDA-MB-231 cells migration in 3D collagen with vertically aligned fiber architecture". Diss., Temple University Libraries, 2019. http://cdm16002.contentdm.oclc.org/cdm/ref/collection/p245801coll10/id/584747.

Pełny tekst źródła

Streszczenie:

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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25

Esmaeili, Pourfarhangi Kamyar. "Movie3: Oscillations of cortactin fluorescent signal in invadopodia". Diss., Temple University Libraries, 2019. http://cdm16002.contentdm.oclc.org/cdm/ref/collection/p245801coll10/id/584749.

Pełny tekst źródła

Streszczenie:

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. "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.

Pełny tekst źródła

Streszczenie:

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

Esmaeili, Pourfarhangi Kamyar. "Movie4: Absence of cortactin oscillations upon F-actin polymerization inhibition by Cytochalasin". Diss., Temple University Libraries, 2019. http://cdm16002.contentdm.oclc.org/cdm/ref/collection/p245801coll10/id/584751.

Pełny tekst źródła

Streszczenie:

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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28

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.

Pełny tekst źródła

Streszczenie:

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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29

Esmaeili, Pourfarhangi Kamyar. "Movie5: Dynamics of calcium spikes measured by Fluo-4-AM". Diss., Cancer Invasion; Cell Migration; Chemotaxis; Contact Guidance; Invadopodia; Mechanobiology, 2019. http://cdm16002.contentdm.oclc.org/cdm/ref/collection/p245801coll10/id/584753.

Pełny tekst źródła

Streszczenie:

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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30

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.

Pełny tekst źródła

Streszczenie:

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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31

Esmaeili, Pourfarhangi Kamyar. "Movie11: FUCCI-MDA-MB-231 cells migration in 3D collagen with random fiber architecture". Diss., Temple University Libraries, 2019. http://cdm16002.contentdm.oclc.org/cdm/ref/collection/p245801coll10/id/584757.

Pełny tekst źródła

Streszczenie:

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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32

Esmaeili, Pourfarhangi Kamyar. "Movie7: Simulation of EGF diffusion within the microchannels". Diss., Cancer Invasion; Cell Migration; Chemotaxis; Contact Guidance; Invadopodia; Mechanobiology, 2019. http://cdm16002.contentdm.oclc.org/cdm/ref/collection/p245801coll10/id/584758.

Pełny tekst źródła

Streszczenie:

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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33

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.

Pełny tekst źródła

Streszczenie:

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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Esmaeili, Pourfarhangi Kamyar. "Movie6: Dynamics of MT1-MMP vesicle delivery to the plasma membrane". Diss., Cancer Invasion; Cell Migration; Chemotaxis; Contact Guidance; Invadopodia; Mechanobiology, 2019. http://cdm16002.contentdm.oclc.org/cdm/ref/collection/p245801coll10/id/584760.

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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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35

Esmaeili, Pourfarhangi Kamyar. "Effect of Extrinsic and Intrinsic Factors on Cancer Invasion". Diss., Temple University Libraries, 2019. http://cdm16002.contentdm.oclc.org/cdm/ref/collection/p245801coll10/id/585155.

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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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Manifacier, Ian. "Understanding adherent cell mechanics and the influence of substrate rigidity". Thesis, Aix-Marseille, 2016. http://www.theses.fr/2016AIXM4106/document.

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L’ingénierie tissulaire est une stratégie médicale qui repose sur la régénération de tissu par les cellules avec ou sans matériaux. Pour maîtriser cette synthèse, il faut comprendre la cellule comme une part intégrante du tissu. Hormis ses interactions biochimiques avec son support, la cellule interagit également mécaniquement avec son environnement. Elle s’accroche à ce dernier et évalue sa dureté pour adapter sa réponse biologique. Dans cette étude, j’ai développé des modèles numériques pour analyser l’influence de la rigidité du substrat sur le comportement mécanique de la cellule, sur sa structure contractile interne et les efforts qu’elle génère. En d’autres termes, j’ai essayé de comprendre comment la cellule ressent la rigidité de son environnement. De plus, au lieu de me focaliser sur les propriétés mécaniques quantitatives, j’ai cherché à développer un modèle conceptuel simplifié plus proche de la structure cellulaire
Tissue engineering is a medical strategy based on utilizing cells and materials to regenerate a new tissue. Yet, it involves intertwined interactions that allow cells to act as integrated parts of an organ. In addition to chemical reactions, the cell interacts mechanically with its environment by sensing its rigidity. Here, we used several computational models to understand how substrate rigidity affects a cell’s structure as it adheres and spreads on it. In other words we tried to understand the way a cell feels how soft or hard it surrounding is, how it affects its internal structure and the forces that transit within it. In addition, instead of focusing on mechanical properties, we developed a simplified, yet coherent conceptual understanding of the cellular structure

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37

Gaut, Ludovic. "Mechanical and molecular signals underlying tendon cell differentiation". Electronic Thesis or Diss., Sorbonne université, 2018. http://www.theses.fr/2018SORUS301.

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Les tendons sont une forme unique de tissu conjonctif au sein du système musculosquelettique. Le développement, l’homéostasie et la réparation du tendon reposent sur des combinaisons de paramètres moléculaires et aussi mécaniques, régulant la production et l’assemblage des fibres de collagène. Notre objectif est de comprendre quelles sont les voies de mécanotransduction impliquées dans la différentiation tendineuse, via deux (co-)facteurs de transcription : EGR1 et YAP. Nous avons montré que l’expression du gène de tendon SCX, de EGR1 et l'activité de YAP sont réduites dans les tendons de membres de fœtus de poulet immobilisés. De plus, la reprise des contractions musculaires entraîne une reprise de l’expression des gènes de tendon comparable à celle des fœtus jamais immobilisés. La mécanobiologie du tendon a été étudiée avec des constructions cellulaires en 3-dimensions (3D) en gel de fibrine ou de collagène, faits de cellules souches mésenchymateuses. La perte de tension de ces constructions a induit une chute de l’expression de Egr1, des gènes de tendon et de l’activité de YAP. Une surexpression de Egr1 dans les constructions 3D en gel de fibrine sans tension a empêché la chute d’expression des gènes de tendon. L’activité de YAP et l’expression de Scx ont augmenté en étirant les constructions en gel de collagène. L’inactivation de l’activité de YAP par traitement à la verteporfin (VTPF) a induit une diminution de l’expression des gènes de tendon, qui n’a pas été restaurée lorsque ces constructions traitées ont été étirées. Ensemble, ces résultats montrent l’importance de YAP et EGR1 en aval des signaux mécaniques pour réguler la différentiation des cellules du tendon
Tendons are unique forms of connective tissue of the musculoskeletal system. Tendon development, homeostasis and repair rely on specific combinations of mechanical and molecular factors regulating the production and assembly of collagen fibers. Our objective is to decipher the mechanotransduction pathways underlying tendon cell differentiation, through the activity of two transcription (co-)factors, EGR1 and YAP. We showed that the expression of the tendon gene SCX, the mechanosensitive gene EGR1 and YAP activity were downregulated in limb tendons of immobilized chicken fetuses. Restored muscle contraction after immobilization led to a recovery of tendon gene expression. Tendon mechanobiology was studied in vitro in fibrin- or collagen-based 3-dimensional (3D) constructs made of mesenchymal stem cells and mimicking tendon formation. Tension release in fibrin and collagen 3D-constructs induced a drop of the expression of Egr1, tendon genes and YAP activity. Overexpression of Egr1 was able to prevent the downregulation of tendon gene expression in de-tensioned fibrin 3D-constructs. YAP activity was upregulated in dynamically stretched collagen 3D-constructs and was paired with the expression of the tendon gene Scx. Chemical knock-down of YAP activity with Verteporfin (VTPF) treatment showed a decrease in the expression of YAP target genes and the tendon genes. Besides, dynamic stretch applied on VTPF-treated constructs did not restore tendon gene expression, conforting the role of YAP as an intracellular relay of mechanical cues in tendon cells. Altogether, these results highlight the importance of EGR1 and YAP downstream of mechanical forces during tendon cell differentiation

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McKenty, Taylor R. "QUANTIFYING THE EFFECTS OF HYDROSTATIC PRESSURE ON FIBROBLAST GROWTH FACTOR-2 BINDING BY THE HUMAN ENDOTHELIUM". UKnowledge, 2017. http://uknowledge.uky.edu/cbme_etds/47.

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Fluid pressures regulate endothelial cell (EC) tubulogenic activity involving fibroblast growth factor 2 (FGF-2) and its receptor, FGF receptor 2 (FGFR2). Our lab has recently shown that sustained 20 mmHg hydrostatic pressure (HP) upregulates EC sprout formation in a FGF2-dependent fashion. This upregulation of sprout formation may be due to enhanced FGF-2 / FGFR2 interactions in the presence of 20 mmHg HP. We hypothesize that exposure of ECs to 20 mmHg sustained HP enhances FGF-2 binding kinetics. We used a custom hydrostatic pressure system, immunofluorescence, and FACS to quantify FGF-2 binding by ECs in the absence or presence of a range of HPs for 30 minutes. Relative to cells maintained under control pressure, ECs exposed to 20, but neither 5 nor 40 mmHg, displayed a significant increase in binding affinity to FGF-2. EC binding of VEGF-A, another angiogenic growth factor, was unaffected by similar pressure stimuli. Additional studies showed that pressure-selective FGF-2 binding was independent of FGFR2 surface expression. These results implicate the FGF-2 axis in the pressure-sensitive, magnitude-dependent angiogenic processes which we have previously described. The present study provides novel insight regarding the involvement of FGF-2 signaling and interstitial pressure changes in various microvascular physiological and pathobiological processes.

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39

Wang, Qian. "Elastomer-based Cellular Micromechanical Stimulators for Mechanobiological Study". The Ohio State University, 2014. http://rave.ohiolink.edu/etdc/view?acc_num=osu1397610258.

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40

Desvignes, Emma. "Dispositifs fluidiques 3D pour l'étude de la migration cellulaire des macrophages". Thesis, Toulouse, INSA, 2018. http://www.theses.fr/2018ISAT0046.

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Au cours des deux dernières décennies, des études ont été réalisée pour mesurer les forces mécaniques exercées par des cellules vivantes sur leur environnement. Cela a conduit au développement de diverses techniques ingénieuses qui ont principalement été réalisées pour comprendre la façon dont les cellules exercent des forces pendant leur migration sur des substrats bidimensionnels (2D). Cependant, in vivo, les cellules migrent à travers des environnements tridimensionnels (3D) et les mécanismes utilisés pour migrer en 3D diffèrent significativement de ceux de la migration 2D. A titre d'exemple, les cellules confinées en 3D rencontrant des constrictions ont besoin de déformer leur noyau, leur organelle le plus grand et le plus rigide. En 2D, les noyaux ne sont pas des facteurs limitants pour la migration. Il est donc nécessaire de développer des outils pour comprendre comment les cellules migrent en 3D. En particulier, des études doivent être menées pour déterminer comment les cellules appliquent des forces en fonction du niveau de confinement auquel elles se trouvent confrontées. Pour répondre à cette question difficile, nous avons développé deux types de micro-dispositifs. Tout d'abord, nous avons conçu et fabriqué un dispositif de microfluidique pour étudier les forces générées par les cellules pendant une migration confinée. Ce dispositif est constitué de microcanaux de dimensions contrôlées équipés de micropiliers, servant de capteurs de forces .Ces capteurs de forces présentent une sensibilité de l’ordre de 70 pN. Nous avons ensuite introduit dans le dispositif des macrophages humains, cellules du système immunitaire, à l'intérieur du dispositif et évalué la flexion des micropiliers engendrée par les forces cellulaires appliquées lors de leur migration. Grâce au développement d’un algorithme permettant l’analyse des images, nous avons pu évaluer les forces générées dans différentes zones cellulaires et révéler que les cellules redirigent les forces de pression de l'intérieur vers l'extérieur lorsque le degré de confinement augmente. Cette observation suggère un mode de migration très spécifique lié au confinement spatial qui est basé sur l’appui sans adhésion sur les obstacles de l’environnement. Dans un deuxième temps nous avons fabriqué des réseaux tri-dimensionnels obtenus par une méthode de lithographie bi-photonique 3D. Les motifs de ces réseaux possèdent des dimensions caractéristiques de l'échelle cellulaire (1-10 μm) et sont composés de poutres suspendues qui peuvent être courbés par les cellules vivantes qui migrent au sein du treillis tri-dimensionnel. En enregistrant une séquence vidéo des déformations de l'échafaudage, nous pouvons étudier l'activité mécanique de la cellule dans l'espace et le temps pendant sa migration 3D. Nos résultats montrent que les macrophages sont capables de pénétrer dans des réseaux de géométrie cubique lorsque la période du réseau est supérieure à 5 μm et que le support de migration lui-même peut être utilisé comme capteur pour mesurer les forces exercées par les cellules. Grâce à la mesure de la rigidité du matériau constituant le treillis 3D et des modélisations de la déformation élastique de la structure 3D, nous avons pu évaluer que la contrainte mécanique globale qu’exerce un macrophage sur son microenvironnement est de l’ordre de 500 kPa. Grâce à la combinaison de la microfabrication, l'imagerie cellulaire et l'analyse automatisée des images, nous sommes parvenus à quantifier les efforts mécaniques cellulaires mis en jeu lors de la migration de macrophages humains au sein d’environnements confinés et nous mettons ainsi en lumière la mécanique spécifique des cellules migrant en 3D
Over the past two decades, studies have been conducted to measure the mechanical forces exerted by living cells on their environment. This has led to the development of a variety of ingenious techniques that have been primarily developed to understand how cells exert forces during their migration on 2D substrates. However, in vivo, cells migrate through three-dimensional (3D) environments and the mechanisms used to migrate in 3D differ significantly from those of 2D migration. For example, confined cells in 3D encountering constrictions need to deform their nucleus, their largest and most rigid organelle. In 2D, kernels are not limiting factors for migration. It is therefore necessary to develop tools to understand how cells migrate in 3D. In particular, studies need to be conducted to determine how cells apply forces based on the level of containment they encounter. To answer this difficult question, we have developed two types of micro-devices. First, we designed and manufactured a microfluidic device to study the forces generated by cells during a confined migration. This device consists of microchannels of controlled dimensions equipped with micropiliers, serving as force sensors. These force sensors have a sensitivity of the order of 70 pN. We then introduced into the device human macrophages, cells of the immune system, inside the device and evaluated the bending of micropiliers generated by the cellular forces applied during their migration. Through the development of an algorithm for image analysis, we have been able to evaluate the forces generated in different cell areas and reveal that cells are redirecting pressure forces from the inside to the outside as the degree of containment increases. This observation suggests a very specific mode of migration related to spatial confinement that is based on the support without adhesion on the obstacles of the environment. In a second time we made three-dimensional networks obtained by a 3D bi-photonic lithography method. Les motifs de ces réseaux possèdent des dimensions caractéristiques de l'échelle cellulaire (1-10 μm) et sont composés de poutres suspendues qui peuvent être courbés par les cellules vivantes qui migrent au sein du treillis tri-dimensionnel. En enregistrant une séquence vidéo des déformations de l'échafaudage, nous pouvons étudier l'activité mécanique de la cellule dans l'espace et le temps pendant sa migration 3D. Nos résultats montrent que les macrophages sont capables de pénétrer dans des réseaux de géométrie cubique lorsque la période du réseau est supérieure à 5 μm et que le support de migration lui-même peut être utilisé comme capteur pour mesurer les forces exercées par les cellules. Grâce à la mesure de la rigidité du matériau constituant le treillis 3D et des modélisations de la déformation élastique de la structure 3D, nous avons pu évaluer que la contrainte mécanique globale qu’exerce un macrophage sur son microenvironnement est de l’ordre de 500 kPa. Grâce à la combinaison de la microfabrication, l'imagerie cellulaire et l'analyse automatisée des images, nous sommes parvenus à quantifier les efforts mécaniques cellulaires mis en jeu lors de la migration de macrophages humains au sein d’environnements confinés et nous mettons ainsi en lumière la mécanique spécifique des cellules migrant en 3D

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Fell, Cody Alexander. "Soft robotic devices for emulating vascular mechanobiology". Thesis, Queensland University of Technology, 2021. https://eprints.qut.edu.au/213109/1/Cody%20Alexander_Fell_Thesis.pdf.

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This thesis comprises two research projects undertaken as part of the dual biofabrication master's program between Queensland University of Technology and Utrecht University. The two projects focused on leveraging biofabrication, tissue-culture, and soft robotics to develop novel methods for fabricating 3D vascular and colon tissue, respectively. The first project developed a novel approach for conditioning cells using soft robotics that emulate vascular biomechanics, whereas the second project combined bioink micromoulding and melt electrospinning writing to fabricate 3D colon organoid constructs that mimic colon crypt morphology. Together, these projects contribute innovative biofabrication methods for creating tissue-culture models with enhanced biomimicry.

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Sotto, David C. "Directing the migration of mesenchymal stem cells with superparamagnetic iron oxide nanoparticles". Diss., Georgia Institute of Technology, 2015. http://hdl.handle.net/1853/54897.

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Cell migration plays an important role in numerous normal and pathological processes. The physical mechanisms of adhesion, protrusion/extension, contractions, and polarization can regulate cell migration speed, persistence time, and downstream effects in paracrine and endocrine signaling. Methods for understanding these biophysical and biochemical responses to date have been limited to the use of external forces acting on mechanotransductive receptors. Additionally, as the use of magnetic nanoparticles for cell tracking and cell manipulation studies continues to gain popularity, so does the importance of understanding the cellular response to mechanical forces caused by these magnetic systems. This thesis work utilizes superparamagnetic iron oxide nanoparticles and static magnets to induce an endogenous magnetic force on the cell membrane. This cell manipulation model is used to better understand the mechanobiological responses of mesenchymal stem cell to SPIO labeling and endogenous force generation. Directionally persistent motility, cytoskeletal reorganization, and altered pro-migratory cytokine secretion is reported in this thesis as a response to SPIO based cell manipulation.

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43

Khalil, Georges. "Modeling of the bone-implant healing : mechanobiology of osteoblasts population in presence of endothelial cells". Toulouse 3, 2011. http://thesesups.ups-tlse.fr/1441/.

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La durée de vie d'une arthroplastie est étroitement liée à la qualité de la cicatrisation post-opératoire de l'interface os-implant. Malgré des résultats cliniques satisfaisants, les problèmes de reprise de prothèse (hanche, genou, épaule) sont en constante augmentation. L'hypothèse centrale du travail de recherche a consisté à supposer que la modélisation des intéractions mécanobiologiques et de la néo-vascularisation au sein des tissus biologiques de la zone périprothétique pouvait permettre d'aider dans la compréhension des phénomènes multifactoriels de cicatrisation. Une méthodologie propre aux transports réactifs en milieux poreux déformables a été associée à des concepts de migrations et de proliférations cellulaires en présence de facteurs de croissance pour proposer des lois de comportement mécanobiologiques de la cicatrisation intramembranaire. Ont été prises en compte les interactions entre les populations cellulaires ostéoblastiques, endotheliales, les facteurs de croissance osseux, les facteurs angiogéniques et fibronectines, pour établir les équations de croissance tissulaire. L'application a concerné un implant de référence (canine micromotion implant) développé dans le cadre d'une collaboration internationale (K. Søballe - Denmark, J. E. Bechtold - USA). La résolution numérique spatio-temporelle a été réalisée par la méthode des éléments finis et implémentée dans l'environnement COMSOL Multiphysics(r). Des études de sensibilités paramétriques ont permis d'évaluer le rôle de l'instabilité mécanique de l'implant et l'apport de la néo-vascularisation dans la zone périprothétique. Les résultats obtenus ont été en bon accord avec la base de données issue du modèle expérimental et avec les observations en environnement clinique. Ces résultats ont permis de conforter la stratégie originale mise en œuvre dans ce travail de recherche
The long term survival of arthoplasty is strongly related to the quality of the immediative post-operative healing of periprosthetic tissue. Despite good clinical results, revisions are increasing (hip, knee, shoulder). The central hypothesis of this work was that modeling of mechanobiological interactions and neo-vascularization into biological tissues of periprosthetic zone might help to investigate the multifactorial events in tissue healing. The methodology of reactive transports in deformable porous media has been associated to computational cell biology (cellular migration and proliferation in presence of anabolic growth factors). The populations of osteoblasts and endothelial cells, the phases of bone growth factors, angiogenic factors and fibronectin have taken into account to propose a set of governing equations describing the process of intramembranous healing. The application concerned a reference experimental implant (canine micromotion implant) developed within the framework of an international collaboration (K. Søballe - Denmark, J. E. Bechtold - USA). The spatio-temporal resolution was achieved by using the finite element method (mixed formulation displacement-pressure) implemented into COMSOL Multiphysics(r). Parametric sensitivity studies were implemented to study the role of mechanical instability of implant and the supply from the neo-vascularization of the periprosthetic zone. The results were in good agreement with the experimental database from the canine experimental model and clinical observations. This confirmed the potential interests of our original methodology

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Rabineau, Morgane. "Influence de l'élasticité du substrat sur la plasticité de la chromatine de cellules épithéliales et sur la division de cellules tumorales". Thesis, Strasbourg, 2013. http://www.theses.fr/2013STRAJ079/document.

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Dans le domaine des biomatériaux, cette thèse s’intéresse à l’influence de l’élasticité du substrat sur la division et la plasticité de la chromatine de cellules épithéliales. La létalité des cellules est corrélée aux faibles rigidités des substrats. Cependant, quelques cellules tumorales SW480, incluant celles portant des anomalies de ségrégation des chromosomes, progressent en mitose. Ces anomalies seraient à l’origine de réarrangements chromosomiques, sources de nombreuses mutations. Les substrats mous conduisent à la formation d’hétérochromatine tandis que les substrats très mous induisent la nécrose des cellules PtK2. Sur ces substrats, l’euchromatine est maintenue après inhibition de HDAC, permettant aux cellules de résister à la nécrose, indépendamment de la compétence transcriptionnelle du noyau. Ces cellules s’étalent à nouveau après transfert sur un substrat rigide. Ces résultats suggèrent 1) une voie de signalisation entrante initiée par le substrat conduisant à la nécrose via la formation d’hétérochromatine 2) une voie de signalisation sortante initiée par l’euchromatine permettant la survie cellulaire
In the biomaterials field, this PhD work is about influence of substrate elasticity on cell division and chromatin plasticity of epithelial cells. Soft substrates cause massive death.However, some SW480 tumor cells, including those bearing chromosomal segregation abnormalities progress in mitosis. These abnormalities could result in more chromosomal rearrangements, increasing mutations. Soft substrates lead to heterochromatin remodelling and very soft substrates promote necrosis of PtK2 cells. On these substrates, euchromatin could be maintained after HDAC inhibition independently of the nuclear transcriptional competence.These cells spread again after tranfer on stiff substrates. These results suggest i) outside-insignalling cascade initiated at the soft substrate surface leading to heterochromatin remodelling and ultimately necrosis, ii) inside-out signaling cascade initiated from euchromatin allowing cell to overcome necrosis on soft substrate

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Gilbert, Hamish. "The response of human annulus fibrosus cells to cyclic tensile strain : evidence for an altered mechanotransduction pathway with intervertebral disc degeneration". Thesis, University of Manchester, 2011. https://www.research.manchester.ac.uk/portal/en/theses/the-response-of-human-annulus-fibrosus-cells-to-cyclic-tensile-strain-evidence-for-an-altered-mechanotransduction-pathway-with-intervertebral-disc-degeneration(e61ab359-7b23-454e-ab4b-2236d3ea9ed9).html.

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The Intervertebral disc (IVD), comprised of two distinct regions, namely the fibrous annulus fibrosus (AF) and the gelatinous nucleus pulposus (NP), is a fibrocartilage pad located between adjoining vertebrae of the spine. The function of the IVD is to provide stability to the spine, while maintaining movement. IVD degeneration, also known as degenerative disc disease (DDD), is the process whereby the IVD tissue degrades, resulting in loss of function to the disc. Low back pain (LBP) is associated with the degeneration of the IVD, making it important to investigate the pathogenesis of DDD, as this could lead to novel therapies for the prevention and/or treatment of LBP. Mechanical stimuli (MS) are known to be important for IVD cell matrix homeostasis, with cells of the AF and NP responding to physiological forces with a trend towards increased matrix anabolism, while non-physiological forces lead to matrix catabolism. Furthermore, recent evidence suggests that IVD cells derived from degenerate tissue may have lost their ability to respond to physiological MS in the 'normal' anabolic manner, potentially leading to the progression of DDD. It is therefore important to investigate the response of IVD cells derived from both non-degenerate and degenerate tissue to MS, to ascertain whether there is a difference with degeneration. If the response is found to be altered with degeneration, then elucidation of the potentially altered mechanotransduction pathway utilised by degenerate cells could lead to the discovery of novel therapeutic targets for the treatment of DDD. To date, the majority of IVD MS studies have concentrated on the response of NP cells to hydrostatic pressure, with only a limited number of AF studies available. Thus, the first aim of this PhD was to investigate the response of human AF cells derived from non-degenerate and degenerate IVDs to the physiologically relevant mechanical stimulus of cyclic tensile strain (CTS), to ascertain whether the response (regulation of matrix protein and matrix degrading enzyme gene expression) was frequency-dependent or altered with IVD degeneration. Using an in vitro mechanical loading system (Flexcell® Tension Plus™ system, Flexcell International) capable of delivering a CTS of 10% strain, 0.33Hz or 1.0Hz for 20 minutes, the response of AF cells derived from non-degenerate IVDs was found to be frequency-dependent (reduced catabolism at 1.0Hz, with decreased MMP -3 and ADAM-TS -4 gene expression; and catabolic at 0.33Hz, with decreased types I and II collagen and increased MMP -9 gene expression). Furthermore, the response of AF cells to 1.0Hz CTS was shown to be altered with IVD degeneration, depicted by a switch from reduced catabolism (decreased MMP -3 and ADAM-TS -4) in non-degenerate AF cells, to reduced anabolism (decreased aggrecan and type I collagen gene expression) in degenerate AF cells. Subsequently, the second aim of the PhD was to attempt to elucidate the mechanotransduction pathways operating in human AF cells derived from non-degenerate and degenerate IVDs, to ascertain whether the mechanotransduction pathway was altered with IVD degeneration. An identical mechanical stimulation regime was used (1.0Hz CTS) in parallel with functional inhibitors against the cytokines interleukin (IL) -1 and -4, and the cell surface receptors, RGD-recognising integrins. Additionally, the involvement of the cytokine associated transcription factors, nuclear factor kappa beta (NFκB) and signal transducer and activator of transcription (STAT) -6, as well as the integrin-associated kinase, focal adhesion kinase (FAK) was investigated in 1.0Hz CTS-treated non-degenerate AF cells. The response to 1.0Hz CTS (reduced catabolism) of AF cells derived from non-degenerate IVDs occurred in an IL -1, IL -4 and RGD-recognising integrin-dependent manner, with FAK being phosphorylated. Of significant interest, the altered response of AF cells derived from degenerate IVDs to 1.0Hz CTS (reduced anabolism) occurred independently of either cytokine and independently of RGD-recognising integrins, suggesting an altered mechanotransduction pathway in operation and warranting further investigation.

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Brunelli, Marzia. "A mechanobiology study on the response to mechanical compression of mesenchymal progenitor cells cultured in a composite scaffold made of 3D Insert PCL and collagen gel". Thesis, University of Sheffield, 2015. http://etheses.whiterose.ac.uk/12767/.

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The increased awareness of the ability of cells in detecting mechanical cues from the external environment [1] led to consider the possibility of triggering a cellular response by applying external mechanical forces [2]. In order to drive the commitment of differentiated cells and obtain in vitro engineered implants as replacement for bone fracture sites, a scaffold closely mimicking the 3D distribution of forces acting on bone cells in vivo is required and is still ongoing research. On this purpose, a composite scaffold embedded with collagen (cPCL) is proposed in this study as structure to transmit externally applied mechanical forces to embryonic human mesenchymal stem cells (hES-MPs) through a gelatinous matrix of collagen. A collagen concentration of 2 mg/ml and plasma treatment of scaffolds were selected as optimal conditions for survival and uniform seeding distribution of cells. Then, the second part of the study allowed to fully characterize, by mechanical testing and x-ray imaging, a novel hybrid scaffold able to provide an optimal environment for controlledbone progenitor cells growth. The objective of the last part of the study focused on the evaluation of how short bursts of compressive strain, applied as series of cycles at early stages (L1) and late stages (L2) of culture, affects cellular proliferation, bone tissue formation and the osteogenic response of hES-MPs. Short bursts of compression were found to strongly affect hES-MPs proliferation, suggesting cyclic compressive loading to delay the proliferation of samples compressed once. On the other side, L2 prevented proliferation to occur over 28 days, although greatly enhancing the production of mineral which, instead, was null for samples undergoing L1. This study underlined the existence of a strong link between proliferation and mineralization potential of cells and confirms the possibility to vary their response by short bursts of compression applied on hES-MPs seeded in 3D hybrid scaffolds.

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Chagnon-Lessard, Sophie. "Cellular Responses to Complex Strain Fields Studied in Microfluidic Devices". Thesis, Université d'Ottawa / University of Ottawa, 2018. http://hdl.handle.net/10393/37915.

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Cells in living organisms are constantly experiencing a variety of mechanical cues. From the stiffness of the extra cellular matrix to its topography, not to mention the presence of shear stress and tension, the physical characteristics of the microenvironment shape the cells’ fate. A rapidly growing body of work shows that cellular responses to these stimuli constitute regulatory mechanisms in many fundamental biological functions. Substrate strains were previously shown to be sensed by cells and activate diverse biochemical signaling pathways, leading to major remodeling and reorganization of cellular structures. The majority of studies had focused on the stretching avoidance response in near-uniform strain fields. Prior to this work, the cellular responses to complex planar strain fields were largely unknown. In this thesis, we uncover various aspects of strain sensing and response by first developing a tailored lab-on-a-chip platform that mimics the non-uniformity and complexity of physiological strains. These microfluidic cell stretchers allow independent biaxial control, generate cyclic stretching profiles with biologically relevant strain and strain gradient amplitudes, and enable high resolution imaging of on-chip cell cultures. Using these microdevices, we reveal that strain gradients are potent mechanical cues by uncovering the phenomenon of cell gradient avoidance. This work establishes that the cellular mechanosensing machinery can sense and localize changes in strain amplitude, which orchestrate a coordinated cellular response. Subsequently, we investigate the effect of multiple changes in stretching directions to further explore mechanosensing subtleties. The evolution of the cellular response shed light on the interplay of the strain avoidance and the newly demonstrated strain gradient avoidance, which were found to occur on two different time scales. Finally, we extend our work to study the influence of cyclic strains on the early stages of cancer development in epithelial tissues (using MDCK-RasV12 system), which was previously largely unexplored. This work reveals that external mechanical forces impede the healthy cells’ ability to eliminate newly transformed cells and greatly promote invasive protrusions, as a result of their different mechanoresponsiveness. Overall, not only does our work reveal new insights regarding the long-range organization in population of cells, but it may also contribute to paving the way towards new approaches in cancer prevention treatments.

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Doyle, Adele Marion. "Conservation of mechanosignaling: responses of human adult mesenchymal stem cells and differentiated vascular cells to applied physical forces". Diss., Georgia Institute of Technology, 2010. http://hdl.handle.net/1853/39526.

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Mesenchymal stem cells (MSCs) may benefit vascular cell-based therapies as smooth muscle or endothelial cell substitutes or through paracrine actions to repair, replace, or regenerate vascular tissue. Previous studies have demonstrated that MSCs can adopt traits of smooth muscle cells (SMCs) or endothelial cells (ECs), as well as secrete specific factors that tune signaling and material properties in the local environment. Few studies have investigated the cell signaling response of MSCs to mechanical forces present in the vasculature: specifically, shear stress due to blood flow and cyclic strain due to pulsatile blood flow. Thus, the central objective of this dissertation was to determine the signaling responses of MSCs to vascular-relevant applied physical forces, in comparison with that of differentiated vascular cells. Vascular-relevant mechanosignaling of MSCs was assessed through two comparisons: (1) MSC and SMC responses to applied cyclic strain and (2) MSC and EC responses to applied fluid shear stress. MSCs and SMCs were seeded on fibronectin-coated silicone and subjected in vitro to cyclic strain (10%, 1 Hz) or parallel static culture using a custom-built equibiaxial cyclic strain device. Gene expression analysis of 84 signal transduction molecules demonstrated both cell types respond with significant (p<0.05, n=3) fold-changes (|FC|≥ 1.5) within 24 hours of applied equibiaxial strain. Most strain-responsive genes identified were significantly strain-responsive in only one cell type. A signaling trio of Interleukin 8, Vascular cell adhesion molecule 1, and Heme oxygenase 1 was significantly altered in both MSCs and SMCs, suggesting cyclic strain regulates immune and inflammatory functions in both cell types. The response to shear stress of MSCs and ECs was compared using cells seeded on type I collagen or fibronectin and exposed to steady laminar shear stress (5 or 15 dyn/sq-cm) using a parallel plate shear chamber system. Gene expression was compared in MSCs and ECs for a panel of immune and inflammation-related markers. Expression of Cox-2 and Hmox-1 increased significantly (p<0.05, n≥3; |FC|≥1:5) in both cell types. Reduced shear stress-responses of Mcp-1, Pecam-1, and VE-Cad in MSCs relative to ECs suggests that MSCs promote less inflammation and immune activation in response to shear stress than ECs. Mechanosensitivity profiles for MSCs and differentiated vascular cells were broadened using whole genome microarrays. These high-throughput studies confirmed that (1) signaling profiles between sample groups vary significantly more (p<0.05, n=3) with cell type than applied force condition and (2) a subset of conserved mechanosensitive genes alter expression levels significantly and in the same direction fold-change in multiple cell types. Bioinformatics analysis of these conserved mechanoresponsive genes highlighted oxidative stress, cell cycle, and DNA replication as functions regulated by vascular-relevant mechanical cues. These studies demonstrate that MSCs partially reproduce differentiated vascular cell mechanosignaling, while simultaneously altering expression of genes not typically force-responsive in vascular cells. This work defines a role for conserved mechanosignals, based on genes whose expression in response to applied force alters significantly (p<0.05, n≥3) and by at least 1.5-fold change in multiple cell types and/or force types. Comparisons completed for this dissertation motivate future studies to track the functional impact of specific similar or unique MSC mechanoresponses. This work contributes to design of MSC-based vascular therapies and an understanding of stem and differentiated cell mechanobiology.

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Jaddivada, Siddhartha. "Mechanobiology of cell-substrate interactions". Thesis, 2022. https://etd.iisc.ac.in/handle/2005/5729.

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Cell adhesion to substrates is a complex process facilitated by focal adhesion (FA) complexes that help them perform vital cellular functions like migration, growth, and division. Cells probe their surroundings through contractile stresses generated via cross-bridge cycling between actin and myosin. These stresses induce exquisite feedback between the underlying substrate and actomyosin stress fibers, resulting in the remodeling of the cytoskeleton and FA. A repertoire of signaling molecules, including calcium and a mechanosensitive protein, talin, facilitates these interactions in FA. Do cells remodel under dynamic mechanical loads in tissues such as arteries? How do individual components of the FA regulate cell adhesions and tractions? I use numerical methods to address these questions on cell-substrate interaction. I quantified the cell tractions using micro-pillar array detectors (mPAD) created using soft lithography as a first study. Our study shows that mPAD topography resulted in persistent migration of fibroblasts. I used image analysis to quantify the micropillar deflection and calculated tractions through the neo-Hookean model to report traction variation along the cell length. I next developed a multiscale cell model, incorporating SF, calcium signaling, and FA dynamics. Using the model, I investigated the effects of cyclic stretch and substrate stiffness on cell-substrate interactions. I used the modified Hill model and reaction-diffusion equations to model SF contractility in the presence of calcium. Furthermore, the Gillespie algorithm was used to simulate the stochastic adaptor protein engagements at FAs. The model shows that cell adhesions and tractions vary along their length under static and cyclic stretch conditions; the maxima occurred behind the cell edge. Cell tractions and adhesion increased initially with substrate stiffness and ligand density but decreased beyond an optimum substrate stiffness. Cyclic stretch enhanced tractions and integrin recruitment on compliant substrates; in contrast, it reduced them on stiff substrates. Talin orchestrates FA formation and aids in force transfer to cytoskeletal actin in the presence of vinculin. I simulated the force response of talin using a composite worm-like chain model. I show that the talin-vinculin assembly is mechanosensitive to substrate stiffness and extension rate. Talin extension on stiffer substrates resulted in higher tension and vinculin recruitment at a low extension rate. In contrast, a high extension rate lowered vinculin recruitment and abolished talin sensitivity to stiffness. These studies show the importance of adaptor protein mechanics in substrate sensing during cell adhesion.

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Pfeiler, Terry Wayne. "Computational and experimental analyses of bone and adult stem cell mechanobiology". 2009. http://www.lib.ncsu.edu/theses/available/etd-11032009-064954/unrestricted/etd.pdf.

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