Matching Items (6)
Description
The goal of the works presented in this volume is to develop a magnetic resonance imaging (MRI) probe for non-invasive detection of extracellular matrix (ECM) underlying fenestrated endothelia. The ECM is the scaffold that supports tissue structure in all organs. In fenestrated structures the such as the kidney glomerulus and the hepatic sinusoid the ECM serves a unique role in blood filtration and is directly exposed to blood plasma. An assessment of the ECM in fenestrated organs such as the kidney and liver reports on the organ's ability to filter blood - a process critical to maintaining homeostasis. Unfortunately, clinical assessment of the ECM in most organs requires biopsy, which is focal and invasive. This work will focus on visualizing the ECM underlying fenestrated endothelia with natural nanoparticles and MRI. The superparamagnetic ferritin protein has been proposed as a useful naturally-derived, MRI-detectable nanoparticle due to its biocompatibility, ease of functionalization, and modifiable metallic core. We will show that cationized ferritin (CF) specifically binds to the anionic proteoglycans of the ECM underlying fenestrated endothelia and that its accumulation is MRI-detectable. We will then demonstrate the use of CF and MRI in identifying and measuring all glomeruli in the kidney. We will also explore the toxicity of intravenously injected CF and consider other avenues for its application, including detection of microstructural changes in the liver due to chronic liver disease. This work will show that CF is useful in detected fenestrated microstructures in small animals and humans alike, indicating that CF may find broad application in detecting and monitoring disease in both preclinical and clinical settings.
ContributorsBeeman, Scott (Author) / Bennett, Kevin M (Thesis advisor) / Kodibagkar, Vikram D (Committee member) / Fayad, Zahi A (Committee member) / Pizziconi, Vincent B (Committee member) / Pipe, James G (Committee member) / Arizona State University (Publisher)
Created2012
Description
Severe cases of congenital heart defect (CHD) require surgeries to fix the structural problem, in which artificial grafts are often used. Although outcome of surgeries has improved over the past decades, there remains to be patients who require re-operations due to graft-related complications and the growth of patients which results in a mismatch in size between the patient’s anatomy and the implanted graft. A graft in which cells of the patient could infiltrate, facilitating transformation of the graft to a native-like tissue, and allow the graft to grow with the patient heart would be ideal. Cardiac tissue engineering (CTE) technologies, including extracellular matrix (ECM)-based hydrogels has emerged as a promising approach for the repair of cardiac damage. However, most of the previous studies have mainly focused on treatments for ischemic heart disease and related heart failure in adults, therefore the potential of CTE for CHD treatment is underexplored. In this study, a hybrid hydrogel was developed by combining the ECM derived from cardiac tissue of pediatric CHD patients and gelatin methacrylate (GelMA). In addition, the influence of incorporating gold nanorods (GNRs) within the hybrid hydrogels was studied. The functionalities of the ECM-GelMA-GNR hydrogels as a CTE scaffold were assessed by culturing neonatal rat cardiomyocytes on the hydrogel. After 8 days of cell culture, highly organized sarcomeric alpha-actinin structures and connexin 43 expression were evident in ECM- and GNR-incorporated hydrogels compared to pristine GelMA hydrogel, indicating cell maturation and formation of cardiac tissue. The findings of this study indicate the promising potential of ECM-GelMA-GNR hybrid hydrogels as a CTE approach for CHD treatment.
As another approach to improve CHD treatment, this study sought the possibility of performing a proteomic analysis on cardiac ECM of pediatric CHD patient tissue. As the ECM play important roles in regulating cell signaling, there is an increasing interest in studying the ECM proteome and the influences caused by diseases. Proteomics on ECM is challenging due to the insoluble nature of ECM proteins which makes protein extraction and digestion difficult. In this study, as a first step to perform proteomics, optimization on sample preparation procedure was attempted.
As another approach to improve CHD treatment, this study sought the possibility of performing a proteomic analysis on cardiac ECM of pediatric CHD patient tissue. As the ECM play important roles in regulating cell signaling, there is an increasing interest in studying the ECM proteome and the influences caused by diseases. Proteomics on ECM is challenging due to the insoluble nature of ECM proteins which makes protein extraction and digestion difficult. In this study, as a first step to perform proteomics, optimization on sample preparation procedure was attempted.
ContributorsSugamura, Yuka (Author) / Nikkhah, Mehdi (Thesis advisor) / Smith, Barbara (Committee member) / Willis, Brigham (Committee member) / Arizona State University (Publisher)
Created2018
Description
Collective cell migration in the 3D fibrous extracellular matrix (ECM) is crucial to many physiological and pathological processes such as tissue regeneration, immune response and cancer progression. A migrating cell also generates active pulling forces, which are transmitted to the ECM fibers via focal adhesion complexes. Such active forces consistently remodel the local ECM (e.g., by re-orienting the collagen fibers, forming fiber bundles and increasing the local stiffness of ECM), leading to a dynamically evolving force network in the system that in turn regulates the collective migration of cells.
In this work, this novel mechanotaxis mechanism is investigated, i.e., the role of the ECM mediated active cellular force propagation in coordinating collective cell migration via computational modeling and simulations. The work mainly includes two components: (i) microstructure and micromechanics modeling of cellularized ECM (collagen) networks and (ii) modeling collective cell migration and self-organization in 3D ECM. For ECM modeling, a procedure for generating realizations of highly heterogeneous 3D collagen networks with prescribed microstructural statistics via stochastic optimization is devised. Analysis shows that oriented fibers can significantly enhance long-range force transmission in the network. For modeling collective migratory behaviors of the cells, a minimal active-particle-on-network (APN) model is developed, in which reveals a dynamic transition in the system as the particle number density ρ increases beyond a critical value ρc, from an absorbing state in which the particles segregate into small isolated stationary clusters, to a dynamic state in which the majority of the particles join in a single large cluster undergone constant dynamic reorganization. The results, which are consistent with independent experimental results, suggest a robust mechanism based on ECM-mediated mechanical coupling for collective cell behaviors in 3D ECM.
For the future plan, further substantiate the minimal cell migration model by incorporating more detailed cell-ECM interactions and relevant sub-cellular mechanisms is needed, as well as further investigation of the effects of fiber alignment, ECM mechanical properties and externally applied mechanical cues on collective migration dynamics.
In this work, this novel mechanotaxis mechanism is investigated, i.e., the role of the ECM mediated active cellular force propagation in coordinating collective cell migration via computational modeling and simulations. The work mainly includes two components: (i) microstructure and micromechanics modeling of cellularized ECM (collagen) networks and (ii) modeling collective cell migration and self-organization in 3D ECM. For ECM modeling, a procedure for generating realizations of highly heterogeneous 3D collagen networks with prescribed microstructural statistics via stochastic optimization is devised. Analysis shows that oriented fibers can significantly enhance long-range force transmission in the network. For modeling collective migratory behaviors of the cells, a minimal active-particle-on-network (APN) model is developed, in which reveals a dynamic transition in the system as the particle number density ρ increases beyond a critical value ρc, from an absorbing state in which the particles segregate into small isolated stationary clusters, to a dynamic state in which the majority of the particles join in a single large cluster undergone constant dynamic reorganization. The results, which are consistent with independent experimental results, suggest a robust mechanism based on ECM-mediated mechanical coupling for collective cell behaviors in 3D ECM.
For the future plan, further substantiate the minimal cell migration model by incorporating more detailed cell-ECM interactions and relevant sub-cellular mechanisms is needed, as well as further investigation of the effects of fiber alignment, ECM mechanical properties and externally applied mechanical cues on collective migration dynamics.
ContributorsNan, Hanqing (Author) / Jiao, Yang (Thesis advisor) / Alford, Terry (Committee member) / Zhuang, Houlong (Committee member) / Arizona State University (Publisher)
Created2019
Description
In 1974, Elizabeth Dexter Hay and Stephen Meier in the US conducted an experiment that demonstrated that the extracellular matrix, the mesh-like network of proteins and carbohydrates found outside of cells in the body, interacted with cells and affected their behaviors. In the experiment, Hay and Meier removed the outermost layer of cells that line the front of the eye, called corneal epithelium, from developing chick embryos. Prior to their experiment, scientists observed that corneal epithelium produced collagen, the primary component of the extracellular matrix, which provides structural support to cells throughout the body. In their experiment, Hay and Meier confirmed that the lens capsule, a collagen-containing structure of the eye’s extracellular matrix, induced the corneal epithelium to produce collagen. That result demonstrated that extracellular matrix interactions affect tissue
development in developing embryos.
ContributorsGleason, Kevin (Author) / Arizona State University. School of Life Sciences. Center for Biology and Society. Embryo Project Encyclopedia. (Publisher) / Arizona Board of Regents (Publisher)
Created2017-06-19
Description
Elizabeth Dexter Hay studied the cellular processes that affect development of embryos in the US during the mid-twentieth and early twenty-first centuries. In 1974, Hay showed that the extracellular matrix, a collection of structural molecules that surround cells, influences cell behavior. Cell growth, cell migration, and gene expression are influenced by the interaction between cells and their extracellular matrix. Hay also discovered a phenomenon later called epithelial-mesenchymal transition, a process that occurs during normal embryo and adult development in which epithelial cells, cells that line external and internal surfaces of the body, transform into mesenchymal stem cells, connective tissue cells that are capable of turning into other cell types. Hay's work helped researchers explain normal developmental processes and enabled research into abnormal processes that can cause developmental defects and diseases.
ContributorsGleason, Kevin (Author) / Arizona State University. School of Life Sciences. Center for Biology and Society. Embryo Project Encyclopedia. (Publisher) / Arizona Board of Regents (Publisher)
Created2017-07-26
Description
Mechanical properties (e.g. deformability or stiffness) are critical to a cancer cell's ability to maneuver through and exert forces upon the extracellular matrix, and thus affect its ability to metastasize. §3.1 introduces the experimental method combining atomic force microscope (AFM) based indentation and confocal laser scanning microscopy (CLSM). §3.2 presents a method combining AFM and confocal microscopy (AFM stiffness nanotomography), and results on normal and pre-cancerous esophageal cells which indicate that even in the earliest stages, cancer cells exhibit increased deformability. §3.3 presents experimental results on weakly metastatic breast cancer cells that compare well with values obtained from other experimental methods and demonstrates that the mechanical response of cells to sharp and mesoscale probes differ significantly. §3.4 presents experimental results indicating that metastatic breast cancer cells are more deformable than normal counterparts, and demonstrates that indentation measurements with sharp probes are capable of identifying mechanical differences between cytoplasmic, nuclear and nucleolar regions of the cell. §3.5 presents results on weakly metastatic breast cancer cells sensitive and resistant to tamoxifen (an estrogen antagonist), and demonstrate that estrogen has a significant effect on cell stiffness. §3.6 applies stiffness nanotomography to study metastatic breast cancer cells allowed to invade 3D collagen gels, demonstrating the ability to use AFM indentation on heterogeneous samples, and shows that cell stiffness increases during the invasion process for partially and fully embedded metastatic breast cancer cells.
ContributorsStaunton, Jack Rory (Author) / Ros, Robert (Thesis advisor) / Lindsay, Stuart M. (Committee member) / Davies, Paul C. W. (Committee member) / Vaiana, Sara M. (Committee member) / Arizona State University (Publisher)
Created2014