Browsing by Subject "Cell mechanics"
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Item Integrated Experimental and Theoretical Approaches toward Understanding Strain-Induced Cytoskeletal Remodeling and Mechanotransduction(2012-10-19) Hsu, Hui-JuActin stress fibers (SFs) are mechanosensitive structural elements that respond to applied strain to regulate cell morphology, signal transduction, and cell function. The purpose of this dissertation is to elucidate the effects of mechanical stretch on cell mechanobiology via the following three aims. First, a sarcomeric model of SFs was developed to describe the role of actomyosin crossbridge cycling in SF tension regulation and reorientation in response to various modes of stretch. Using model parameters extracted from literature, this model described the dependence of cyclic stretch-induced SF alignment on a two-dimensional (2-D) surface on positive perturbations in SF tension caused by the rate of lengthening, which was consistent with experimental findings. Second, the sarcomeric model was used to predict how stretch-induced pro-inflammatory mechanotransduction depends on the mode of strain application. Together with experimental data, the results indicated that stretch-induced stress fiber alignment, MAPK activations and downstream pro-inflammatory gene expressions are dependent on SF strain rate (and related changes in SF tension) rather than SF turnover. Third, to produce biocompatible materials that are both mechanically resilient under (physiological) load and also mechanosensitive, a novel hybrid engineered tissue was developed that transmits strain stimuli to cells residing in three-dimensional (3-D) collagen microspheres. However, the macroscopic stress is largely borne by a more resilient acellular polyethylene glycol diacrylate (PEGDA) hydrogel supporting the microspheres. Careful analysis indicated that cell alignment occurs prior to significant collagen fibril alignment.Item Integrated roles of mechanics, motility, and disease progression in cancer(2010-12) Baker, Erin Lynnette; Bonnecaze, R. T. (Roger T.); Zaman, Muhammad H. (Muhammad Hamid); Schmidt, Christine E.; Dunn, Andrew K.; Liechti, Kenneth M.The broad objective of this research is to examine the relationship between the cellular micromechanical environment and disease progression in cancer. The mechanical stiffness of cancerous tissue is a key feature that distinguishes it from normal tissue and thus facilitates its detection clinically. While numerous inroads have been achieved toward elucidating molecular mechanisms that underlie diseases such as cancer, quantitative characterization of associated cellular mechanical properties and biophysical attributes remains largely incomplete. To this end, the present research provides insight into the following questions: (1) What is the effect of extracellular matrix (ECM) stiffness and architecture on internal cancer cell rheology and cytoskeletal organization? (2) What are the integrated effects of ECM stiffness and cell metastatic potential on the intracellular rheology and morphology of breast cancer cells? (3) What are the integrated effects of ECM stiffness, ECM architecture, and cell metastatic potential on the motility of breast cancer cells? To examine these phenomena, the present research utilizes a multidisciplinary engineering approach that integrates experimental rheology, theoretical mechanics, confocal microscopy, computational algorithms, and experimental cell biology. Briefly, genetically altered cancer-mimicking cells are cultured within synthetic ECMs of varying mechanical stiffness and structure, where they are then observed using time-lapsed confocal microscopy. Image analyses and computational algorithms are then employed to extract measures of cell migration speed and intracellular stiffness via particle-tracking microrheology techniques. Major results show that ECM stiffness elicits an intracellular mechanical response only within the framework of physiologically relevant matrix environments and that a key cell-matrix attachment protein (the integrin) plays an essential role in this phenomenon. Additional results indicate that a well-known breast cancer-associated biomarker (ErbB2) is responsible for sensitizing mammary cells to ECM stiffness. Finally, results also show that a switch in ECM architecture significantly hinders the migratory capacity of ErbB2-associated cells, which may explain why the ErbB2 biomarker is detected with much higher frequency in early stage breast cancer than in later stage invasive and metastatic cancers. In total, these findings inform the fields of mechanobiology and cancer biology by systematically linking cell rheology, cell motility, matrix mechanics, and disease progression in cancer.