Effects of substrate stiffness, cadherin junction and shear flow on tensional homeostasis in cells and cell clusters
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Cytoskeletal tension plays an important role in numerous biological functions of adherent cells, including mechanosensing of the cell’s microenvironment, mechanotransduction, cell spreading and migration, cell shape stability, and in stem cell lineage. It is believed that for normal biological functions the cell must maintain its cytoskeletal tension stable, at a preferred set-point level, under external perturbations. This is known as tensional homeostasis. Any breakdown of tensional homeostasis is closely associated with disease progression, including cancer, atherosclerosis, and thrombosis. The exact mechanism and the relevant environmental conditions for the maintenance of tensional homeostasis are not yet fully understood. This thesis investigates the impacts of substrate stiffness, availability of functional cadherin junctions and steady shear stress on tensional homeostasis of cells and cell clusters. We define tensional homeostasis as the ability of cells to maintain a consistent level of tension with low temporal traction field fluctuations. Traction forces of isolated cells, multicellular clusters, and monolayer are measured using micropattern traction microscopy. Temporal fluctuations of the traction field are calculated from time-lapsed traction measurements. Results demonstrated that substrate stiffness, cadherin cell-cell junctions and shear stress all impact tensional homeostasis. In particular, we found that stiffer substrates promoted tensional homeostasis in endothelial cells, but were detrimental to tensional homeostasis in vascular smooth muscle cells. We also found that E-cadherins were essential for tensional homeostasis of gastric cancer cells and that extracellular and intracellular mutations of E-cadherin had domain-specific effects on tensional homeostasis. Finally, laminar flow-induced shear stress led to increased traction field fluctuations in endothelial cell monolayers, contrary to reports of physiological shear promoting vascular homeostasis. A possible reason for this discrepancy might be the limitation of our approach which could not account for mechanical balance of traction forces in the monolayers. Through the exploration of these environmental factors, we also found that tensional homeostasis was a length scale-dependent and cell type-dependent phenomenon. These insights suggest that future studies need to take a more comprehensive approach and aim to make observations of different cell types on multiple length scales, in order decipher the mechanism of tensional homeostasis and its role in (patho)physiology.
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