QBioS Thesis Dissertation Defense

Abstract: Cell adhesion and migration are essential to fundamental processes throughout the lifespan of multicellular organisms, including in embryonic development, tissue maintenance, and disease. Over the past several decades, researchers have established a deep molecular understanding of the mechanisms governing the attachment of cells to the extracellular matrix (ECM) through assemblies of adhesion proteins at the cell-ECM interface. However, sizable sugars and glycoproteins residing at the very same cell-ECM interface may also play an important yet unrecognized mechanical role in the regulation of cell adhesion and migration. Hyaluronan (HA), a giant sugar synthesized on the cell membrane by the HA synthase family is often confined at the cell-ECM interface as part of the membrane-bound HA-rich glycocalyx or embedded into macromolecular structures in the ECM. We hypothesized that confined HA at the cell-ECM interface is compressed, and the consequent repulsion may counteract adhesive forces to decrease the effective cell adhesion strength, and thereby modulate cell migration speed. We explored the potential biomechanical role of HA in vitro, ex vivo and in vivo, by manipulating cells to change the levels of interfacial HA and by quantifying the resulting cell morphology, adhesion, and migration responses. We then compared our results with polymer physics-based theoretical predictions and integrated them into experiment-driven models that predicted the repulsion force by compressed HA at the interface as well as HA-induced membrane configurations at the dorsal and ventral sides of the cell. Taken together, our results suggest another layer of regulation by HA exists in the molecular mechanisms governing cell adhesion and migration and they emphasize the hidden mechanical role sugars may play in other biological processes.