Hyaluronan Disrupts Cardiomyocyte Organization within 3D Fibrin-Based Hydrogels

The extracellular matrix in vivo contains variable but often large amounts of glycosaminoglycans that influence cell and tissue function. Hyaluronan (HA) is an abundant glycosaminoglycan within the extracellular matrix of the myocardium during early development and in the aftermath of a myocardial infarction. Its flexible anionic structure has a strong influence on mechanical response and interstitial fluid flow within the matrix. Additionally, HA has a direct, biochemical effect on cells through an array of cell-surface receptors, including CD44, RHAMM/CD168, and other surface-exposed structures. Recent studies have shown that HA modulates the response of cardiomyocytes and other cell types to two-dimensional substrates of varying elastic moduli. This study investigates the force response to HA of cardiomyocytes and cardiac fibroblasts within three-dimensional matrices of variable composition and mechanical properties in vitro. HA significantly decreased the force exerted by the cell-matrix constructs in a tensiometer testing platform and within microfabricated tissue gauges. However, its effect was no different from that of alginate, an anionic polysaccharide with the same charge density but no specific transmembrane receptors. Therefore, these results establish that HA exerts a generic physical-chemical effect within three-dimensional hydrogels that must be accounted for when interrogating cell-matrix interactions.