Engineering lymphatic collecting vessel phenotypes through combined hyaluronic acid cues and oscillatory shear stress.

The engineering of a 3D lymphatic collecting vessel has been of recent interest due to the lack of treatments for lymphatic valve disruptions. While oscillatory shear stress has been shown to regulate lymphatic collecting vessel morphogenesis, its effect in the context of physiologically relevant extracellular matrix remains elusive. In this study, we used a microfluidic device to elucidate the effect of oscillatory shear stress on human lymphatic endothelial cells cultured on dopamine-modified hyaluronic acid or fibronectin. Here, we show that hyaluronic acid can synergistically enhance mechanoresponsive morphological changes, activate cytoskeleton localization, induce nuclear expression of key mechanosensitive markers (PROX1 and FOXC2), amplify mechanotransduction pathways (VE-CAD and mTORC1), and downregulate capillary lymphatic markers (PDPN and LYVE-1). These results highlight the potential of hyaluronic acid-based materials for the generation of 2D and 3D lymphatic collecting vessel models.