Frank W. Charbonier

Collective migration of epithelial tissues is a critical feature of developmental morphogenesis and tissue homeostasis. Coherent motion of cell collectives requires large-scale coordination of motion and force generation and is influenced by mechanical properties of the underlying substrate. While tissue viscoelasticity is a ubiquitous feature of biological tissues, its role in mediating collective cell migration is unclear. Here, we have investigated the impact of substrate stress relaxation on the migration of micropatterned epithelial monolayers. Epithelial monolayers exhibit faster collective migration on viscoelastic alginate substrates with slower relaxation timescales, which are more elastic, relative to substrates with faster stress relaxation, which exhibit more viscous loss. Faster migration on slow-relaxing substrates is associated with reduced substrate deformation, greater monolayer fluidity, and enhanced leader cell formation. In contrast, monolayers on fast-relaxing substrates generate substantial substrate deformations and are more jammed within the bulk, with reduced formation of transient lamellipodial protrusions past the monolayer edge leading to slower overall expansion. This work reveals features of collective epithelial dynamics on soft, viscoelastic materials and adds to our understanding of cell–substrate interactions at the tissue scale.

Collective migration of epithelial tissues is a critical feature of developmental morphogenesis and tissue homeostasis. Coherent motion of cell collectives requires large scale coordination of motion and force generation and is influenced by mechanical properties of the underlying substrate. While tissue viscoelasticity is a ubiquitous feature of biological tissues, its role in mediating collective cell migration is unclear. Here, we have investigated the impact of substrate stress relaxation on the migration of micropatterned epithelial monolayers. Epithelial monolayers exhibit faster collective migration on viscoelastic alginate substrates with slower relaxation timescales, which are more elastic, relative to substrates with faster stress relaxation, which exhibit more viscous loss. Faster migration on slow-relaxing substrates is associated with reduced substrate deformation, greater monolayer fluidity, and enhanced leader cell formation. In contrast, monolayers on fast-relaxing substrates generate substantial substrate deformations and are more jammed within the bulk, with reduced formation of transient lamellipodial protrusions past the monolayer edge leading to slower overall expansion. This work reveals features of collective epithelial dynamics on soft, viscoelastic materials and adds to our understanding of cell-substrate interactions at the tissue scale. Significance Statement Groups of cells must coordinate their movements in order to sculpt organs during development and maintain tissues. The mechanical properties of the underlying substrate on which cells reside are known to influence key aspects of single and collective cell migration. Despite being a nearly universal feature of biological tissues, the role of viscoelasticity (i.e., fluid-like and solid-like behavior) in collective cell migration is unclear. Using tunable engineered biomaterials, we demonstrate that sheets of epithelial cells display enhanced migration on slower-relaxing (more elastic) substrates relative to faster-relaxing (more viscous) substrates. Building our understanding of tissue-substrate interactions and collective cell dynamics provides insights into approaches for tissue engineering and regenerative medicine, and therapeutic interventions to promote health and treat disease.

The endothelial cells (ECs) that line the inner layer of blood vessels are responsible for maintaining vascular homeostasis under physiological conditions. In the presence of disease or injury, ECs can become dysfunctional and contribute to a progressive decline in vascular health. ECs are constantly exposed to a variety of dynamic mechanical stimuli, including hemodynamic shear stress, pulsatile stretch, and passive signaling cues derived from the extracellular matrix. This review describes the molecular mechanisms by which ECs perceive and interpret these mechanical signals. The translational applications of mechanosensing are then discussed in the context of endothelial‐to‐mesenchymal transition and engineering of vascular grafts.