Unleashing shear: Role of intercellular traction and cellular moments in collective cell migration

In the field of endothelial biology, the term “shear forces” is tied to the forces exerted by the flowing blood on the quiescent cells. But endothelial cells themselves also exert physical forces on their immediate and distant neighbors. Specific factors of such intrinsic mechanical signals most relevant to immediate neighbors include normal (F(n)) and shear (F(s)) components of intercellular tractions, and those factors most relevant to distant neighbors include contractile or dilatational (M(c)) and shear (M(s)) components of the moments of cytoskeletal forces. However, for cells within a monolayer, F(n), F(s), M(c), and M(s) remain inaccessible to experimental evaluation. Here, we present an approach that enables quantitative assessment of these properties. Remarkably, across a collectively migrating sheet of pulmonary microvascular endothelial cells, F(s) was of the same order of magnitude as F(n). Moreover, compared to the normal components (F(n), M(c)) of the mechanical signals, the shear components (F(s), M(s)) were more distinctive in the cells closer to the migration front. Individual cells had an innately collective tendency to migrate along the axis of maximum contractile moment – a collective migratory process we referred to as cellular plithotaxis. Notably, larger F(s) and M(s) were associated with stronger plithotaxis, but dilatational moment appeared to disengage plithotactic guidance. Overall, cellular plithotaxis was more strongly associated with the “shear forces” (F(s), M(s)) than with the “normal forces” (F(n), M(c)). Finally, the mechanical state of the cells with fast migration speed and those with highly circular shape were reminiscent of fluid-like and solid-like matter, respectively. The results repeatedly pointed to neighbors imposing shear forces on a cell as a highly significant event, and hence, the term “shear forces” must include not just the forces from flowing fluid but also the forces from the substrate and neighbors. Collectively, these advances set the stage for deeper understanding of mechanical signaling in cellular monolayers.