Mechano-induced patterned domain formation by monocytes

Matrix stiffness and the corresponding mechanosignalling play indispensable roles in cellular phenotypes and functions. How tissue stiffness influences the behaviour of monocytes, a major circulating leukocyte of the innate system, and how it may promote the emergence of collective cell behaviour is less understood. Here we show that human primary monocytes, uniquely among key immune cells, undergo a dynamic local phase separation to form highly regular, reversible, multicellular, multilayered domains on soft collagen-coated hydrogels of physiological stiffnesses. Local activation of the β2 integrin-ICAM-1 complex initiates intercellular adhesion, while global soluble inhibitory factors maintain the steady-state domain pattern over days. While inhibiting their phagocytic capability, domain formation promotes the survival of monocytes. A computational model incorporating the Cahn-Hilliard equation of phase separation with the Turing mechanism of local activation and global inhibition suggests that cell seeding density and chemotactic and random cell migration contribute to domain pattern formation, which is experimentally validated. This work reveals that cells can generate complex phases by exploiting their mechanosensing abilities and combined short-range interactions and long-range signals to enhance their survival.