Collective cell behaviour during embryogenesis and tissue repair requires the coordination of intercellular junctions, cytoskeleton-dependent shape changes controlled by Rho GTPases, and integrin-dependent cell-matrix adhesion. Many different integrins are simultaneously expressed during wound healing, embryonic development, and sprouting angiogenesis, suggesting that there is extensive integrin/integrin cross-talk to regulate cell behaviour. Here, we show that fibronectin-binding β1 and β3 integrins do not act synergistically, but rather antagonize each other during collective cell processes in neuro-epithelial cells, placental trophoblasts, and endothelial cells. Reciprocal β1/β3 antagonism controls RhoA activity in a kindlin-2-dependent manner, balancing cell spreading, contractility, and intercellular adhesion. In this way, reciprocal β1/β3 antagonism controls cell cohesion and cellular plasticity to switch between extreme and opposing states, including epithelial versus mesenchymal-like phenotypes and collective versus individual cell migration. We propose that integrin/integrin antagonism is a universal mechanism to effectuate social cellular interactions, important for tissue morphogenesis, endothelial barrier function, trophoblast invasion, and sprouting angiogenesis.

胚胎发生和组织修复过程中的集体细胞行为需要细胞间连接、由 Rho GTPase 控制的细胞骨架依赖性形状变化和整合素依赖性细胞基质粘附的协调。许多不同的整合素在伤口愈合、胚胎发育和新生血管生成过程中同时表达，这表明存在广泛的整合素/整合素串扰来调节细胞行为。在这里，我们表明结合纤连蛋白的 β1 和 β3 整联蛋白不会协同作用，而是在神经上皮细胞、胎盘滋养细胞和内皮细胞的集体细胞过程中相互拮抗。相互的 β1/β3 拮抗作用以 kindlin-2 依赖性方式控制 RhoA 活性，平衡细胞扩散、收缩性和细胞间粘附。这样，相互的 β1/β3 拮抗作用控制细胞内聚力和细胞可塑性以在极端和相反状态之间切换，包括上皮与间充质样表型以及集体与个体细胞迁移。我们提出整合素/整合素拮抗作用是实现社会细胞相互作用的通用机制，对组织形态发生、内皮屏障功能、滋养层侵袭和发芽血管生成很重要。