Asymmetric division coordinates collective cell migration in angiogenesis

Abstract

The asymmetric division of stem or progenitor cells generates daughters with distinct fates and regulates cell diversity during tissue morphogenesis1. However, roles for asymmetric division in other more dynamic morphogenetic processes, such as cell migration, have not previously been described. Here we combine zebrafish in vivo experimental and computational approaches to reveal that heterogeneity introduced by asymmetric division generates multicellular polarity that drives coordinated collective cell migration in angiogenesis. We find that asymmetric positioning of the mitotic spindle during endothelial tip cell divisions generates daughters of distinct size with differentially partitioned vascular endothelial growth factor receptor (vegfr) mRNA and discrete “tip” or “stalk” thresholds of pro-migratory Vegfr signalling. Consequently, post-mitotic Vegfr asymmetry drives intrinsic self-organisation of daughters into leading tip or trailing stalk cells, and disruption of asymmetry randomises daughter tip/stalk selection. Importantly, post-mitotic tip/stalk selection via Vegfr asymmetry is near instantaneous and promotes rapid re establishment of tip-stalk identity. Hence, asymmetric division functionally integrates cell proliferation with seamless reestablishment of the tip-stalk hierarchy to ensure uninterrupted directed collective migration during vessel growth. Considering that robust maintenance of leaderfollower hierarchies is a hallmark of all collectively migrating cell systems, asymmetric division may drive integrated growth of many tissues during development, regeneration and cancer invasion.