Establishment & maintenance of collective cell migration in angiogenesis: Lessons from zebrafish.

During tissue development, growth and regeneration, assembly of almost all new blood and lymphatic vessels arises via their branching from pre-existing vessels, processes termed angiogenesis and lymphangiogenesis, respectively. Furthermore, imbalances in these branching processes contribute to numerous disease states, including cancer, blindness, arthritis and ischemic disorders. At its core, new vessel branching is driven by the coordinated collective migration of specialized endothelial "tip" cells that lead sprouting vessels and "stalk" cells that trail the tip. Thus, studies defining the fundamental mechanisms directing angiogenesis and lymphangiogenesis not only have key therapeutic implications but have also defined core conserved principles dictating collective cell migration. In this review we focus on recent insights into the roles of intracellular, intercellular and cell morphology-driven positive- and negative-feedback loops in the establishment and maintenance of tip versus stalk cell identities and behaviour. Moreover, we highlight recent insights into the role of asymmetric cell divisions in self-organisation of the tip-stalk cell hierarchy during vessel assembly. Considering that many of the principles underpinning collective movement are broadly conserved between tissue systems, concepts described here likely play key roles in the control of collective cell migration in diverse tissue contexts.