Endothelial cells can migrate as a sheet of cells during embryonic development, wound healing, and angiogenesis. Using pools of small interfering RNAs (siRNAs) targeting the mRNAs for 2400 human signaling genes, Vitorino and Meyer identified 100 different regulators that affected the migration of monolayer endothelial sheets into cell-free areas, which they subdivided into groups of functionally related factors, including one that controlled directed migration and another involved in cell-cell coordination. Using fibroblast growth factor receptor 1 (FGFR1) and vascular endothelial cadherin [also known as cadherin 5, type 2 (CDH5)] as representative members of the “directed migration” and “cell-cell coordination” groups, respectively, they examined the effects of these two proteins on directional movement into cell-free areas in response to FGF. Individual endothelial cells transfected with siRNA directed against FGFR1 (FGFR1– cells) exhibited nearly random movements when exposed to FGF. In endothelial sheets comprising cells with FGFR1 (FGFR1+ cells) and FGFR– cells, FGFR1+ cells were enriched at the edges and acted as “pioneers” that extended projections into cell-free spaces. FGFR1 signaling appeared to act non–cell autonomously, because FGFR1– cells located along the edges of the endothelial sheet moved directionally. In contrast, siRNA knockdown of CDH5, which mediates cell-cell contacts, decreased orientation of “follower cells” within the sheet without affecting the polarity of the pioneer cells at the border. A mixed population of CDH5+ and CDH5– cells displayed misoriented movement to nearly the degree as a pure population of CDH5– cells, suggesting that cell-cell contacts were necessary for coordinated, directed movement in follower cells. The authors proposed a model for endothelial sheet movement: Pioneer cells at the borders move in a growth factor–dependent manner, and follower cells within the sheet move in the same direction as the pioneer cells in a growth factor–independent manner, which requires cell-cell contacts.
- Follow the Leader
One set of signaling proteins directs migration at the edge of a sheet of endothelial cells, whereas a distinct set coordinates cell movements within the sheet.Permalink: