Chapter 5 - Endothelial tip, stalk, and phalanx cells

Abstract

Initiation of sprouting requires the specification of endothelial cells into tip and stalk cells bearing different morphologies and functional properties. Endothelial tip cells primarily migrate but proliferate only minimally, in contrast to endothelial stalk cells, which do proliferate. In 2003, the concept of the “tip” and “stalk” cell phenotype was described for emerging sprouts (Gerhardt et al., 2003), even though filopodia-studded cells at the front were already described before this work by Kurz et al. (1996) and, later, by Ruhrberg et al. (2002). According to this “new” model, two principal cells are involved in sprouting angiogenesis, namely, “tip cell” and “stalk cell.” Tip cells express high levels of Dll-4 compared with those of stalk cells, which have higher levels of Notch signaling activity. Dll-4 is expressed in tip cells, which binds to Notch receptors on stalk cells, thus preventing their transformation into tip cells. Notch signaling induces the transition of tip cells to stalk cells, whereas inhibition of Notch signaling results in a dramatic increase in sprouting, branching, and extension of filopodia by tip cells.