Dll4 and PDGF-BB Convert Committed Skeletal Myoblasts to Pericytes without Erasing Their Myogenic Memory

Pericytes are endothelial-associated cells that con- tribute to vessel wall. Here, we report that pericytes may derive from direct conversion of committed skeletal myoblasts. When exposed to Dll4 and PDGF-BB, but not Dll1, skeletal myoblasts down- regulate myogenic genes, except Myf5, and upregu- late pericyte markers, whereas inhibition of Notch signaling restores myogenesis. Moreover, when co- cultured with endothelial cells, skeletal myoblasts, previously treated with Dll4 and PDGF-BB, adopt a perithelial position stabilizing newly formed vessel- like networks in vitro and in vivo. In a transgenic mouse model in which cells expressing MyoD acti- vate Notch, skeletal myogenesis is abolished and pericyte genes are activated. Even if overexpressed, Myf5 does not trigger myogenesis because Notch induces Id3, partially sequestering Myf5 and inhibit- ing MEF2 expression. Myf5-expressing cells adopt a perithelial position, as occasionally also observed in wild-type (WT) embryos. These data indicate that endothelium, via Dll4 and PDGF-BB, induces a fate switch in adjacent skeletal myoblasts.