title: Dll4 and PDGF-BB convert committed skeletal myoblasts to pericytes without erasing their myogenic memory.
abstract: Pericytes are endothelial-associated cells that contribute 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 downregulate myogenic genes, except Myf5, and upregulate pericyte markers, whereas inhibition of Notch signaling restores myogenesis. Moreover, when cocultured 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 activate 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 inhibiting 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.
authors.affiliation: Department of Cell and Developmental Biology and Centre for Stem Cells and Regenerative Medicine, University College London, WC1E 6DE London, UK.
authors.forename: Ornella
authors.initials: O
authors.lastname: Cappellari
authors.forename: Sara
authors.initials: S
authors.lastname: Benedetti
authors.forename: Anna
authors.initials: A
authors.lastname: Innocenzi
authors.forename: Francesco Saverio
authors.initials: FS
authors.lastname: Tedesco
authors.forename: Artal
authors.initials: A
authors.lastname: Moreno-Fortuny
authors.forename: Gonzalo
authors.initials: G
authors.lastname: Ugarte
authors.forename: Maria Grazia
authors.initials: MG
authors.lastname: Lampugnani
authors.forename: Graziella
authors.initials: G
authors.lastname: Messina
authors.forename: Giulio
authors.initials: G
authors.lastname: Cossu
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D000077214:Becaplermin; D002135:Calcium-Binding Proteins / Q000494:pharmacology; D002478:Cells, Cultured; D018920:Coculture Techniques; D042783:Endothelial Cells; D018507:Gene Expression Regulation, Developmental; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D051796:Inhibitor of Differentiation Proteins / Q000096:biosynthesis; D036341:Intercellular Signaling Peptides and Proteins / Q000494:pharmacology; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000494:pharmacology*; D008565:Membrane Proteins / Q000235:genetics / Q000494:pharmacology*; D051379:Mice; D008822:Mice, Transgenic; D024510:Muscle Development; D018482:Muscle, Skeletal / Q000378:metabolism; D017570:MyoD Protein / Q000378:metabolism*; D032446:Myoblasts / Q000166:cytology* / Q000378:metabolism*; D032448:Myoblasts, Skeletal / Q000378:metabolism; D051787:Myogenic Regulatory Factor 5 / Q000378:metabolism*; D018006:Myogenic Regulatory Factors / Q000235:genetics / Q000378:metabolism; D000072041:PAX3 Transcription Factor; D051761:Paired Box Transcription Factors / Q000096:biosynthesis; D020286:Pericytes / Q000166:cytology* / Q000378:metabolism*; D020574:Proto-Oncogene Proteins c-sis / Q000494:pharmacology*; D000072099:Serrate-Jagged Proteins; D015398:Signal Transduction; D015533:Transcriptional Activation
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D002135:Calcium-Binding Proteins; C519665:DLL4 protein, mouse; C512925:Dlk1 protein, mouse; D051796:Inhibitor of Differentiation Proteins; D036341:Intercellular Signaling Peptides and Proteins; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; C497418:Myf5 protein, mouse; D017570:MyoD Protein; C057363:MyoD1 myogenic differentiation protein; D051787:Myogenic Regulatory Factor 5; D018006:Myogenic Regulatory Factors; D000072041:PAX3 Transcription Factor; D051761:Paired Box Transcription Factors; D020574:Proto-Oncogene Proteins c-sis; D000072099:Serrate-Jagged Proteins; C067679:Idb3 protein, mouse; C068686:Pax3 protein, mouse; D000077214:Becaplermin