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

• Published in: Developmental cell Vol. 24; no. 6; pp. 586 - 599
• Main Authors: Cappellari, Ornella, Benedetti, Sara, Innocenzi, Anna, Tedesco, Francesco Saverio, Moreno-Fortuny, Artal, Ugarte, Gonzalo, Lampugnani, Maria Grazia, Messina, Graziella, Cossu, Giulio
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 25.03.2013
• Subjects: Adaptor Proteins, Signal Transducing; Animals; Becaplermin; Calcium-Binding Proteins - pharmacology; Cells, Cultured; Coculture Techniques; Endothelial Cells; Gene Expression Regulation, Developmental; Human Umbilical Vein Endothelial Cells; Humans; Inhibitor of Differentiation Proteins - biosynthesis; Intercellular Signaling Peptides and Proteins - pharmacology; Intracellular Signaling Peptides and Proteins - genetics; Intracellular Signaling Peptides and Proteins - pharmacology; Membrane Proteins - genetics; Membrane Proteins - pharmacology; Mice; Mice, Transgenic; Muscle Development; Muscle, Skeletal - metabolism; Myoblasts - cytology; Myoblasts - metabolism; Myoblasts, Skeletal - metabolism; MyoD Protein - metabolism; Myogenic Regulatory Factor 5 - metabolism; Myogenic Regulatory Factors - genetics; Myogenic Regulatory Factors - metabolism; Paired Box Transcription Factors - biosynthesis; PAX3 Transcription Factor; Pericytes - cytology; Pericytes - metabolism; Proto-Oncogene Proteins c-sis - pharmacology; Serrate-Jagged Proteins; Signal Transduction; Transcriptional Activation
• ISSN: 1534-5807; 1878-1551
• DOI: 10.1016/j.devcel.2013.01.022

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. ► Skeletal myoblasts can be converted to a pericyte fate in vitro and in vivo ► In these cells, Dll4 and PDGF-BB silence muscle genes and activate pericyte genes ► Other Notch ligands silence myogenesis but do not activate pericyte genes ► Paradoxically, Myf5 is upregulated by Dll4/PDGF-BB but fails myogenesis activation Pericytes are cells tightly associated with blood vessels; in some contexts, they behave as stem cells, but their origins are mysterious. Cappellari et al. show that skeletal muscle myoblasts can change their fate and become pericytes in response to signals emanating from the vascular endothelium.