Dll4 and PDGF-BB convert committed skeletal myoblasts to pericytes without erasing their myogenic memory

Dev Cell. 2013 Mar 25;24(6):586-99. doi: 10.1016/j.devcel.2013.01.022. Epub 2013 Mar 7.

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.

MeSH terms

  • 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
  • MyoD Protein / metabolism*
  • Myoblasts / cytology*
  • Myoblasts / metabolism*
  • Myoblasts, Skeletal / metabolism
  • Myogenic Regulatory Factor 5 / metabolism*
  • Myogenic Regulatory Factors / genetics
  • Myogenic Regulatory Factors / metabolism
  • PAX3 Transcription Factor
  • Paired Box Transcription Factors / biosynthesis
  • Pericytes / cytology*
  • Pericytes / metabolism*
  • Proto-Oncogene Proteins c-sis / pharmacology*
  • Serrate-Jagged Proteins
  • Signal Transduction
  • Transcriptional Activation

Substances

  • Calcium-Binding Proteins
  • DLL4 protein, mouse
  • Dlk1 protein, mouse
  • Inhibitor of Differentiation Proteins
  • Intercellular Signaling Peptides and Proteins
  • Intracellular Signaling Peptides and Proteins
  • Membrane Proteins
  • Myf5 protein, mouse
  • MyoD Protein
  • MyoD1 myogenic differentiation protein
  • Myogenic Regulatory Factor 5
  • Myogenic Regulatory Factors
  • PAX3 Transcription Factor
  • Paired Box Transcription Factors
  • Proto-Oncogene Proteins c-sis
  • Serrate-Jagged Proteins
  • Idb3 protein, mouse
  • Pax3 protein, mouse
  • Becaplermin