Transdifferentiation of fast skeletal muscle into functional endothelium in vivo by transcription factor etv2

Veldman, M.B., Zhao, C., Gomez, G.A., Lindgren, A.G., Huang, H., Yang, H., Yao, S., Martin, B.L., Kimelman, D., and Lin, S.
PLoS Biology   11(6): e1001590 (Journal)
Registered Authors
Gomez, Gustavo, Huang, Haigen, Kimelman, David, Lin, Shuo, Martin, Benjamin, Veldman, Matt
Embryos, Muscle fibers, Transdifferentiation, Wnt signaling cascade, Muscle cells, Gene expression, Endothelial cells, VEGF signaling
MeSH Terms
  • Animals
  • Cell Line
  • Cell Transdifferentiation*
  • Embryo, Nonmammalian/cytology
  • Embryo, Nonmammalian/metabolism
  • Endothelium, Vascular/cytology*
  • Endothelium, Vascular/metabolism
  • Gene Expression Regulation, Developmental
  • Mice
  • Muscle Fibers, Fast-Twitch/cytology
  • Muscle Fibers, Fast-Twitch/metabolism
  • Muscle, Skeletal/cytology*
  • Muscle, Skeletal/metabolism
  • Signal Transduction/genetics
  • Transcription Factors/genetics
  • Transcription Factors/metabolism*
  • Vascular Endothelial Growth Factor A/metabolism
  • Wnt Proteins/metabolism
  • Zebrafish/embryology
  • Zebrafish/genetics
  • Zebrafish/metabolism*
  • Zebrafish Proteins/genetics
  • Zebrafish Proteins/metabolism*
23853546 Full text @ PLoS Biol.

Etsrp/Etv2 (Etv2) is an evolutionarily conserved master regulator of vascular development in vertebrates. Etv2 deficiency prevents the proper specification of the endothelial cell lineage, while its overexpression causes expansion of the endothelial cell lineage in the early embryo or in embryonic stem cells. We hypothesized that Etv2 alone is capable of transdifferentiating later somatic cells into endothelial cells. Using heat shock inducible Etv2 transgenic zebrafish, we demonstrate that Etv2 expression alone is sufficient to transdifferentiate fast skeletal muscle cells into functional blood vessels. Following heat treatment, fast skeletal muscle cells turn on vascular genes and repress muscle genes. Time-lapse imaging clearly shows that muscle cells turn on vascular gene expression, undergo dramatic morphological changes, and integrate into the existing vascular network. Lineage tracing and immunostaining confirm that fast skeletal muscle cells are the source of these newly generated vessels. Microangiography and observed blood flow demonstrated that this new vasculature is capable of supporting circulation. Using pharmacological, transgenic, and morpholino approaches, we further establish that the canonical Wnt pathway is important for induction of the transdifferentiation process, whereas the VEGF pathway provides a maturation signal for the endothelial fate. Additionally, overexpression of Etv2 in mammalian myoblast cells, but not in other cell types examined, induced expression of vascular genes. We have demonstrated in zebrafish that expression of Etv2 alone is sufficient to transdifferentiate fast skeletal muscle into functional endothelial cells in vivo. Given the evolutionarily conserved function of this transcription factor and the responsiveness of mammalian myoblasts to Etv2, it is likely that mammalian muscle cells will respond similarly.

Genes / Markers
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Mutation and Transgenics
Human Disease / Model Data
Sequence Targeting Reagents
Engineered Foreign Genes
Errata and Notes