title: Transdifferentiation of fast skeletal muscle into functional endothelium in vivo by transcription factor Etv2.
abstract: 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.
authors.affiliation: State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, West China Medical School, Sichuan University, Chengdu, Sichuan, People's Republic of China.
authors.forename: Matthew B
authors.initials: MB
authors.lastname: Veldman
authors.forename: Chengjian
authors.initials: C
authors.lastname: Zhao
authors.forename: Gustavo A
authors.initials: GA
authors.lastname: Gomez
authors.forename: Anne G
authors.initials: AG
authors.lastname: Lindgren
authors.forename: Haigen
authors.initials: H
authors.lastname: Huang
authors.forename: Hanshuo
authors.initials: H
authors.lastname: Yang
authors.forename: Shaohua
authors.initials: S
authors.lastname: Yao
authors.forename: Benjamin L
authors.initials: BL
authors.lastname: Martin
authors.forename: David
authors.initials: D
authors.lastname: Kimelman
authors.forename: Shuo
authors.initials: S
authors.lastname: Lin
mesh_terms: D000818:Animals; D002460:Cell Line; D054338:Cell Transdifferentiation; D004625:Embryo, Nonmammalian / Q000166:cytology / Q000378:metabolism; D004730:Endothelium, Vascular / Q000166:cytology* / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental; D051379:Mice; D018656:Muscle Fibers, Fast-Twitch / Q000166:cytology / Q000378:metabolism; D018482:Muscle, Skeletal / Q000166:cytology* / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D051153:Wnt Proteins / Q000378:metabolism; D015027:Zebrafish / Q000196:embryology / Q000235:genetics / Q000378:metabolism*; D029961:Zebrafish Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: C509408:Etv2 protein, zebrafish; D014157:Transcription Factors; D042461:Vascular Endothelial Growth Factor A; D051153:Wnt Proteins; D029961:Zebrafish Proteins