Transdifferentiation of Fast Skeletal Muscle Into Functional Endothelium in Vivo by Transcription Factor Etv2

Matthew B Veldman,Benjamin L Martin,Haigen Huang,Anne G Lindgren,Shuo Lin,Chengjian Zhao,David Kimelman,Hanshuo Yang,Shaohua Yao,Gustavo A Gomez,Derek L Stemple

doi:10.1371/journal.pbio.1001590

Matthew B Veldman, Benjamin L Martin + Show 9 more

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https://doi.org/10.1371/journal.pbio.1001590

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Abstract

Author SummaryThe endothelial cell is a specialized cell type that lines blood vessels. These cells are involved in normal cardiovascular function and become damaged in cardiovascular disease states such as atherosclerosis and stroke. We have discovered that developing muscle cells in the zebrafish embryo can be converted into endothelial cells by the expression of a transcription factor called Etv2. Etv2 normally functions during embryonic development to specify blood and blood vessels. When expressed in muscle cells, Etv2 induces the expression of genes that are normally expressed in endothelial cells; it also represses muscle gene expression. On expressing Etv2, muscle cells change shape and go on to form lumenized blood vessels that connect to the existing circulatory system and support blood flow. The Wnt and VEGF signaling pathways are required for this fate transformation. Our results suggest that muscle cells may be a viable source for the de novo generation of endothelial cells for use in transplantation therapies and they highlight signalling pathways that might be manipulated to improve the efficiency of this process in mammalian cells.

Highlights

IntroductionThe ETS family transcription factor Etv ( known as Etsrp or ER71) is an evolutionarily conserved early mediator of blood vessel and blood cell development
The ETS family transcription factor Etv2 is an evolutionarily conserved early mediator of blood vessel and blood cell development
Knocking down this gene using morpholino antisense oligonucleotides or a genetic mutation causes defects in vasculogenesis, angiogenesis, and arteriovenus specification accompanied by decreased expression of many vascular genes including transcription factors fli1a and tal1, and kdrl, a vascular endothelial growth factor (VEGF) receptor [1,2]

Summary

Introduction

The ETS family transcription factor Etv ( known as Etsrp or ER71) is an evolutionarily conserved early mediator of blood vessel and blood cell development. Etv is expressed in the lateral plate mesoderm at early somitogenesis stages and defines the first population of angioblasts to arise in the embryo [1] Knocking down this gene using morpholino antisense oligonucleotides or a genetic mutation causes defects in vasculogenesis, angiogenesis, and arteriovenus specification accompanied by decreased expression of many vascular genes including transcription factors fli1a and tal ( known as scl), and kdrl (formerly flk1), a vascular endothelial growth factor (VEGF) receptor [1,2]. Chimeric mouse analysis with Etv knockout cells demonstrated that these cells are not capable of contributing to the blood or endothelial cell lineages [8] These studies demonstrate that Etv is necessary for vascular development in multiple species

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